Change of collective orientation through an interprofessional training with medical students and student nurses depending on presence and professional group.

BACKGROUND: Teamwork is an important success factors for patient treatment. The willingness of a healthcare provider to work in a team can be descripted with the construct of "Collective Orientation" (CO). The level of CO can be trained and is related to team performance. In this study, we investigated the effect of a simulator-based interprofessional training on the subject of patient fall in a hospital setting upon participations CO. To evaluate whether the course could be integrated into a longitudinal education concept, the participants were medical students and student nurses. Since effects of simulations can be influenced by the perceived reality, the results were measured as a function of Presence. METHOD: In this observation study, 62 medical students and student nurses took part in six one-day interprofessional simulation trainings with the topic patient fall. The primary outcome was the mean difference between the CO measured immediately before (T1) and after the training (T2). The Presence of the participants was measured by questionnaire immediately after the course (T2). RESULTS: Cronbach´s alpha for all scales and measurement points was higher than 0.69. CO increases over all professional groups from M = 3.42 (SD = 0.39) to M = 3.68 (SD = 0.54) significantly (p < .00; r = .5). Only the subscale "Dominance" in the professional group of the student nurses did not increase significantly. There was no correlation between Presence and the change in CO. CONCLUSION: The questionnaires of CO and Presence can be applied to medical students and student nurses. The simulation course with the topic patient fall influences the CO and can be integrated in a longitudinal curriculum of teamwork training. The subscale "Dominance" of student nurses did not change. Preparatory learning units may increase the effects. The perceived reality of the scenario is not a main success factor.

Induction chemotherapy (IC) followed by radiotherapy (RT) versus cetuximab plus IC and RT in advanced laryngeal/hypopharyngeal cancer resectable only by total laryngectomy-final results of the larynx organ preservation trial DeLOS-II.

Background: The German multicenter randomized phase II larynx organ preservation (LOP) trial DeLOS-II was carried out to prove the hypothesis that cetuximab (E) added to induction chemotherapy (IC) and radiotherapy improves laryngectomy-free survival (LFS; survival with preserved larynx) in locally advanced laryngeal/hypopharyngeal cancer (LHSCC). Patients and methods: Treatment-naïve patients with stage III/IV LHSCC amenable to total laryngectomy (TL) were randomized to three cycles IC with TPF [docetaxel (T) and cisplatin (P) 75 mg/m2/day 1, 5-FU (F) 750 mg/m2/day days 1-5] followed by radiotherapy (69.6 Gy) without (A) or with (B) standard dose cetuximab for 16 weeks throughout IC and radiotherapy (TPFE). Response to first IC-cycle (IC-1) with ≥30% endoscopically estimated tumor surface shrinkage (ETSS) was used to define early responders; early salvage TL was recommended to non-responders. The primary objective was 24 months LFS above 35% in arm B. Results: Of 180 patients randomized (July 2007 to September 2012), 173 fulfilled eligibility criteria (A/B: larynx 44/42, hypopharynx 41/46). Because of 4 therapy-related deaths among the first 64 randomized patients, 5-FU was omitted from IC in the subsequent 112 patients reducing further fatal toxicities. Thus, IC was TPF in 61 patients and TP in 112 patients, respectively. The primary objective (24 months LFS above 35%) was equally met by arms A (40/85, 47.1%) as well as B (41/88, 46.6%). One hundred and twenty-three early responders completed IC+RT; their overall response rates (TPF/TP) were 94.7%/87.2% in A versus 80%/86.0% in B. The 24 months overall survival (OS) rates were 68.2% and 69.3%. Conclusions: Despite being accompanied by an elevated frequency in adverse events, the IC with TPF/TP plus cetuximab was feasible but showed no superiority to IC with TPF/TP regarding LFS and OS at 24 months. Both early response and 24 months LFS compare very well to previous LOP trials and recommend effective treatment selection and stratification by ETSS. Clinical trial information: NCT00508664.

Stereotactic body radiotherapy (SBRT) for multiple pulmonary oligometastases: Analysis of number and timing of repeat SBRT as impact factors on treatment safety and efficacy.

