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In advanced squamous cell carcinoma of the head and neck, concomitant radiotherapy with cisplatin and/or cetuximab is frequently combined with cisplatin-based induction chemotherapy, which can cause severe hypomagnesemia, hypocalcemia, and hypokalemia. The aim of our study was to analyze the effects of magnesium sulfate supplementation on the incidence of hypomagnesemia, hypokalemia, and hypocalcemia during four cycles of TPF (docetaxel, cisplatin, and 5-fluorouracil) induction chemotherapy followed by concomitant radiotherapy (CRT) with cisplatin and cetuximab. Twenty-five patients included in a phase II prospective study received routine magnesium sulfate infusions before each cycle of cisplatin, and additional supplementation based on laboratory findings. During TPF, the incidence of grade 1/2 and grade 3/4 hypomagnesemia was 16% and 4%, respectively; and increased despite magnesium supplementation during CRT to 72% and 8%, respectively. During TPF, a grade 2 and grade 4 hypocalcemia occurred in 8% and 4%, respectively; and during CRT, it reached 36% (grade 1/2). Grade 1 hypokalemia only was observed during TPF (4%) and CRT (8%). The median amounts of supplemented magnesium sulfate during TPF and CRT were 20 mEq and 50 mEq, respectively. It appears that a low incidence of grade 3/4 hypomagnesemia and hypocalcemia in our patients resulted from intensive magnesium supplementation. Thorough measurements of magnesium and calcium during cisplatin-based chemoradiation protocols in patients with head and neck cancer are crucial in preventing the development of grade 3/4 hypomagnesemia and hypocalcemia.

Despite professional recommendations malnutrition is not adequately addressed in cancer patients. Here, we explored whether nutritional status (NS) is associated with HRQoL in men with metastatic castrate-resistant prostate cancer (mCRPC). Methods: Men with mCRPC enrolled into this prospective observational study were allocated to one of the four NS categories based on clinical, laboratory, and patient self-reported criteria: well-nourished (WN), nutritional risk without criteria for cachexia/sarcopenia (NR), sarcopenia, and cachexia. The HRQoL was evaluated by the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire. Association between NS and self-reported HRQoL was sought by the linear regression model, which was adjusted for known prognostic variables and body mass index. Results: Over the period of two years, 141 patients were enrolled. Their median age was 74.1 years (IQR 68.6–79.4 years) and majority of them were minimally symptomatic. Fifty-nine patients (41.8%) were WN, followed by 24 (17%), 42 (29.8%), and 16 (11.4%) patients with NR, sarcopenia, and cachexia, respectively. As compared to WN patients, all three other NS categories were significant negative predictors of HRQoL (P

Background The aim of our study was to describe the survival of Slovenian cancer patients diagnosed in the last twenty years. An insight is given into the improvement made in different cancer types, population groups and prognostic factors. Materials and methods The principal data source was the population-based Slovenian Cancer Registry. The survival analysis included patients diagnosed with cancer in twenty years period from 1997 to 2016, which has been divided into four consecutive five-year periods. In addition, the analysis was stratified by cancer type, gender, age and stage. The survival was estimated using net survival calculated by the Pohar-Perme method and the complete approach has been applied. Results The survival of Slovenian cancer patients has been increasing over time. During the 20 years observed, five-year net survival increased by 11 percentage points. Significantly higher growth was observed in men. Age and stage at diagnosis are still crucial for the survival of cancer patients. Five-year net survival is lowest in those over 75 years of age at diagnosis but has also improved by seven percentage points over the past 20 years. The five-year net survival of patients in the localized stage increased by ten percentage points over the 20 years under observation. Survival of patients in the distant stage has not been improving. In both sexes, survival for melanoma, colorectal and lung cancers have increased significantly over the last 20 years. Progress has also been made in the two most common gender specific cancers: breast cancer in women and prostate cancer in men. Still, the significant progress in prostate cancer is probably mostly due to lead-time bias as during the study period, Slovenia used indiscriminate PSA testing, which probably artificially prolonged survival. Conclusions The survival of Slovenian cancer patients has been increasing over time, which gives us a basis and an incentive for future improvements. To monitor the effectiveness of managing the cancer epidemic, the cancer burden needs to be monitored also in the future, using quality data and scientifically justified methodological approaches. In this process a well organised population-based cancer registries should play a key role.

Background and purposeThe Meta-Analysis of Chemotherapy in squamous cell Head and Neck Cancer (MACH-NC) demonstrated that concomitant chemotherapy (CT) improved overall survival (OS) in patients without distant metastasis. We report the updated results.Materials and methodsPublished or unpublished randomized trials including patients with non-metastatic carcinoma randomized between 1965 and 2016 and comparing curative loco-regional treatment (LRT) to LRT+CT or adding another timing of CT to LRT+CT (main question), or comparing induction CT+radiotherapy to radiotherapy+concomitant (or alternating) CT (secondary question) were eligible. Individual patient data were collected and combined using a fixed-effect model. OS was the main endpoint.ResultsFor the main question, 101 trials (18951 patients, median follow-up of 6.5years) were analyzed. For both questions, there were 16 new (2767 patients) and 11 updated trials. Around 90% of the patients had stage III or IV disease. Interaction between treatment effect on OS and the timing of CT was significant (p&nbsp

Patients with recurrent or metastatic squamous cell head and neck cancer (R/M SCHNC) exhibit a poor prognosis with a median overall survival (OS) time of 2 infusion reaction to cetuximab and 27.3% had grade 3 skin rash. There were no differences in diarrhoea, hypomagnesaemia, infections and febrile neutropenia; however, the mortality on active treatment was high (13.4%). In conclusion, patients treated with PFE had similar PFS, but improved OS compared with patients treated with the PF protocol. The proportion of patients who died under treatment due to disease progression and toxicity was high in both treatment arms. A thorough selection of patients for this treatment is crucial.

Background: Cardiotoxicity is an important side effect of trastuzumab therapy and cardiac surveillance is recommended. Objectives: The aim of our study was to prospectively assess baseline patients' characteristics, level of N-terminal pro-brain natriuretic peptide (NT-proBNP) and echocardiographic parameters as possible predictors of trastuzumab-related cardiac dysfunction. Methods: In a prospective cohort study, clinical, echocardiographic and neurohumoral assessment was performed at baseline, after 4, 8 and 12 months in breast cancer patients undergoing post-anthracycline (3-4 cycles) adjuvant therapy with trastuzumab. Trastuzumab-related cardiac dysfunction was defined as a decline of ≥ 10% in left ventricular ejection fraction (LVEF). Results: 92 patients (mean age, 53.6 ± 9.0 years) were included. Patients who developed trastuzumab-related LVEF decline ≥ 10% (20.6%) during treatment had significantly higher baseline LVEF (70.7 ± 4.4%) than those without (64.8 ± 5.5%) (p = 0.0035). All other measured baseline parameters (age, body mass index, arterial hypertension, level of NT-proBNP and other echocardiographic parameters) were not identified as significant. Conclusions: Our findings suggest that baseline patient' characteristics, level of NT-proBNP and echocardiographic parameters, as long as they are within normal range, are not a reliable tool to predict early trastuzumab-related cardiac dysfunction in patients undergoing post-low dose anthracycline adjuvant trastuzumab therapy. A LVEF decline in patients with high-normal baseline level although statistically significant is not clinically relevant. Resumo Fundamento: Cardiotoxicidade é um importante efeito colateral da terapia com trastuzumabe, recomendando-se vigilância cardíaca. Objetivos: Avaliar prospectivamente as características basais de pacientes, nível de fração N-terminal do pró-peptídeo natriurético cerebral (NT-proBNP) e parâmetros ecocardiográficos como possíveis preditores de disfunção cardíaca relacionada ao trastuzumabe. Métodos: Em um estudo clínico prospectivo de coorte, realizou-se avaliação ecocardiográfica e neuro-humoral basal, aos 4, 8 e 12 meses em pacientes com câncer de mama submetidas a terapia adjuvante com trastuzumabe após antraciclina (3-4 ciclos). Definiu-se disfunção cardíaca relacionada ao trastuzumabe como uma redução na fração de ejeção ventricular esquerda (FEVE) ≥ 10%. Resultados: Este estudo incluiu 92 pacientes (idade média, 53,6 ± 9,0 anos). Pacientes que desenvolveram redução na FEVE ≥ 10% (20,6%) relacionada ao trastuzumabe durante tratamento tinham FEVE basal significativamente maior (70,7 ± 4,4%) do que aqueles sem (64,8 ± 5,5%) (p = 0,0035). Todos os demais parâmetros basais medidos (idade, índice de massa corporal, hipertensão arterial, nível de NT-proBNP e outros parâmetros ecocardiográficos) não foram identificados como significativos. Conclusões: Nossos achados sugerem que as características basais das pacientes, nível de NT-proBNP e parâmetros ecocardiográficos, contanto que dentro da variação normal, não são ferramentas confiáveis para predição precoce de disfunção cardíaca relacionada ao trastuzumabe em pacientes submetidas a terapia adjuvante com trastuzumabe após baixa dose de antraciclina. Uma redução na FEVE em pacientes com FEVE basal alta-normal, ainda que estatisticamente significativa, não é clinicamente relevante.

