Pain and quality of life in patients undergoing radiotherapy for spinal metastatic disease treatment

Abstract Background Radiotherapy is an important tool in the control of pain in patients with spinal metastatic disease. We aimed to evaluate pain and of quality of life of patients with spinal metastatic disease undergoing radiotherapy with supportive treatment. Methods The study enrolled 30 patients. From January 2008 to January 2010, patients selection included those treated with a 20 Gy tumour dose in five fractions. Patients completed the visual analogue scale for pain assessment and the SF-36 questionnaire for quality of life assessment. Results The most frequent primary sites were breast, multiple myeloma, prostate and lymphoma. It was found that 14 spinal metastatic disease patients (46.66%) had restricted involvement of three or fewer vertebrae, while 16 patients (53.33%) had cases involving more than three vertebrae. The data from the visual analogue scale evaluation of pain showed that the average initial score was 5.7 points, the value 30 days after the end of radiotherapy was 4.60 points and the average value 6 months after treatment was 4.25 points. Notably, this final value was 25.43% lower than the value from the initial analysis. With regard to the quality of life evaluation, only the values for the functional capability and social aspects categories of the questionnaire showed significant improvement. Conclusion Radiotherapy with supportive treatment appears to be an important tool for the treatment of pain in patients with spinal metastatic disease.

MVP expression in the prediction of clinical outcome of locally advanced oral squamous cell carcinoma patients treated with radiotherapy

[EN] Objective: To explore the role of Major Vault Protein (MVP) in oral cavity squamous cell carcinoma patients. Subjects and Methods: 131 consecutive patients suffering from oral cavity squamous cell carcinoma were included in the study. In the whole series, the mean follow-up for survivors was 123.11 ± 40.36 months. Patients in tumour stages I and II were referred to surgery; patients in stage III-IV to postoperative radiotherapy (mean dose = 62.13 ± 7.74 Gy in 1.8–2 Gy/fraction). MVP expression was studied by immunohistochemistry in paraffin-embedded tumour tissue. Results: MVP expression was positive in 112 patients (85.5%) and no relation was found with clinic pathological variables. MVP overexpression (those tumours with moderate or strong expression of the protein) was related to insulin-like growth factor receptor-1 (IGF-1R) expression (P = 0.014). Tumour stage of the disease was the most important prognostic factor related to survival. Tumours overexpressing MVP and IGF-1R were strongly related to poor disease-free survival (P = 0.008, Exp(B) = 2.730, CI95% (1.302-5.724)) and cause-specific survival (P = 0.014, Exp(B) = 2.570, CI95% (1.215-5.437)) in patients achieving tumour stages III-IV, in multivariate analysis. Conclusions: MVP and IGF-1R expression were related in oral squamous cell carcinoma and conferred reduced long-term survival in patients suffering from advanced stages of the disease.

Combined low initial DNA damage and high radiation-induced apoptosis confers clinical resistance to long-term toxicity in breast cancer patients treated with high-dose radiotherapy

[EN] Background: Either higher levels of initial DNA damage or lower levels of radiation-induced apoptosis in peripheral blood lymphocytes have been associated to increased risk for develop late radiation-induced toxicity. It has been recently published that these two predictive tests are inversely related. The aim of the present study was to investigate the combined role of both tests in relation to clinical radiation-induced toxicity in a set of breast cancer patients treated with high dose hyperfractionated radical radiotherapy. Methods: Peripheral blood lymphocytes were taken from 26 consecutive patients with locally advanced breast carcinoma treated with high-dose hyperfractioned radical radiotherapy. Acute and late cutaneous and subcutaneous toxicity was evaluated using the Radiation Therapy Oncology Group morbidity scoring schema. The mean follow-up of survivors (n = 13) was 197.23 months. Radiosensitivity of lymphocytes was quantified as the initial number of DNA double-strand breaks induced per Gy and per DNA unit (200 Mbp). Radiation-induced apoptosis (RIA) at 1, 2 and 8 Gy was measured by flow cytometry using annexin V/propidium iodide. Results: Mean DSB/Gy/DNA unit obtained was 1.70 ± 0.83 (range 0.63-4.08; median, 1.46). Radiation-induced apoptosis increased with radiation dose (median 12.36, 17.79 and 24.83 for 1, 2, and 8 Gy respectively). We observed that those "expected resistant patients" (DSB values lower than 1.78 DSB/Gy per 200 Mbp and RIA values over 9.58, 14.40 or 24.83 for 1, 2 and 8 Gy respectively) were at low risk of suffer severe subcutaneous late toxicity (HR 0.223, 95%CI 0.073-0.678, P = 0.008; HR 0.206, 95%CI 0.063-0.677, P = 0.009; HR 0.239, 95%CI 0.062-0.929, P = 0.039, for RIA at 1, 2 and 8 Gy respectively) in multivariate analysis. Conclusions: A radiation-resistant profile is proposed, where those patients who presented lower levels of initial DNA damage and higher levels of radiation induced apoptosis were at low risk of suffer severe subcutaneous late toxicity after clinical treatment at high radiation doses in our series. However, due to the small sample size, other prospective studies with higher number of patients are needed to validate these results.