BACKGROUND: Stereotactic body radiotherapy (SBRT) for oligometastatic disease is characterized by an excellent safety profile; however, experiences are mostly based on treatment of one single metastasis. It was the aim of this study to evaluate safety and efficacy of SBRT for multiple pulmonary metastases. PATIENTS AND METHODS: This study is based on a retrospective database of the DEGRO stereotactic working group, consisting of 637 patients with 858 treatments. Cox regression and logistic regression were used to analyze the association between the number of SBRT treatments or the number and the timing of repeat SBRT courses with overall survival (OS) and the risk of early death. RESULTS: Out of 637 patients, 145 patients were treated for multiple pulmonary metastases; 88 patients received all SBRT treatments within one month whereas 57 patients were treated with repeat SBRT separated by at least one month. Median OS for the total patient population was 23.5 months and OS was not significantly influenced by the overall number of SBRT treatments or the number and timing of repeat SBRT courses. The risk of early death within 3 and 6 months was not increased in patients treated with multiple SBRT treatments, and no grade 4 or grade 5 toxicity was observed in these patients. CONCLUSIONS: In appropriately selected patients, synchronous SBRT for multiple pulmonary oligometastases and repeat SBRT may have a comparable safety and efficacy profile compared to SBRT for one single oligometastasis.

Nomogram based overall survival prediction in stereotactic body radiotherapy for oligo-metastatic lung disease.

BACKGROUND: Radical local treatment of pulmonary metastases is practiced with increasing frequency due to acknowledgment and better understanding of oligo-metastatic disease. This study aimed to develop a nomogram predicting overall survival (OS) after stereotactic body radiotherapy (SBRT) for pulmonary metastases. PATIENTS AND METHODS: A multi-institutional database of 670 patients treated with SBRT for pulmonary metastases was used as training cohort. Cox regression analysis with bidirectional variable elimination was performed to identify factors to be included into the nomogram model to predict 2-year OS. The calibration rate of the nomogram was assessed by plotting the actual Kaplan-Meier 2-year OS against the nomogram predicted survival. The nomogram was externally validated using two separate monocentric databases of 145 and 92 patients treated with SBRT for pulmonary metastases. RESULTS: The median follow up of the trainings cohort was 14.3months, the 2-year and 5-year OS was 52.6% and 23.7%, respectively. Karnofsky performance index, type of the primary tumor, control of the primary tumor, maximum diameter of the largest treated metastasis and number of metastases (1 versus >1) were significant prognostic factors in the Cox model (all p<0.05). The calculated concordance-index for the nomogram was 0.73 (concordance indexes of all prognostic factors between 0.54 and 0.6). Based on the nomogram the training cohort was divided into 4 groups and 2-year OS ranged between 24.2% and 76.1% (predicted OS between 30.2% and 78.4%). The nomogram discriminated between risk groups in the two validation cohorts (concordance index 0.68 and 0.67). CONCLUSIONS: A nomogram for prediction of OS after SBRT for pulmonary metastases was generated and externally validated. This tool might be helpful for interdisciplinary discussion and evaluation of local and systemic treatment options in the oligo-metastatic setting. KEY MESSAGE: A nomogram for prediction of overall survival after stereotactic body radiotherapy (SBRT) for pulmonary metastases was developed and externally validated. This tool might be helpful for interdisciplinary discussion and evaluation of local and systemic treatment options in the oligo-metastatic setting.

[Pneumopericardium due to thorax compression : Overlooked resuscitation injury]. / Pneumoperikard durch Thoraxkompression : Übersehene Reanimationsverletzung.