BACKGROUND/AIM It can be hypothesized that in patients with locally advanced head and neck cancer and prominent cetuximab (CMb)-induced skin rash, immunoradiotherapy would result in a survival advantage over chemoradiotherapy with cisplatin (CP). PATIENTS AND METHODS After a loading dose of CMb, one weekly cycle of CMb and CP concurrently with RT, patients who developed a grade ≥2 rash proceeded with immunoradiotherapy, and those with a grade 0-1 rash had chemoradiotherapy. RESULTS A grade 3-4 allergic reaction to CMb developed in 11/39 (28.2%) patients and further recruitment was stopped. These patients proceeded treatment with CP. In early assessment of skin rash 10/28 patients qualified for chemoradiotherapy and 18/28 patients for immunoradiotherapy. There was no difference in survival between the two groups. CONCLUSION Rate of serious CMb-induced hypersensitivity reactions was unacceptably high. Even though immunoradiotherapy was administered only to the prognostically most favorable group of patients, it resulted in no advantage over chemoradiotherapy.

580 Background: Papillary renal cell carcinoma type 1(PRCC1) is associated with MET alterations. Our phase II trial assessed the efficacy and safety of crizotinib in patients (pts) with advanced/metastatic PRCC1 with/without MET mutations( MET+, MET-). Methods: Eligible pts with reference pathology-confirmed PRCC1 received oral crizotinib 250mg twice-daily. Pts were attributed to MET+/ MET- sub-cohorts by sequencing of MET exons 16-19 in tumour tissue. Primary endpoint was objective response rate (ORR). If at least 2 of the first 12 eligible/evaluable MET+ pts achieved a confirmed partial (PR) or complete response (RECIST 1.1), a maximum of 35 pts were enrolled. Other endpoints included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS) and rate (PFSR), overall survival (OS) and safety. Results: 23 of 41 pts consenting were eligible, treated and evaluable. In 4 MET+ pts, 2 achieved a PR and 1 had stable disease (SD) (ORR 50%; 95% CI: 6.8-93.7%), DOR was 666 and 1138 days, 1-year PFSR was 75.0% (12.8-96.1%), 1-year OS: 75.0% (12.8-96.1%). Among 16 MET- pts, 1 achieved a PR lasting 302+ days and 11 had SD (ORR: 6.3%; 0.2-30.2%), 1-year PFSR: 27.3% (8.5-50.4%), 1-year OS: 71.8% (41.1-88.4%). Among 3 pts with unknown MET status ( MET?) due to technical failure, 1 achieved a PR lasting 211+ days and 1 had SD (ORR 33.3%, 0.8%-90.6%), 1-year PFSR: 66.7% (5.4-94.5%), 1-year OS: 100%. MET amplification was found post hoc in 1 MET+ (PR, DOR: 1138 days) and 1 MET- case (SD). Common treatment-related AEs were oedema (47.8%), fatigue (47.8%), nausea (39.1%), diarrhoea (39.1%), and blurred vision (34.8%). Conclusions: Crizotinib is active and well tolerated in advanced, metastatic PRCC1, achieving objective responses and long-lasting disease control in pts with MET mutations or amplification. Sporadic, durable responses are also seen in MET-/ MET? cases, suggesting the presence of other alterations of MET or alternative pathways. Clinical trial information: NCT01524926.

Background: Alveolar soft part sarcoma (ASPS) is an orphan malignancy associated with a rearrangement of transcription factor E3 (TFE3), leading to abnormal MET gene expression. We prospectively assessed the efficacy and safety of the MET tyrosine kinase inhibitor crizotinib in patients with advanced or metastatic ASPS. / Patients and methods: Eligible patients with reference pathology-confirmed ASPS received oral crizotinib 250 mg bd. By assessing the presence or absence of a TFE3 rearrangement, patients were attributed to MET+ and MET− sub-cohorts. The primary end point was the objective response rate (ORR) according to local investigator. Secondary end points included duration of response, disease control rate (DCR), progression-free survival (PFS), progression-free rate, overall survival (OS) and safety. / Results: Among 53 consenting patients, all had a centrally confirmed ASPS and 48 were treated. A total of 45 were eligible, treated and assessable. Among 40 MET+ patients, 1 achieved a confirmed partial response (PR) that lasted 215 days and 35 had stable disease (SD) as best response (ORR: 2.5%, 95% CI 0.6% to 80.6%). Further efficacy end points in MET+ cases were DCR: 90.0% (95% CI 76.3% to 97.2%), 1-year PFS rate: 37.5% (95% CI 22.9% to 52.1%) and 1-year OS rate: 97.4% (95% CI 82.8% to 99.6%). Among 4 MET− patients, 1 achieved a PR that lasted 801 days and 3 had SD (ORR: 25.0%, 95% CI 0.6% to 80.6%) for a DCR of 100% (95% CI 39.8% to 100.0%). The 1-year PFS rate in MET− cases was 50% (95% CI 5.8% to 84.5%) and the 1-year OS rate was 75% (95% CI 12.8% to 96.1%). One patient with unknown MET status due to technical failure achieved SD but stopped treatment due to progression after 17 cycles. The most common crizotinib-related adverse events were nausea [34/48 (70.8%)], vomiting [22/48 (45.8%)], blurred vision [22/48 (45.8%)], diarrhoea (20/48 (41.7%)] and fatigue [19/48 (39.6%)]. / Conclusion: According to European Organization for Research and Treatment of Cancer (EORTC) efficacy criteria for soft tissue sarcoma, our study demonstrated that crizotinib has activity in TFE3 rearranged ASPS MET+ patients. / Clinical trial number: EORTC 90101, NCT01524926

INTRODUCTION: Retroperitoneal sarcoma (RPS) is a rare disease accounting for 0.1%–0.2% of all malignancies. Management of RPS is complex and requires multidisciplinary, tailored treatment strategies at all stages, but especially in the context of metastatic or multifocal recurrent disease. Due to the rarity and heterogeneity of this family of diseases, the literature to guide management is limited. METHODS: The Trans-Atlantic Retroperitoneal Sarcoma Working Group (TARPSWG) is an international collaboration of sarcoma experts from all disciplines convened in an effort to overcome these limitations. The TARPSWG has compiled the available evidence surrounding metastatic and multifocally recurrent RPS along with expert opinion in an iterative process to generate a consensus document regarding the complex management of this disease. The objective of this document is to guide sarcoma specialists from all disciplines in the diagnosis and treatment of multifocal recurrent or metastatic RPS. RESULTS: All aspects of patient assessment, diagnostic processes, local and systemic treatments, and palliation are reviewed in this document, and consensus recommendations provided accordingly. Recommendations were guided by available evidence, in conjunction with expert opinion where evidence was lacking. CONCLUSIONS: This consensus document combines the available literature regarding the management of multifocally recurrent or metastastic RPS with the practical expertise of high-volume sarcoma centers from multiple countries. It is designed as a tool for decision making in the complex multidisciplinary management of this condition and is expected to standardize management across centers, thereby ensuring that patients receive the highest quality care.