Constitutive gene expression profile segregates toxicity in locally advanced breast cancer patients treated with high-dose hyperfractionated radical radiotherapy

[EN] Breast cancer patients show a wide variation in normal tissue reactions after radiotherapy. The individual sensitivity to x-rays limits the efficiency of the therapy. Prediction of individual sensitivity to radiotherapy could help to select the radiation protocol and to improve treatment results. The aim of this study was to assess the relationship between gene expression profiles of ex vivo un-irradiated and irradiated lymphocytes and the development of toxicity due to high-dose hyperfractionated radiotherapy in patients with locally advanced breast cancer. Raw data from microarray experiments were uploaded to the Gene Expression Omnibus Database http://www.ncbi.nlm.nih.gov/geo/ (GEO accession GSE15341). We obtained a small group of 81 genes significantly regulated by radiotherapy, lumped in 50 relevant pathways. Using ANOVA and t-test statistical tools we found 20 and 26 constitutive genes (0 Gy) that segregate patients with and without acute and late toxicity, respectively. Non-supervised hierarchical clustering was used for the visualization of results. Six and 9 pathways were significantly regulated respectively. Concerning to irradiated lymphocytes (2 Gy), we founded 29 genes that separate patients with acute toxicity and without it. Those genes were gathered in 4 significant pathways. We could not identify a set of genes that segregates patients with and without late toxicity. In conclusion, we have found an association between the constitutive gene expression profile of peripheral blood lymphocytes and the development of acute and late toxicity in consecutive, unselected patients. These observations suggest the possibility of predicting normal tissue response to irradiation in high-dose non-conventional radiation therapy regimens. Prospective studies with higher number of patients are needed to validate these preliminary results.

Stereotactict body radiotherapy (SBRT)

Purpose: evaluation and comparison of volumetric modulated RapidarcTM radiotherapy (RA-IMRT) vs linac based Stereotactic body radiotherapy (SBRT) in the salvage treatment of isolated lymph node recurrences in patients affected by gynaecological cancer. Materials and Methods From January 2010 to September 2011, 15 patients affected by isolated lymph nodes recurrence of gynaecological cancer underwent salvage radiotherapy after conventional imaging staging with CT and 18-FDG-PET/CT. Two different radiotherapy techniques were used in this study: RA-IMRT (RapidarcTM implemented radiotherapy Varian Medical System, Palo Alto, CA, USA) or SBRT (BrainLAB, Feldkirchen, Germany). Five patients underwent CT scan and all patients underwent 18FDG-PET/CT for pre-treatment evaluation and staging. The mean total dose delivered was 54.3 Gy (range 50-60 Gy with conventional fractionation and 27.4 Gy (range 12-40 Gy hypofractionation) for RA-IMRT and SBRT respectively. The mean number of fractions was 27.6 fractions (range 25-31) and 3-4 fractions , the mean overall treatment duration was 40.5 days (range 36-45) and 6.5 days (range 5-8 days) for RA-IMRT and SBRT respectively. Results: At the time of the analysis, October 2011, the overall survival was 92.3 % (80% for RA-IMRT and 100% for SBRT). Six patients are alive with no evidence of disease and also six patients are alive with clinically evident disease in other sites (40% and 50% patients RA-IMRT vs SBRT respectively, one patient died for systemic progression of disease and two patient were not evaluable at this time. Conclusions: Our preliminary results showed that, the use of RA-IMRT and SBRT are an excellent local therapy for isolated lymph nodes recurrences of gynaecological cancer with a good toxicity profile and local control rate, even if any long term survivors would be expected. New treatment modalities like Cyberknife are also being implemented.