On postoperative day 15 after right upper lobectomy of a non-small cell lung cancer a 75-year-old patient developed bradycardia followed by asystole during hospitalization on the intensive care unit. After approximately 4 min of chest compressions, circulatory function was re-established but the patient suffered from tachycardia and required continuous vasopressor support. To exclude hypovolemia and assess contractility, transthoracic echocardiography (TTE) was conducted. During the TTE examination neither the intensive care physician nor the cardiologist on call could obtain usable images, which was explained by the lack of experience of both physicians with TTE. Both chest ultrasound and chest x-ray imaging did not reveal any signs of a pneumothorax. A small zone of increased transparency in the cardiac silhouette was not considered to be of pathological relevance. Slowly, the patient recovered. On the following day, a thoracic computed tomography (CT) scan showed an extensive pneumopericardium of the entire pericardium with a seam width of 3 cm. Because of the patient's clinical improvement, a decision for a conservative therapeutic approach was made and 24 h later the seam width was reduced to 2 cm and 9 days later it was no longer detectable. After a total stay of 24 days in the intensive care unit the patient was transferred to a long-term pulmonary care weaning facility. In retrospect, the pneumopericardium as a rare resuscitation injury was the cause for the poor TTE conditions and was overlooked due to a fixation error, because too much attention had been focused only on the detection of a pneumothorax.

Generation of prostate IMAT plans adaptable to the inter-fractional changes of patient geometry.

We present the results of 2-Step generation of adaptable IMAT plans for prostate carcinoma cases. The 2-Step IMAT plans show clinical and dosimetric equivalence to the reference SmartArc™-generated VMAT plans. The 2-Step plans are adapted to inter-fractional changes of prostate-rectum geometry using 2-Step adaptation rules for a cohort of ten adaptation cases. The adapted 2-Step IMAT plans show statistically significant improvement (Wilcoxon 1-tail p < 0.05) of target coverage and of rectum sparing when compared to isocenter relocated plans.

Survival and prognostic factors after moderately hypofractionated palliative thoracic radiotherapy for non-small cell lung cancer.

BACKGROUND: Survival and prognostic variables in patients with advanced or metastatic non-small cell lung cancer (NSCLC) requiring thoracic palliative radiotherapy using a moderately hypofractionated regime (13-15 × 3 Gy) were evaluated. METHODS: From March 2006 to April 2012, 120 patients with a physician estimated prognosis of 6-12 months were treated with this regime using CT-based 3D conformal radiotherapy. We collected data on patient characteristics, comorbidities, toxicity, and treatment parameters. RESULTS: Radiotherapy was completed as prescribed in 114 patients (95.0 %, premature termination 5.0 %). Acute grade 3 toxicity was seen in 6.4 % of patients. The median survival of all patients was 5.8 months. Nonmetastatic patients survived significantly longer than patients with metastatic disease (median 11.7 months vs 4.7 months, p = 0.0001) and 18.6 % of nonmetastatic patients survived longer than 2 years. In 12.7 % radiotherapy started less than 30 days before death and 14.2 % of patients received radiotherapy within 14 days before death. In the multivariate analysis, good general condition, nonmetastatic disease, and a stable or improved general condition at the end of radiotherapy were significant. The treatment parameters, age, and comorbidities were not statistically significant. CONCLUSION: Our data confirm considerable effectiveness of 13 × 3 Gy with conformal radiotherapy for patients with locally confined NSCLC not fit for radical treatment and raise doubt for this regimen in metastatic patients and ECOG ≥ 2 when burden, acute toxicity, and resources are considered.

Moderately hypofractionated radiotherapy for localized prostate cancer: long-term outcome using IMRT and volumetric IGRT.

PURPOSE: To evaluate long-term outcome after dose-escalated, moderately hypofractionated radiotherapy for prostate cancer. METHODS: Since 2005, 150 consecutive patients were treated with primary radiotherapy for localized prostate cancer. Intensity modulated radiotherapy (IMRT) using the simultaneous integrated boost (SIB) technique was practiced in all patients and doses of 73.9 Gy (n = 41) and 76.2 Gy (n = 109) were delivered in 32 and 33 fractions, respectively. The pelvic lymph nodes were treated in 41 high-risk patients. Treatment was delivered using cone-beam CT based image-guided radiotherapy (IGRT). Toxicity was assessed prospectively using CTCAE 3.0; biochemical failure was defined according to the Phoenix definition of nadir + 2 ng/ml. RESULTS: Median follow-up of living patients was 50 months. Gastrointestinal (GI) toxicity was mild with > 80% of the patients free from any GI toxicity during follow-up and no time trend to increased rates or to higher grade of GI toxicity. Two patients suffered from late grade 3 GI toxicity. Acute genitourinary (GU) toxicity grade 1-2 was observed in 85% of the patients; most patients recovered quickly within 6 weeks after treatment. The rate of GU toxicity grade ≥ 2 was <10% at 6-12 month but increased continuously to 22.4% at 60 months; grade 3 GU toxicity remained below 5% during follow-up. The 5-year freedom from biochemical failure (FFBF) was 82% for all patients and 88, 80, and 78% for low-, intermediate-, and high-risk disease. CONCLUSION: Favorable FFBF with simultaneously low rates of toxicity was observed after moderately hypofractionated radiotherapy with 2 Gy-equivalent doses ≥ 80 Gy. Conformal IMRT planning and accurate IGRT treatment delivery may have contributed to these results.