Background. The aim of the study was to investigate how the expression of tumor markers p21, p27, p53, cyclin D1, EGFR, Ki-67, and CD31 influenced the outcome of advanced inoperable oropharyngeal carcinoma patients, treated with concomitant radiochemotherapy. Patients and methods. The pretreatment biopsy specimens of 74 consecutive patients with inoperable stage IV oropharyngeal squamous cell carcinoma treated with concomitant radiochemotherapy were in retrospective study processed by immunochemistry for p21, p27, p53, cyclin D1, EGFR, Ki-67, and CD31. Disease-free survival (DFS) was assessed according to the expression of tumor markers. Results. Patients with a high expression of p21 (≥10%), p27 (>50%), Ki-67 (>50%), CD31 (>130 vessels/mm2) and low expression of p53 ( Conclusions. Statistical significance in survival between FL and UL emerged only for p27 and cyclin D1. The number of markers per tumor with UL of expression was an independent prognostic factor for an adverse outcome.

Background Osteosarcoma patients are commonly treated with cisplatin-based preoperative and postoperative chemotherapy. Cisplatin binds to DNA and forms both intrastrand and interstrand crosslinks, inhibiting DNA replication. Glutathione-S-transferases (GSTs) participate in cisplatin detoxification, while several independent DNA repair mechanisms repair cisplatin-induced lesions. The aim of our study was to investigate the influence of genetic variability of DNA repair mechanisms and GSTs on efficacy and toxicity of cisplatin-based chemotherapy in osteosarcoma patients. Methods A total of 66 osteosarcoma patients were genotyped for ERCC1 , ERCC2 , NBN , RAD51 , XRCC3 , and GSTP1 polymorphisms, as well as GSTM1 and GSTT1 gene deletion. We determined the influence of polymorphisms on survival and treatment outcome using Cox regression and logistic regression. Results Carriers of at least one polymorphic ERCC2 rs1799793 allele had longer event-free survival (EFS) ( P =0.006; hazard ratio (HR)=0.28; 95% confidence interval (CI)=0.11–0.70). Polymorphic GSTP1 rs1138272 allele was associated with both shorter EFS and OS ( P =0.005; HR=3.67; 95%CI=1.47–9.16; and P =0.004; HR=3.52; 95%CI=1.51–8.22, respectively). Compared to the reference NBN CAA haplotype, NBN CGA haplotype was associated with shorter EFS ( P =0.001; HR=4.12; 95%CI=1.77–9.56). Conclusions Our results suggest that DNA repair polymorphisms and GST polymorphisms could be used as predictive factors for cisplatin-based chemotherapy in osteosarcoma patients and could contribute to treatment personalization.

Purpose Papillary renal-cell carcinoma type 1 (PRCC1) is associated with MET gene alterations. Our phase II trial prospectively assessed the efficacy and safety of crizotinib in patients with advanced/metastatic PRCC1 with or without MET mutations (MET+ and MET−). Experimental design Eligible patients with reference pathology-confirmed PRCC1 received 250 mg oral crizotinib twice daily. Patients were attributed to MET+/MET− sub-cohorts by the sequencing of exons 16–19 of the MET gene in tumour tissue. The primary end-point was objective response rate (ORR). If at least two of the first 12 eligible and evaluable MET+ patients achieved a confirmed partial response (PR) or complete response (CR) (in accordance with the Response Evaluation Criteria in Solid Tumours, version 1.1), a maximum of 35 patients were enrolled. Secondary end-points included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), PFS rate (PFSR), overall survival (OS) and safety. Results Forty-one patients provided consent, of whom 23 were eligible, treated and evaluable. In four MET+ patients, two achieved PR and one had stable disease (SD) (ORR 50%; 95% confidence interval [CI]: 6.8–93.2), DOR was 21.8 and 37.3 months, 1-year PFSR: 75.0% (95% CI: 12.8–96.1) and 1-year OS: 75.0% (95% CI: 12.8–96.1). Among 16 MET− patients, one achieved a PR lasting more than 9.9 months and 11 had SD (ORR: 6.3%; 95% CI: 0.2–30.2), 1-year PFSR: 27.3% (95% CI: 8.5–50.4) and 1-year OS: 71.8% (95% CI: 41.1–88.4). Among three patients with unknown MET status (MET?) due to technical failure, one achieved PR lasting more than 6.9 months, and one had SD (ORR 33.3%, 95% CI: 0.8–90.6), 1-year PFSR: 66.7% (95% CI: 5.4–94.5) and 1-year OS: 100%. MET amplification was found post hoc in one MET+ patient (PR, DOR: 37.3 months), and one MET− case who had SD. Common treatment-related adverse events were oedema (47.8%), fatigue (47.8%), nausea (39.1%), diarrhoea (39.1%) and blurred vision (34.8%). Conclusion Crizotinib is active and well tolerated in advanced, metastatic PRCC1, achieving objective responses and long-lasting disease control in patients with MET mutations or amplification. Sporadic, durable responses are also seen in MET− and MET? cases, suggesting the presence of other alterations of MET or alternative pathways.

Background The purpose of this study was to assess the efficacy and toxicity of docetaxel, cisplatin/5-fluorouracil (TPF) induction chemotherapy and concomitant immunochemoradiotherapy with cetuximab and cisplatin in unresectable head and neck carcinoma. Methods Treatment consisted of TPF induction chemotherapy (docetaxel 75 mg/m2 day 2; cisplatin, 75 mg/m2 day 2; and 5-fluorouracil 750 mg/m2 days 1–4; 4 cycles), followed by radiotherapy (RT) and concomitant weekly cetuximab, (250 mg/m2, after a loading dose of 400 mg/m2) and cisplatin (30 mg/m2). Results Twenty-five of 30 patients completed 4 cycles of induction chemotherapy. Six or more concomitant infusions of cisplatin and cetuximab were administered in 13 of 25 and 18 of 25 patients, respectively. The 2-year locoregional control, disease-free survival (DFS), and overall survival (OS) were 47%, 47%, and 50%, respectively. Patients with grade ≥2 skin reaction to cetuximab had a superior outcome. Conclusion The tested regimen was effective; however, cetuximab and low-dose cisplatin after induction TPF increased the treatment toxicity. A grade ≥2 skin rash correlated with improved efficacy. © 2013 Wiley Periodicals, Inc. Head Neck 36: 1555–1561, 2014

Background Guidance on cardiac surveillance during adjuvant trastuzumab therapy remains elusive. The recommended methods are two-dimensional echocardiography (2D-ECHO) and electrocardiography gated equilibrium radionuclide ventriculography (RNV). We assessed the correlation and possible specific merits of these two methods. Methods In a prospective cohort study in patients undergoing post-anthracycline adjuvant trastuzumab therapy, clinical assessment, 2D-ECHO and RNV were performed at baseline, 4, 8 and 12 months. The correlation between used methods was estimated with Pearson's correlation coefficient and Bland-Altman analysis. Results Ninety-two patients (mean age 53.6±9.0 years) were included. The correlation of LVEF measured by ECHO and RNV at each time point was statistically insignificant. Values obtained by ECHO were on average higher (3.7% to 4.5%). A decline in LVEF of ≥10% from baseline was noticed in 19 (24.4%) and 13 (14.9%) patients with ECHO and RNV, respectively, however in only one patient by both methods simultaneously. A decline in LVEF of ≥10% to below 50% was found in three and none patients according to RNV and ECHO measurements, respectively. Conclusions There is a weak correlation of ECHO and RNV measurements in individual patient, the results obtained by the methods are not interchangeable. LVEF values determined by 2D-ECHO were on average higher compared to RNV determined ones. When in an asymptomatic patient a decline in LVEF requiring treatment interruption is detected by RNV ECHO re-evaluation and referral to a cardiologist is advised.