Conformal breast irradiation with the arm of the affected side parallel to the body.

PURPOSE: To propose a simple, forward-planned three-dimensional conformal radiotherapy (3D-CRT) technique for breast cancer patients with frozen shoulder. MATERIALS AND METHODS: A technique is described that avoids lateral beams transmitting through the arm of the affected side. One medial, tangentially applied beam deposits most of the dose. Further beams with little weight are used to attain dose homogeneity. In order to quantify dose distribution and homogeneity in the planning target volume (PTV), as well as the scattered dose in organs at risk (OAR), the parameters D95, D5, D1, mean and median dose were determined for the individual volumes. Intensity-modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT) plans were created in order to compare these with the proposed technique. RESULTS: The described technique achieved homogenous dose deposition within the PTV. A regimen comprising 25 fractions of 2 Gy prescribed to the PTV resulted in the following dose parameters: PTV(D95): 44.3 Gy, PTV(D5): 52.7 Gy, PTV(D1): 54.8 Gy, PTV(mean): 49.3 Gy and PTV(median): 49.9 Gy. Mean lung dose was 7.0 Gy. The ipsilateral lung received a mean dose of 9.9 Gy. This plan was accepted for treatment. The IMRT and VMAT plans achieved a similar dose distribution in the PTV. These techniques also reduced dose deposition in the OAR. CONCLUSION: The proposed 3D-CRT technique allows treatment of breast cancer patients who are not able to raise their arms above their head. Homogenous dose distribution in the PTV was achieved while avoiding lateral beams that transmit through the arm of the affected side. Mean lung dose was comparable to that of the conventional technique using opposed tangential beams. IMRT and VMAT also provide good target dose homogeneity with good sparing of OAR. However, these techniques are more demanding in terms of planning and quality assurance.

Radiotherapy in pediatric pilocytic astrocytomas. A subgroup analysis within the prospective multicenter study HIT-LGG 1996 by the German Society of Pediatric Oncology and Hematology (GPOH).

PURPOSE: We evaluated clinical outcomes in the subset of patients who underwent radiotherapy (RT) due to progressive pilocytic astrocytoma within the Multicenter Treatment Study for Children and Adolescents with a Low Grade Glioma HIT-LGG 1996. PATIENTS AND METHODS: Eligibility criteria were fulfilled by 117 patients. Most tumors (65 %) were located in the supratentorial midline, followed by the posterior fossa (26.5 %) and the cerebral hemispheres (8.5 %). Median age at the start of RT was 9.2 years (range 0.7-17.4 years). In 75 cases, external fractionated radiotherapy (EFRT) was administered either as first-line nonsurgical treatment (n = 58) or after progression following primary chemotherapy (n = 17). The median normalized total dose was 54 Gy. Stereotactic brachytherapy (SBT) was used in 42 selected cases. RESULTS: During a median follow-up period of 8.4 years, 4 patients (3.4 %) died and 33 (27.4 %) experienced disease progression. The 10-year overall (OS) and progression-free survival (PFS) rates were 97 and 70 %, respectively. No impact of the RT technique applied (EFRT versus SBT) on progression was observed. The 5-year PFS was 76 ± 5 % after EFRT and 65 ± 8 % after SBT. Disease progression after EFRT was not influenced by gender, neurofibromatosis type 1 (NF1) status, tumor location (hemispheres versus supratentorial midline versus posterior fossa), age or prior chemotherapy. Normalized total EFRT doses of more than 50.4 Gy did not improve PFS rates. CONCLUSION: EFRT plays an integral role in the treatment of pediatric pilocytic astrocytoma and is characterized by excellent tumor control. A reduction of the normalized total dose from 54 to 50.4 Gy appears to be feasible without jeopardizing tumor control. SBT is an effective treatment alternative.

Patients with recurrent glioblastoma multiforme. Initial experience with p-[(131)I]iodo-L-phenylalanine and external beam radiation therapy.

AIM: The objective of this study was to assess the feasibility, dosimetry, tolerability and efficacy of systemically administrated p-[(131)I]iodo-L-phenylalanine ((131)IPA) combined with hypo-fractionated external beam radiation therapy (EBRT) in patients with recurrent glioblastoma multiforme (GBM). PATIENTS, METHODS: Five patients (2 women, 3 men, aged 27-69) with recurrent GBM and exhaustion of regular therapy options were included. All had a positive O-(2-[(18)F]Fluoroethyl)-L-tyrosine positron emission tomography (FET-PET) and pretherapeutic dosimetry was performed. Tumour targeting was verified by (131)IPA-SPECT up to six days after radiotracer administration. After (131)IPA therapy, patients were treated with hypo-fractionated EBRT in six fractions of 5 Gy (n = 4) or in eleven fractions of 2 Gy in one case. RESULTS: Based on the individual dosimetry, the patients received a single intravenous administration of 2 to 7 GBq of (131)IPA, resulting in radiation absorbed doses to the blood of 0.80-1.47 Gy. The treatment was well tolerated; only minor complaints of nausea and vomiting that responded to ondansetron and pantoprazol were noticed in the first two patients. After preventive medication, the last three patients had no complaints during therapy. In none of the patients a decrease of leukocyte or thrombocyte counts below the baseline level or the lower normal limit was observed. Tumour doses from (131)IPA were low (≤ 1 Gy) and all patients died three to eight (median 5.5) months after therapy. CONCLUSION: In this initial experience, treatment of GBM with (131)IPA in combination with EBRT was demonstrated to be safe and well tolerated, but less effective than suggested by the animal studies.

Influence of osteopontin silencing on survival and migration of lung cancer cells.

BACKGROUND AND PURPOSE: Osteopontin (OPN) is a multifunctional protein overexpressed in many cancers and is involved in tumor progression and metastasis. In lung cancer, elevated OPN expression is associated with an unfavorable prognosis. Therefore, inhibition of OPN is an attractive approach for improving survival. MATERIALS AND METHODS: We used siRNA to specifically downregulate OPN expression in A549 lung cancer cells. OPN silencing was evaluated with quantitative reverse transcriptase polymerase chain reaction (RT-PCR) for mRNA levels and with Western blotting for protein levels. Effects on cell proliferation were measured by cell counting. The influence on tumor cell migration was detected using a modified Boyden chamber. Changes in cell cycle distribution were assessed by flow cytometry. Using the colony formation assay, we determined changes in radiosensitivity. RESULTS: A specific and effective downregulation of OPN expression was detected in both RNA and protein levels. Cell proliferation and cell migration were significantly reduced by OPN silencing after 24 h and the effects were further increased by the addition of irradiation. The cell cycle distribution showed a reduction in S phase and an increase in cells arrested in both G(0)/G(1) and G(2)/M phases. Specific enhancement of radiosensitivity was clearly shown after OPN knockdown. CONCLUSION: The combination of OPN silencing and irradiation showed a synergistic effect leading to reduced cell survival.

Comparison of preoperative short-course radiotherapy and long-course radiochemotherapy for locally advanced rectal cancer.