11540Background: ASPS is an orphan disease associated with rearrangement of transcription factor E3 (TFE3), leading to abnormal MET expression. We assessed crizotinib in pts with ASPS (NCT01524926)...

Study Design. A case report is of a giant dumbbell-shaped synovial sarcoma of the thoracolumbar spine is presented. Objective. To report a case of a rare dumbbell-shaped tumor treated by multimodal approach. Surgical procedures, adjuvant treatment, and outcome were discussed. Summary of Background Data. Synovial sarcomas of the spine are very rare tumors. Radical surgical resection is the goal, but is often not feasible. Dumbbell-shaped spinal synovial sarcoma with a giant extraspinal extension has not yet been reported. The rationale for 2-step surgical procedure and adjuvant therapy is discussed in light of the clinical picture, preoperative imaging and extension of the disease. Methods. A 32-year-old male patient presented with signs of quickly progressive paraparesis. A dumbbell-shaped tumor at the level Th12–L1 was found with a giant retroperitoneal extension. Tumor was nonradically excised in a 2-step operation: first through a dorsal approach with laminectomy and removal of the intraspinal extradural part, and later through a laparotomy with removal of the retroperitoneal part. Histologic examination revealed highly malignant synovial sarcoma. Patient was treated with chemotherapy and radiotherapy after surgery. Results. Patient was in remission and symptom free for 1 year after surgery; he then developed a local recurrence and died soon afterwards. Conclusion. A good treatment result was achieved initially. A combined approach in cases like this is warranted, with as radical surgery as possible in order to avoid local recurrence, a common cause of treatment failure in sarcomas.

Purpose To evaluate the toxicity and efficacy of concomitant chemoradiotherapy with mitomycin C and cisplatin in the treatment of advanced unresectable squamous cell carcinoma of the head and neck. Patients and Methods Treatment consisted of conventional radiotherapy (70 Gy in 35 fractions), mitomycin C 15 mg/m 2 IV, applied after the delivery of 10 Gy, and cisplatin at an initial dose of 10 mg/m 2 /d IV, applied during the last 10 fractions of irradiation ("chemoboost"). The cisplatin dose was escalated with respect to the toxic side effects by 2 mg/m 2 /d up to the maximum tolerated dose (MTD) or at the most 14 mg/m 2 /d (Phase I study), which was tested in the subsequent Phase II study. Results All 36 patients had Stage T4 and/or N3 disease, and the majority had oropharyngeal (50%) or hypopharyngeal (39%) primary tumors. Six patients were treated at each of the three cisplatin dose levels tested (Phase I study). Dose-limiting toxicity was not reached even at 14 mg/m 2 /d of cisplatin, which was determined as the MTD and tested in an additional 18 patients (Phase II study). After a median follow-up time of 48 months, 4-year locoregional control, failure-free, and overall survival rates were 30%, 14%, and 20%, respectively. In 24 patients treated at the cisplatin dose level of 14 mg/m 2 /d, the corresponding rates were 40%, 20%, and 22%, respectively. Conclusion Concomitant chemoradiotherapy with mitomycin C and cisplatin "chemoboost" at 14 mg/m 2 /d is feasible, with encouraging survival results if the extremely poor disease profile of the treated patients is considered.

Objectives Osteosarcoma is the most common primary bone malignancy that occurs mostly in adolescents. Treatment protocols usually include multiagent preoperative and postoperative chemotherapy based on methotrexate, cisplatin, doxorubicin and ifosfamide. Despite a favourable prognosis, there are considerable interindividual differences in treatment outcome. Genetic variability of enzymes involved in the metabolism and transport of methotrexate could contribute towards observed differences in response to chemotherapy. Our aim was to evaluate how polymorphisms in the folate pathway and transporter genes influence treatment outcome in osteosarcoma patients. Patients and methods In total, 44 osteosarcoma patients treated with methotrexate were genotyped for eleven polymorphisms in four folate pathway and five folate transporter genes. Cox regression was used in survival analysis. Logistic regression was used to assess the influence of polymorphisms on treatment efficacy and toxicity and nonparametric tests were used to determine the influence on serum methotrexate levels. Results Polymorphic SLCO1B1 rs4149056 and rs11045879 alleles were associated with significantly higher serum methotrexate area under the curve (P=0.001 and 0.011, respectively). Carriers of at least one polymorphic SLCO1B1 rs4149056 and rs11045879 allele tended to have longer event-free survival compared with patients with two wild-type alleles [P=0.040, hazard ratio (HR)=0.26, 95% confidence interval (CI)=0.07-0.94; and P=0.034, HR=0.20, 95% CI=0.05-0.89, respectively]. Compared with the most common haplotype, carriers of both polymorphic alleles had significantly longer event-free survival (P=0.009, HR=0.27, 95% CI=0.10-0.72). Conclusion We have shown that SLCO1B1 polymorphisms influence methotrexate disposition and survival in methotrexate-treated osteosarcoma patients and therefore might serve as pharmacogenetic markers of treatment outcome.

As compared to tamoxifen aromatase inhibitors (AIs) may increase the risk of heart disease. Here we explored the association between the use of AIs and coronary artery disease (CAD) in a population-based observational study. In a small and heterogeneous population of 74 women with early breast cancer who received adjuvant hormonal therapy and subsequently underwent cardiac angiography, AIs significantly increased the hazard for CAD (HR 3.23, 95% confidence intervals [CI] 1.26–8.25, p = .01) compared to tamoxifen. Our results suggest that therapy with AIs may increase the risk for CAD.

Background. Human epidermal growth factor receptor 2 (HER2) positive breast cancer is an entity with aggressive behaviour. One year of adjuvant trastuzumab significantly improves the disease free survival in the range of 40-50% and reduces the risk of dying from HER2 positive breast cancer by one third. Adjuvant treatment with trastuzumab became available in Slovenia in 2005 and the aim of this study is to explore, if the exceptional results reported in adjuvant clinical trials are achieved also in daily clinical practice. Patients and methods. An analysis of tumour and patient characteristics, type of treatment and outcome (relapse free and overall survival) of 313 patients (median age 52 years) treated at the Institute of Oncology Ljubljana in years 2005-2009 was performed. Results. Median follow-up was 4.4 years. Sixty-one patients relapsed and 24 died. Three and four years relapse free survival was 84.2% and 80.8% and the overall survival was 94.4% and 92.5%, respectively. Independent prognostic factors for relapse were tumour grade (HR 2.10; 95% CI 1.07-4.14; p = 0.031) and nodal stage (HR 1.35; 1.16-1.56; p < 0.0001) and for the overall survival nodal stage only (HR 1.36; 1.05-1.78; p = 0.021). Conclusions. The outcome in patients with adjuvant trastuzumab in daily clinical practice, treated by medical oncologists, is comparable to results obtained in international adjuvant studies.

Purpose: To compare the efficacy of concomitant irradiation with mitomycin C and bleomycin in patients with inoperable head and neck carcinoma with radiotherapy alone. Methods and materials: Between March 1991 and December 1993, 64 patients with inoperable head and neck carcinoma (41 with oropharyngeal site) were randomized to radiotherapy alone (group A) or radiotherapy combined with simultaneous application of mitomycin C and bleomycin (group B). In both groups patients were irradiated five times weekly with 2 Gy to a total dose of 66–70 Gy. The planned concomitant treatment in group B was: bleomycin 5 units twice a week IM, total dose 70 units, mitomycin C 15 mg/m 2 IV after delivery of 10 Gy, and 10 mg/m 2 IV on the last day of radiotherapy. To enhance the effect of these two drugs, patients received also nicotinamide, chlorpromazine, and dicoumarol. Because significantly better results were achieved in arm B for patients with inoperable oropharyngeal carcinoma, the study was closed and such patients were after December 1993 routinely treated with the combined therapy (as in arm B). Until October 1996, we treated and followed up 48 such consecutive patients. Results: Median follow-up of our study patients is 42 months. Complete remission (CR) rate in group A was 31% and in group B 59% (p = 0.04); disease-free survival (DFS) in group A was 8% and in group B 37% (P = 0.01); and overall survival (OS) was 7% in group A and 26% in group B (p = 0.08). CR rate for patients with oropharyngeal carcinoma was 29% in group A (N = 21) and 75% in group B (N = 20) (p = 0.007); DFS in group A was 10% and in group B 48% (p = 0.001); and the OS was 10% in group A and 38% in group B (p = 0.019). In patients with inoperable oropharyngeal carcinoma treated after December 1993, complete remission was achieved in 32/48 (67%, 95% CI: 52%–80%). DFS at the median follow-up of 14 months was 60% (95% CI 43–77%) and OS 58% (95% CI 42–74%). Conclusion: From the results of our study it seems that the concomitant treatment significantly improves CR rate, DFS, and OS in patients with inoperable oropharyngeal carcinoma in comparison with radiotherapy alone.

Muscle-invasive bladder cancer (MIBC) is a disease associated with several unresolved therapeutic questions. Radical cystectomy still represents the most frequent treatment approach. The aim of our study was to evaluate the effect and feasibility of bladder-sparing treatment by transurethral resection (TUR) and sequential chemoradiotherapy in patients with biopsy-proven invasive bladder cancer.After maximal TUR, 105 patients were treated with two to four cycles of methotrexate, cisplatinum, and vinblastine polychemotherapy. In complete responders, the treatment was continued by radiotherapy (50 Gy to the bladder and 40 Gy to the regional lymph nodes), whereas in nonresponders, cystectomy was performed when feasible.Complete response after TUR and chemotherapy was achieved in 52% of patients. After a median follow-up of 42 months, 52 of 75 patients (69%) selected for bladder preservation were without evidence of disease in the bladder. Freedom from local failure in complete responders to chemotherapy was 80% [95% confidence interval (CI), 69-91%) at 4 years. The actuarial survival of the entire group was 58% (95% CI, 47-69%), whereas the survival rate with the bladder intact was 45% (95% CI, 34-56%) at 4 years. Survival was significantly better in patients who responded to chemotherapy (79%) than in nonresponders (35%, p0.0001). There was no significant difference in survival between nonresponders who underwent cystectomy and nonresponders who completed treatment with radiotherapy (approximately 30% at 3 years).The present study confirms that MIBC is a heterogeneous disease, and that in more than half of patients who are affected, a bladder-sparing approach is safe. Our study has also demonstrated that in nonresponders, radical cystectomy as the treatment of choice is questionable.

Purpose: Retrospective analysis was performed to assess the influence fo primary surgical or irradiation treatment on local control, survival, and final preservation of larynx in comparable groups of patients with T1N0 and T2N0 glottic cancer. Methods and Materials: Two hundred sixty-three previously untreated patients with invasive squamous cell carcinoma of the glottis (187T1 and 76T2) were treated with primary radiotherapy (159T1 and 60T2) or primary surgery (28T1 and 16T2) between January 1976 and December 1990, at the University of Ljubljana, Slovenia. Conventional one daily fraction of 2 Gy to doses of 60–74 Gy (median: 65 Gy) were used in 98% of primarily irradiated patients through out the observed period. To enable better comparison between the two treatment groups, primarily irradiated patients were retrospectively stratified by the criteria of suitability for primary voice-sparing operation. Several host, tumor, and treatment parameters were analyzed. Results: Only the stage of the disease significantly influenced both 10-year recurrence-free and disease-specific survival regardless primary treatment modality (p = 0.0002). In all primary irradiated patients local control was significantly better for those with overall treatment time of less than 48 days (p = 0.007). In patients suitable for voice-sparing operation, local control of primarily operated patients was similar to that of patients primarily irradiated with shorter overall treatment time, which was 93 and 88% for T1 and 67 and 64% for T2 tumors, respectively. Ultimate local control in primary surgery and radiotherapy group was 96 and 96% for T1 and 89 and 88% for T2 tumors, respectively. Equal larynx preservation of 100% in T1 and 90% in T2 patients was achieved in finally cured primarily operated patients and those patients primarily irradiated with a shorter overall treatment time. If treatment time was longer than 48 days, significantly worse final larynx preservation of 84% in T1 and 75% in T2 patients was observed (p = 0.003). In patients unsuitable for voice sparing operation, 87% of T1 and 50% of T2 patients in primary radiotherapy group finally had their larynx preserved. Conclusions: Stratification based on criteria of possibility for initial voice-sparing operation is important when comparing primary surgery with primary radiotherapy treatment in ealry glottic cancer. The detrimental effect of prolonged treatment time of irradiation resulted not only in inferior local control rate but also in worse final larynx preservation.

Background: EORTC 90101 prospectively assesses the activity and safety of the ALK/ROS/MET inhibitor Crizotinib in 6 independent tumor types including advanced PRCC1, an orphan, treatment-refractory malignancy. PRCC1 is associated with mutations of the MET gene encoding the MET tyrosine kinase receptor, which leads to activation of the pathway and induces tumor cell proliferation, survival, migration, invasion, and angiogenesis. Methods: Pts with local diagnosis of advanced/metastatic PRCC1 consented for shipment of tumor tissue and trial participation and were screened for active treatment after central confirmation of the diagnosis by a reference pathologist. Eligible pts received oral Crizotinib at a starting dose of 250 mg twice daily in 3-weekly cycles. Direct bi-directional Sanger sequencing of MET exons 16-19 of archival tumor tissue was used to assign pts to MET+ and MET-PRCC1 sub-cohorts. A Simon's optimal two stage design was implemented independently in each disease-specific sub-cohort. If at least 2 out of the first 12 eligible and evaluable PRCC1 MET+ pts achieved a confirmed partial (PR) or complete response (RECIST 1.1), a maximum of 35 pts were to be enrolled and treated to assess the activity of Crizotinib. Results: Between 12/2012 - 01/2016, 13 high-volume sites in 8 European countries recruited 41 pts with local diagnosis of PRCC1, of whom only 23 had a centrally confirmed diagnosis of PRCC1 and were treated. This abstract summarizes preliminary efficacy results; more mature data will be presented at the meeting. Among 4 pts with MET+ disease, 2 achieved a confirmed PR and one had stable disease (SD); all 3 had long lasting disease control (? 14 treatment cycles). Among 13 pts with MET- disease, none achieved a response and treatment duration was short except for one who achieved long term SD and was found to have MET amplification. Among 6 pts with “unknown” mutational status (technical failure, insufficient material), 2 achieved long term SD (? 20 cycles), suggesting the presence of other MET activating alterations. The safety analysis is pending. Conclusions: EORTC is able to perform molecularly driven screening phase II trials in rare cancers with mandatory collection of tissue blocks, real time reference pathology and genetic profiling. PRCC1 is very rare and frequently misdiagnosed. With 2 out of 4 MET+ PRCC1 patients achieving a PR, Crizotinib did meet the stage 1 success criteria of the study design. The low incidence of reference-pathology proven MET+ PRCC1, with an accrual rate of only 0.1 MET+ PRCC1 per month in our multinational network, will preclude completion of stage 2. Innovative trial methodology and new regulatory mechanisms are required to provide pts with orphan diseases with active drugs such as Crizotinib. Clinical trial information: NCT01524926. Citation Format: Patrick Schoffski, Agnieszka Wozniak, Bernard Escudier, Piotr Rutkowski, Alan Anthoney, Sebastian Bauer, Jozef Sufliarsky, Carla van Herpen, Lars Lindner, Viktor Grünwald, Branko Zakotnik, Evelyne Lerut, Sandrine Marréaud, Michela Lia, Tiana Raveloarivahy, Sandra Collette, Laurence Albiges. Crizotinib achieves objective responses and long-lasting disease control in patients (pts) with metastatic papillary renal cell carcinoma type 1 (PRCC1) with somatic MET mutations. EORTC phase II trial 90101 “CREATE”. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT006.