BACKGROUND: The purpose of this work was to perform a single institution comparison between preoperative short-course radiotherapy (SC-RT) and long-course radiochemotherapy (LC-RCHT) for locally advanced rectal cancer. METHODS: A total of 225 patients with clinical stage UICC II-III rectal cancer were treated with SC-RT (29 Gy in 10 twice daily fractions followed by immediate surgery; n = 108) or LC-RCHT (54 Gy in 28 fractions with simultaneous 5-fluorouracil (5-FU) ± oxaliplatin chemotherapy followed by delayed surgery; n = 117). All patients in the LC-RCHT cohort and patients in the SC-RT with pathological UICC stage ≥ II received adjuvant chemotherapy. Before 2004, the standard of care was SC-RT with LC-RCHT reserved for patients where downstaging was considered as required for sphincter preservation or curative resection. In the later period, SC-RT was practiced only for patients unfit for radiochemotherapy. RESULTS: Patients in the LC-RCHT cohort had a significantly higher proportion of cT4 tumors, clinical node positivity, and lower tumor location. The 5-year local control (LC) and overall survival (OS) were 91% and 66% without differences between the SC-RT and LC-RCHT groups. Acute toxicity was increased during LC-RCHT (grade ≥ II 1% vs. 33%) and there were no differences in postoperative complications. Severe late toxicity grade ≥ III was increased after SC-RT (12% vs. 3%). Of patients aged > 80 years, 7 of 7 patients and 4 of 9 patients received curative surgery after SC-RT and LC-RCHT, respectively. CONCLUSION: Despite the fact that patients with worse prognostic factors were treated with LC-RCHT, there were no significant differences in LC and OS between the SC-RT and LC-RCHT group. Age > 80 years was identified as a significant risk factor for LC-RCHT and these patients could be treated preferably with SC-RT.

Micronucleus formation kinetics in buccal mucosa cells of head and neck cancer patients undergoing radiotherapy.

In head and neck cancer, radiotherapy is one of the main treatment modalities besides surgery and chemotherapy either in a primary or an adjuvant setting. Radiation kills tumor cells by damaging the DNA within these cells. One of the methods to assess the degree of genomic damage is the micronucleus (MN) test. The effect of radiation therapy on the MN frequency in buccal mucosa cells has only been investigated in small studies looking at single time points or including a limited number of patients. In the present study, normal tissue buccal mucosa cells from 17 patients were analyzed for genomic damage at four different time points during radiation therapy. A clear increase was observed for every time point. Additionally, buccal mucosa cells of a cohort of 16 patients were analyzed after the end of the therapy and compared to samples from 25 patients sampled before the therapy. 10 healthy controls were included, of which 5 were sampled once, and 5 were sampled four times similar to the patients. Also, the influence of additional chemotherapy was investigated. No difference was observed between radiation-only patients and patients receiving additional chemotherapy. Age, gender, and tumor stage did not have an influence on the MN formation kinetics.

Radiosensitizing effect of the novel Hsp90 inhibitor NVP-AUY922 in human tumour cell lines silenced for Hsp90α.

BACKGROUND: Hsp90 inhibitors can enhance the tumour sensitivity to ionising radiation (IR). However, Hsp90 inhibition leads to the up-regulation of anti-apoptotic Hsp90 and Hsp70, which might diminish the radiosensitizing effects of the inhibitors. Therefore, inhibition of the up-regulation of Hsp90 by siRNA might be a promising strategy to enhance drug-mediated radiosensitization. MATERIALS AND METHODS: The expression of Hsp90α was silenced in A549 and GaMG tumour cell lines by siRNA treatment. Pre-silenced for Hsp90α cells were treated with NVP-AUY922, a novel Hsp90 inhibitor, for 24 h and then irradiated. Radiation response was determined by colony-forming ability. The expression of several marker proteins was analysed by Western blot. DNA damage and repair were assessed by histone γH2AX measurements. RESULTS: We found that transfection with siRNA against Hsp90α reduced Hsp90α at mRNA and protein levels. Pre-silencing of Hsp90α reduced NVP-AUY922-mediated up-regulation of Hsp90α but it did not increase drug-mediated radiosensitization in both tumour cell lines. As revealed by Western blot, pre-silencing of Hsp90α followed by NVP-AUY922 did not change the expression of Hsp90 client proteins (Akt, Raf-1, Cdk1 and Cdk4) compared with drug treatment alone, suggesting unchanged chaperone function in transfected cells. CONCLUSION: Pre-silencing of Hsp90α followed by Hsp90 inhibition did not enhance the radiosensitizing effect of NVP-AUY922 in both tested tumour cell lines. Future work will be done on stable transfection with shRNA against Hsp90α or simultaneous silencing of both Hsp90 isoforms, Hsp90α and Hsp90ß, in order to optimize tumour cell killing.