Although there have been no significant social, religious, or political changes in Slovenia in the last 15 years, a tremendous leap forward has occurred in the field of communication with cancer patients. Among the main reasons for this are probably the Internet, which is globalizing the world in all possible fields and ways; democracy, which came to our country with the fall of the Berlin wall and Yugoslavia; and an increased cancer burden, which has had a huge political impact, since cancer patients with their families represent an important voting bloc, thus affecting political programs, which have to incorporate cancer in their agendas. This has actually happened, since Slovenia, as a new member of the EU, has put cancer as the first health priority during her 6-month presidency of the EU. This had quite a huge impact on cancer care and communication in Slovenia, and I am sure also in other European countries, at least in the new member states. Improved communication in the field of cancer in Slovenia is definitely not a result of a systematic approach in communication skills teaching, which has not yet been introduced, although it is known to have a significant impact on patient–doctor communication. If to tell or not to tell is no longer a question when communicating cancer diagnosis and treatment, this question has moved to the palliative care setting, where communication is of the utmost importance.

Introduction Defining the Elderly Biology of Aging and Changes in Organ Function Changes in Cognition Cancer and Aging Clinical Aspects Further Reading Cancer Epidemiology Introduction Population Demographics Cancer Demographics Society-Related Problems Conclusions Further Reading Evaluation of the Senior Cancer Patient: Comprehensive Geriatric Assessment and Screening Tools for the Elderly Introduction Short Screening Tools The Vulnerable Elders Survey 13 MGA Packages Further Reading Frailty in the Elderly Frailty in the Elderly The Impact of Frailty on Cancer Assessment of Frailty Conclusion Further Reading Surgical Treatment Introduction Indications for Surgery Patients Selection Outcomes Survival Palliation Side Effects Conclusion Further Reading Radiotherapy in the Elderly Cancer Patient Indications for Radiotherapy in the Elderly Side Effects of Radiotherapy in the Elderly (Acute and Late) Efficacy and Outcome of Radiotherapy in the Aging Palliative Setting: Toxicity and Efficacy Ratio Curative Setting: Combinations of Chemotherapy and Radiotherapy Selection Criteria for Radiotherapy in the Elderly Conclusions Further Reading Hormonal Anticancer Treatment in the Senior Cancer Patient Introduction Breast Cancer Prostate Cancer Further Reading Cytotoxic and Targeted Anticancer Treatment in the Senior Cancer Patient Introduction Chemotherapy in Senior Adults Targeted Therapies in Senior Adults Further Reading Treatment of Lymphoma in the Elderly Population Introduction Diagnosis and Prognosis Treatment Conclusions Further Reading Management of Myeloproliferative Diseases in Senior Patients Diagnosis and Classification of Myeloproliferative Disorders Treatment Strategies of MPD in the Senior Patient Conclusions Future Outlook Further Reading Myelodysplastic Syndromes in the Senior Patient The Relevance of Myelodysplastic Syndromes in the Elderly Classification and Risk Scoring in MDS Age-Adjusted Models and Assessment in Elderly MDS Patients Treatment Options in Elderly MDS Patients Future Perspectives Further Reading Breast Cancer in the Senior Patient Introduction Early Breast Cancer Metastatic Breast Cancer Conclusions Further Reading Lung Cancer in the Elderly Introduction Early Non-Small Cell Lung Cancer in the Elderly Advanced Non-Small Cell Lung Cancer in the Elderly Small Cell Lung Cancer in the Elderly Palliative Treatment in Elderly Lung Cancer Patients Conclusion Further Reading Colorectal Cancer Introduction Adjuvant Chemotherapy Metastatic Disease Conclusion Further Reading Prostate Cancer Introduction and General Background Treatment of Localized Prostate Cancer in Senior Adult Patients Treatment of Metastatic Prostate Cancer in Senior Adult Patients Conclusion Acknowledgments Further Reading Bladder Cancer Incidence and Mortality Etiology and Risk Factors Pathology Natural History and Tumor Biology Signs and Symptoms Imaging, Cystoscopy, and Urinary Cytopathology Staging Treatment of NMIBC Surgical Treatment Radiotherapy Organ-Sparing Treatments Systemic Chemotherapy Prognosis of BC Follow-Up Further Reading Gynecological Cancer in the Senior Patient Introduction Cervical Cancer Uterine Cancer Special Types of Endometrial Malignancy Vaginal Cancer Vulvar Cancer Ovarian Cancer, Fallopian Tube Cancer, and Primary Peritoneal Cancer Conclusion Further Reading Head and Neck Cancer in the Elderly Introduction Surgery Radiotherapy Chemotherapy Targeted Therapies Conclusion Further Reading Renal Cell Cancer Introduction Surgery in the Senior Cancer Patient Systemic Therapy of Metastatic Renal Cell Carcinoma in the Senior Cancer Patient Patient-Focused Approach Conclusion Further Reading Psychological Problems in Older Cancer Patients Introduction Depression Anxiety Conclusions Further Reading Social and Ethical Aspects Introduction Respect Admiration Attention Information Protection Diagnosis Care Time Caution Freedom Further Reading The Role of the Multidisciplinary Team Introduction The Assessment of Age Polypharmacy Management of the Caregiver Function of the Team Conclusions and Perspectives Further Reading

Systemic chemotherapy plays the major role in the management of patients with small cell lung cancer. Cisplatin plus etoposide is the most widely used regimen and is considered as standard in patients with limited disease. Cisplatin plus irinotecan improved survival compared to cisplatin plus etoposide in a Japanese trial but failed to do so in two trials in Caucasians. Cisplatin plus topotecan had similar efficacy compared to cisplatin plus etoposide in patients with extensive disease. In the second-line setting, topotecan showed similar efficacy but better tolerability compared to cyclophosphamide, doxorubin plus vincristine. Oral topotecan was as efficacious as its intravenous formulation and was shown to improve survival compared to best supportive care alone in patients previously treated with chemotherapy. Thus topotecan is considered as the standard second-line chemotherapy in patients with small cell lung cancer.

Background. Gemcitabine is a potent cytotoxic agent used in the treatment of many solid tumours, sarcomas and lymphomas. Vascular toxicity and thrombotic events related to gemcitabine seem to be underreported. Case report. We report two cases of gemcitabine related digital ischemic events. Case 1. A 65-year-old man was given the first-line treatment with gemcitabine for the advanced adenocarcinoma of pancreas. After four weekly doses of gemcitabine (total dose 4000 mg/m2) he presented with Raynaud's like phenomenon and ischemic fingertips necrosis in five digits of both hands. Symptoms resolved in all but one digit after stopping chemotherapy and treatment with iloprost trometamol infusion. Case 2. A 77-year-old man, ex-smoker, was administered a combination of gemcitabine and cisplatin as the first-line treatment for the locally advanced bladder cancer. After 4 cycles of the treatment (total dose of gemcitabine 4000 mg/m2) the patient suffered digital ischemia and necrosis on two digits of a right leg. Arteriography revealed preexisting peripheral arterial occlusive disease (PAOD) of both legs with very good peripheral collateral circulation and absent microcirculation of affected two digits. The gemcitabine treatment was stopped and the patient was treated with iloprost trometamol infusion and percutaneous transluminal angioplasty with dilatation of the right superficial femoral artery. Digital changes resolved without consequences. Severe thrombocytosis (platelet count 1211 × 109/L) might have also contributed to the ischemic digital event in the second case. Conclusions. Digital ischemic events associated with gemcitabine chemotherapy seem to be more common in patients with tobacco-associated cancers, especially when used in combination with platinum salt. The treatment with gemcitabine in patients with evolving Raynaud's phenomenon and/or preexisting PAOD should be done with caution.