Novel HSP90 inhibitors, NVP-AUY922 and NVP-BEP800, radiosensitise tumour cells through cell-cycle impairment, increased DNA damage and repair protraction.

BACKGROUND: Heat-shock protein 90 (Hsp90) has a crucial role in both the stabilisation and regulation of various proteins, including those related to radioresistance. Inhibition of Hsp90 may therefore provide a strategy for enhancing the radiosensitivity of tumour cells. This study explores the responses of four tumour cell lines (A549, GaMG, HT 1080 and SNB19) to combined treatment with ionising radiation (IR) and two novel inhibitors of Hsp90, NVP-AUY922 and NVP-BEP800. The techniques used included cell and colony counts, expression of Hsp90, Hsp70, Akt, survivin, cleaved caspase 3, p53, cell-cycle progression and associated proteins. DNA damage was analysed by histone gammaH2AX and Comet assays. RESULTS: We found that NVP-AUY922 and NVP-BEP800 enhanced radiosensitivity in all tested cell lines. In contrast, only two cell lines (HT 1080 and GaMG) exhibited an increased rate of apoptosis after drug pretreatment, as revealed by western blot. In all tested cell lines, the expression of histone gammaH2AX, a marker of DNA double-strand breaks, after combined drug-IR treatment was higher and its decay rate was slower than those after each single treatment modality. Drug-IR treatment also resulted in impaired cell-cycle progression, as indicated by S-phase depletion and G2/M arrest. In addition, the cell cycle-associated proteins, Cdk1 and Cdk4, were downregulated after Hsp90 inhibition. INTERPRETATION: These findings show that the novel inhibitors of Hsp90 can radiosensitise tumour cell lines of different entities through destabilisation and depletion of several Hsp90 client proteins, thus causing the depletion of S phase and G2/M arrest, increased DNA damage and repair protraction and, to some extent, apoptosis. The results might have important implications for the radiotherapy of solid tumours.

Phase I trial of dose-escalated cisplatin with concomitant cetuximab and hyperfractionated-accelerated radiotherapy in locally advanced squamous cell carcinoma of the head and neck.

BACKGROUND: Cetuximab is active in the treatment of squamous cell carcinoma of the head and neck (SCCHN), enhancing both radiotherapy and chemotherapy effects. This phase I study was designed to investigate the safety and tolerability of combining weekly cisplatin treatment with cetuximab and hyperfractionated-accelerated radiotherapy (HART) for locally advanced SCCHN. PATIENTS AND METHODS: Patients with unresectable stage III or IVA/B SCCHN were treated with cetuximab, 400 mg/m² initial dose on day -7 of HART, followed by 250 mg/m² weekly during the administration of HART, which started with 2.0 Gy/day (5 days/week) for 3 weeks followed by 1.4 Gy/twice-daily (Monday to Friday) for another 3 weeks, resulting in a total dose of 70.6 Gy. Cisplatin was administered weekly starting on the first day of radiotherapy until week 6. Cisplatin was dose escalated of four dose levels from 20 to 40 mg/m² using a classical 3 + 3 dose escalation algorithm. RESULTS: Eighteen patients were enrolled. Sixteen patients were eligible for toxicity, and 15 for response. No maximum tolerated dose was reached for cisplatin. One of six patients of dose level 4 had grade 4 neutropenia. This patient died 1 week after the end of the study treatment. The most common types of grade 3+ adverse events were mucositis (9 of 16 patients), in-field dermatitis (6 of 16 patients) and neutropenia (4 of 16 patients). Cetuximab-related hypersensitivity was observed in 1 out of 18 patients. Six weeks after the end of the study treatment, 5 complete responses, 8 partial responses and 1 progressive disease (at distant sites) were documented in a total of 15 patients (objective response rate 87%). CONCLUSIONS: The combination of cisplatin with cetuximab and HART is active, well tolerated and merits additional investigation. The recommended weekly dose of cisplatin for phase II studies is 40 mg/m².