Testicular cancer affects men mostly in their reproductive age with a cure rate over 90% and fertility is one of the main concerns of survivors. To further elucidate the question of fertility after treatment for testicular cancer, we performed a survey in patients treated in our institution.We sent a questionnaire to patients treated for testicular cancer at our institute from 1976 to 2002 (n = 490) of whom 297 (60.6%) responded. We considered the patients to have conserved fertility if they had children after treatment without assisted reproductive technologies.Before treatment 119/297 (40.1%) of patients and after treatment 150/297 (50.5%) of patients tried to have children (p = 0.019). Of 119 patients who tried to have children before treatment for testicular cancer 98 (82.4%) succeeded and 74/150 (49.3%) were successful after treatment (p0.001). After treatment patients had 1-3 (median 1) children. The median time to birth of first child from diagnosis was 12 years. The post-treatment fatherhood in patients treated with surgery only (orchidectomy +/- retroperitoneal lymphnode dissection-RPLND) was 59%, in those with additional radiotherapy 68%, and chemotherapy 50% (p = 0.233). Fertility rate in patients where a non nerve sparing RPLND was performed was only 37%, 62% in patients with nerve sapring RPLND, and 77% in patients where RPLND was not performed (p0.0001).Fertility rate after treatment for testicular cancer is reduced. From our data, the most important treatment modality that influences fertility is non nerve sparing RPLND that should be avoided whenever possible in order improve the quality of life our patients.

Purpose: The long term results and patterns of failure in patients with squamous cell head and neck carcinoma (SCHNC) treated in a prospective randomized trial in which concomitant postoperative radiochemotherapy with Mitomycin C and Bleomycin (CRT) was compared with radiotherapy only (RT), were analyzed. Patients and Methods: Between March 1997 and December 2001, 114 eligible patients with Stage III or IV SCHNC were randomized. Primary surgical treatment was performed with curative intent in all patients. Patients in both groups were postoperatively irradiated to the total dose of 56–70 Gy. Chemotherapy included Mitomycin C 15 mg/m 2 after 10 Gy and 5 mg of Bleomycin twice weekly during irradiation. Median follow-up was 76 months (48–103 months). Results: At 5 years in the RT and CRT arms, the locoregional control was 65% and 88% ( p = 0.026), disease-free survival 33% and 53% ( p = 0.035), and overall survival 37% and 55% ( p = 0.091) respectively. Patients who benefited from chemotherapy were those with high-risk factors. The probability of distant metastases was 22% in RT and 20% in CRT arm ( p = 0.913), of grade III or higher late toxicity 19% in RT and 26% in CRT arm ( p = 0.52) and of thyroid dysfunction 36% in RT and 56% in CRT arm ( p = 0.24). The probability to develop a second primary malignancy (SPM) was 34% in the RT and 8% in the CRT arm ( p = 0.023). One third of deaths were due to infection, but there was no difference between the 2 groups. Conclusion: With concomitant radiochemotherapy, locoregional control and disease free survival were significantly improved. Second primary malignancies in the CRT arm compared to RT arm were significantly less frequent. The high probability of post treatment hypothyroidism in both arms warrants regular laboratory evaluation.

To determine the effectiveness of combination chemotherapy with cisplatin, methotrexate and vinblastine (CMV), we treated 21 chemotherapy naive patients with metastatic transitional cell carcinoma of the bladder. Chemotherapy consisted of methotrexate (30 mD/m2 i.v. days 1 and 8), vinblastine (3 mg/m2i.v. days 1 and 8) and cisplatin (100 mg/m2 i.v. day 2) every three weeks. Dominant metastatic sites were: soft tissues (7 patients), bone (6 patients), lung and liver (8 patients). A complete remission was achieved in 5/21 patients (24%, 95% CI 8-47%) and partial remission in 9/21 patients (43%, 95% CI 22-66%). The median duration was 6 months (2-11) and 9 months (2-26) for complete and partial remissions, respectively. The median survival for all 21 patients was 10 months. Although overall toxicity was mild, we observed myelosuppression grade IV in 2 patients, stomatitis grade III in 2 patients, cystitis grade III in 1 patient and infection grade III in 6 patients. There were no treatment-related deaths. Our data indicate that treatment with the CMV regimen is effective and that side effects are tolerable.

Purpose In a prospective randomized clinical study, simultaneous postoperative application of irradiation (RT), mitomycin C, and bleomycin was tested in a group of patients with operable advanced head-and-neck carcinoma. It was expected that the planned combined postoperative therapy would reduce the number of locoregional recurrences and prolong survival. Methods and materials A total of 114 eligible patients with Stage III or IV squamous cell head-and-neck carcinoma were randomized to receive postoperative RT alone (Group 1) or RT combined with simultaneous mitomycin C and bleomycin (Group 2). Patients were stratified according to the stage and site of the primary tumor and the presence or absence of high-risk prognostic factors. Primary surgical treatment was performed with curative intent in all patients. Patients in both groups were postoperatively irradiated to the total dose of 56–70 Gy. Chemotherapy included mitomycin C 15 mg/m 2 after 10 Gy and 5 mg of bleomycin twice a week during RT to the planned total dose of 70 mg. Results At 2 years, patients in the radiochemotherapy group had better locoregional control (86%) than those in the RT alone group (69%; p = 0.037). Disease-free survival and overall survival was also better in the radiochemotherapy group compared with the RT-alone group (76% vs. 60%, p = 0.099; and 74% vs. 64%, p = 0.036, respectively). Patients who benefited from chemotherapy were those with high-risk factors. Conclusion The results of the present study indicate that concomitant postoperative radiochemotherapy with mitomycin C and bleomycin improves locoregional control and survival in patients with advanced head-and-neck carcinoma. The patients who benefited from chemotherapy were those with high-risk factors.

Introduction About 15% of breast cancer (BC) patients are HER2 positive (HER2+) with high risk of cancer recurrence and death. With adjuvant trastuzumab (T) treatment the risk of reccurence almost halved and the risk of death decreased for one third. Adjuvant treatment with T has been available in Slovenia since August 2005, immediatelly after the first positive trial results. Aim Retrospective analysis of relapse free (RFS) and overall survival (OS) in HER2+ BC patients treated with adjuvant trastuzumab in years 2005-09. Results Adjuvant T received 317 patients, median age 53 (min 23; max 78) years. Ninety five percent were invasive ductal carcinoma and 97% grade 2/3, 55% were ER positive. Tumor stage was T1 (29%), T2 (48%), T3 (11%), T4 (10%), unknown (2%). N stage was N0 (26%), N1 (50%), N2 (16%), N3 (7%), unknown (1%). All patients recieved adjuvant chemotherapy, 41% anthracycline-based, 48% anthracycline and taxane- based. The median follow-up time was 4.5 (min 0.7; max 6.9) years. There were 66 relapses and 28 deaths. RFS was 98.1, 92.3, 84.2 and 80.8% at 1, 2, 3, 4 years, resp. OS was 99.7, 96.6, 93.4 and 92.5%, at 1, 2, 3, 4 years, resp. The independent prognostic factor for RFS were T stage (HR 1.2 95% CI1.0-1.4) and N stage (HR1.3 (1.1-1.5). Chemotherapy regimen was not found as a prognostic factor for RFS. Conclusions This is one of the first reports of the population based results of the adjuvant T treatment. Our results, based on adjuvant T treatment of real-life HER2 + BC patients, are fully comparable to the results obtained in HERA and Joint American study with 4-years RFS around 80%. Disclosure All authors have declared no conflicts of interest.

Aim: Cardiotoxicity is the main reason for premature discontinuation of neo/adjuvant trastuzumab therapy. Guidelines currently recommend follow-up of left ventricular ejection fraction (LVEF) measured either by multiple gated acquisition scan (MUGA) or echocardiography (ECHO), without specifying the preferred method and an interruption of treatment if LVEF declines ≥10%. In a prospective study we assessed the separate and combined impact of MUGA, ECHO, and a comprehensive cardio-oncology team approach in detecting cardiotoxicity thus safely minimizing premature therapy discontinuation. Methods: Breast cancer patients undergoing post-anthracycline trastuzumab neo/adjuvant therapy were included. MUGA, ECHO and clinical evaluation of potential cardiotoxicity was performed at baseline, after 4, 8 and 12 months. Therapy discontinuation because of cardiotoxicity was considered not only based on LVEF decline as determined by either method alone, but after thorough assessment of both methods and clinical status by a dedicated cardio-oncology team. Results: From October 2011 to November 2013 a total of 92 patients were included, all female, median age was 53 (35-76) years. We found a significant overall correlation between MUGA-LVEF and ECHO-LVEF (Interclass correlation coefficient 0.87, 95% CI 0.81-0.91, p Conclusions: We found a significant correlation between MUGA-LVEF and ECHO-LVEF. Determination of LVEF decline by MUGA or ECHO may overestimate the incidence of clinically significant trastuzumab-induced left ventricular dysfunction. Findings of our study suggest that therapy discontinuation might be minimized by integrating both methods with a comprehensive cardio-oncology team approach in case of LVEF decline detected by the preferred routinely used method. Disclosure: All authors have declared no conflicts of interest.

Metastatic breast cancer (MBC) is still in most cases an uncurable disease and the main goal of treatment is a good quality of life for these patients. Therefore it is very important to select patients who are appropriate candidates for the particular salvage chemotherapy (CT) schedule. The aim of our study was to assess treatment response to oral etoposide, and to analyze its relationship with patients' and disease characteristics. Seventy-five patients with bidimensionally measurable MBC were included into our study. For most of the patients treatment with etoposide was third-line CT regimen and most of them (90%) had been exposed to previous anthracycline-based CT. Etoposide was administered orally at a dose of 100 mg/day for 10 days every 3 weeks. The overall response rate was 37% (95% CI: 27-50%) with a median time to progression (TTP) and survival of 4.5 and 12 months, respectively. Patients with a long disease-free interval, predominant soft tissue and bone metastases, and less than three metastatic sites responded better to oral etoposide; however, a significantly better response was achieved only in those who had responded to previous CT (46 versus 19%, p=0.04), especially to anthracyclines (50 versus 17%, p=0.016). Response to previous anthracycline-based regimen was the only characteristic that significantly influenced TTP (median TTP: 7 versus 2.5 months, p=0.0066) and survival (median survival: 13.8 versus 5 months, p=0.0072). Toxic side effects were generally mild. Salvage CT with oral etoposide is an appropriate treatment for patients who respond to previous CT, particularly to anthracyclines. It combines a favorable toxicity profile with the major advantage of an oral drug administered at home.

To search for a possible source of hepatitis C virus (HCV) in saliva, the presence and shedding patterns of HCV in gingival crevicular fluid (GCF) and saliva of HCV viremic patients were assessed based on clinical, biochemical, histological, virological, and oral health parameters.Saliva and GCF samples of 50 HCV viremic patients were collected to detect HCV RNA by a modified commercial polymerase chain reaction (PCR) assay. Clinical oral examination was performed and periodontal status at the collection sites was monitored. The results were correlated to specified parameters.HCV RNA was detected in 59% (29/49) of the GCF specimens and in 35% (17/48) of the saliva specimens. In saliva specimens, HCV RNA was detected only in cases which also had detectable HCV RNA in the GCF samples (P=0.00002) and was significantly related to the presence of blood in saliva (P=0.03). Higher, but not significant, values of oral clinical parameters at the sites of fluid collection were found in GCF specimens harboring HCV RNA. In GCF specimens with no blood detected, HCV RNA was more often present in cases with higher plasma viral load (P=0.05).The results suggest that besides blood, the other most probable source of HCV in saliva is GCF. Unknown endogenous HCV inhibitory mechanisms in the oral cavity may explain the discrepancies in HCV appearance between saliva and GCF. The results provide a biologic basis for further investigation of the role of HCV in the pathogenesis of periodontal disease.

Forty-seven patients with muscle-invasive bladder cancer (T2-T4, Nx, MO) were treated by transurethral resection, followed by 3–4 cycles of combination chemotherapy (methothrexate 30 mg/m2 on days 1, 14; cis-platinum 100 mg/m2 on day 2; vinblastine 3 mg/m2 on days 1, 14; repeated every 21 days), and external beam irradiation (64– 66 Gy to the bladder and 40 Gy to the pelvic lymphatics). Complete remission after trans urethral resection and chemotherapy was achieved in 24 out of 45 patients (53%). Cystectomy was performed in patients without complete response to transurethral resection and chemotherapy. The therapy was completed as planned in 4547 patients. After transurethral resection, chemotherapy, and radiation therapy, biopsy proven complete response was achieved in 62% (2845); Stage T2T3 in 67% (2334), Stage T4 in 45% (511) of patients. Among 19 patients with positive biopsy findings after transurethral resection and chemotherapy, 14 underwent cystectomy. After follow-up of 4–55 months (median 23 months) 75% (3445) are alive, 68% (3145) have had their bladders preserved, and 53% (2445) are free of the primary tumor. The actuarial survival of all 45 patients is 73%. Moderate nausea and vomiting during treatment were common; severe leukopenia and mucositis were observed in five patients. Late side effects such as miction disorders and diarrhea were predominately mild. Although the observation period has been too short to allow a definitive evaluation of treatment results, we feel both from the point of bladder preservation and disease-free survival that the presented treatment approach is successful in a majority of T2T3 patients, whereas a large tumor size (T4) renders this treatment less effective.

P-glycoprotein (P-gp), a membrane protein that was originally found to be involved in the efflux of cytotoxic drugs out of the tumor cells, is also present in a variety of normal human and animal tissues, such as the adrenal cortex. The function of P-gp in the adrenal cortex has not been defined yet. The aim of our study was to determine whether the blockade of P-gp by cyclosporine A (CsA) dissolved in Cremophor EL (Crem) inhibits cortisol secretion in rabbits. In 14 rabbits, the baseline and ACTH stimulated serum cortisol levels were measured before and after CsA treatment. Seven rabbits were treated with 2 x 30 mg/kg CsA and seven with 2 x 90 mg/kg CsA injected s.c. Serum cortisol levels were determined by radioimmunoassay adjusted for expected values. The whole blood CsA levels were determined by a commercially available fluorescence polarization immunoassay. Serum cortisol levels, both baseline and ACTH stimulated, significantly increased after both low and high dose CsA treatment. The increase was dose dependent. The mean baseline cortisol levels increased from 5.7 (SD = 6.3) to 15.0 nmol/l (SD = 7.2) in the low dose group and from 7.7 (SD = 4.9) to 44.9 nmol/l (SD = 13.8) in the high dose group. The mean cortisol levels 8 h after ACTH stimulation increased from 53.3 (SD = 34.5) to 106.0 nmol/l (SD = 33.0) in the low dose group and from 47.7 (SD = 12.2) to 153.0 nmol/l (SD = 55.1) in the high dose group.(ABSTRACT TRUNCATED AT 250 WORDS)

Several studies have investigated medical intervention in common aspects of lifestyle, and the subject has been discussed from a legal, ethical, and practical point of view.1 Fluoridation of water supplies, legal enforcement of safety measures such as compulsory wearing of seat belts or helmets, and restriction of unhealthy habits such as drinking alcohol or smoking are typical examples of paternalistic programmes—actions that aim to prevent harm or promote the good of others, irrespective of the individual's own wishes. 2 3 What is the position, however, when a doctor's action is neither solicited nor part of his or her contractual duties? In such a situation—which we define as unsolicited medical intervention—the doctor can only speculate about whether his or her action will be welcomed and hence understood as an act of beneficence or whether it will be regarded as an unjustified paternalistic intrusion into privacy.4 According to the 1949international code of medical ethics of the World Medical Association5 and to legislation in many different countries, doctors are obliged to offer first aid in an emergency. However, apart from this relatively clear situation, dilemmas in relation to unsolicited medical intervention have rarely been discussed. The European Code of Medical Ethics, issued in Paris in January 1987by representatives of the medical associations of the European Community, emphasises the principle that “doctors can only use professional knowledge to improve and maintain the health of those who put themselves in their care.”5 We aimed to assess the attitudes of doctors and the expectations of the lay public to unsolicited medical intervention by asking them to consider the ethics of unsolicited medical intervention in three scenarios. We believed that a comparison of the responses of doctors, subgroups of doctors, and lay people would help us to identify gaps between expectations and reality. …