Solubility and permeability as in vitro predictors for in vivo performance of fenofibrate IR solid dosage forms

This current work focused on the simulation of in vivo dissolution and permeation in order to be able to predict the in vivo performance of orally administered fenofibrate immediate release formulations. Therefore, the effects of the formulation surfactants on in vivo solubility and permeation of fenofibrate under physiologically relevant excipient concentrations were emphasized.rnIt was shown that the surfactant sodium dodecyl sulfate (SDS) may decrease rather than increase the solubility of fenofibrate in vivo. This was related to the interference of SDS with the vesicular system of the biorelevant medium, FaSSIFmod, and therefore its solubilization capacity. rnMoreover, in vitro permeation studies revealed that SDS concentrations inversely correlated with fenofibrate permeability. Through combination of the observed permeation and solubility data a good in vitro/in vivo correlation regarding Cmax values in humans could be established for five fenofibrate formulations which were based on the same manufacturing technique.rnBesides the experimental part, the major characteristics and their potential implementation in a dissolution/permeation device were discussed based on the promising realization of the in vitro solubility and permeation methods. rn

Nuovi protocolli chemioterapici per i sarcomi dei tessuti molli ad alto grado di malignita' negli adulti: Risultati clinici, radiologici e istologici comparando chemioterapia standard e orientata sull'isotopo

I sarcomi dei tessuti molli sono un gruppo eterogeneo di tumori maligni di origine mesenchimale che si sviluppa nel tessuto connettivo. Il controllo locale mediante escissione chirurgica con margini ampi associato alla radioterapia e chemioterapia è il trattamento di scelta. Negli ultimi anni le nuove scoperte in campo biologico e clinico hanno sottolineato che i diversi istotipi posso essere considerati come entità distinte con differente sensibilità alla chemioterapia pertanto questa deve essere somministrata come trattamento specifico basato sull’istologia. Tra Ottobre 2011 e Settembre 2014 sono stati inclusi nel protocollo di studio 49 pazienti con sarcomi dei tessuti molli di età media alla diagnosi 48 anni (range: 20 - 68 anni). I tumori primitivi più frequenti sono: liposarcoma mixoide, sarcoma pleomorfo indifferenziato, sarcoma sinoviale. Le sedi di insorgenza del tumore erano più frequentemente la coscia, il braccio e la gamba. 35 pazienti sono stati arruolati nel Braccio A e trattati con chemioterapia standard con epirubicina+ifosfamide, 14 sono stati arruolati nel Braccio B e trattati con chemioterapia basata sull’istotipo. I dati emersi da questo studio suggeriscono che le recidive locali sembrano essere correlate favorevolmente alla radioterapia ed ai margini chirurgici adeguati mentre la chemioterapia non sembra avere un ruolo sul controllo locale della malattia. Anche se l'uso di terapie mirate, che hanno profili di tossicità più favorevoli e sono quindi meglio tollerate rispetto ai farmaci citotossici è promettente, tali farmaci hanno prodotto finora risultati limitati. Apparentemente l’insieme delle terapie mirate non sembra funzionare meglio delle terapie standard, tuttavia esse devono essere esaminate per singolo istotipo e confrontate con il braccio di controllo. Sono necessari studi randomizzati controllati su ampie casistiche per valutare l’efficacia delle terapie mirate sui differenti istotipi di sarcomi dei tessuti molli. Inoltre, nuovi farmaci, nuove combinazioni e nuovi schemi posologici dovranno essere esaminati per ottimizzare la terapia.

Hydrodynamics and solid dosage form disintegration/dissolution : immediate release tablets and novel in situ polyelectrolyte gastroretentive drug delivery systems

Solid oral dosage form disintegration in the human stomach is a highly complex process dependent on physicochemical properties of the stomach contents as well as on physical variables such as hydrodynamics and mechanical stress. Understanding the role of hydrodynamics and forces in disintegration of oral solid dosage forms can help to improve in vitro disintegration testing and the predictive power of the in vitro test. The aim of this work was to obtain a deep understanding of the influence of changing hydrodynamic conditions on solid oral dosage form performance. Therefore, the hydrodynamic conditions and forces present in the compendial PhEur/USP disintegration test device were characterized using a computational fluid dynamics (CFD) approach. Furthermore, a modified device was developed and the hydrodynamic conditions present were simulated using CFD. This modified device was applied in two case studies comprising immediate release (IR) tablets and gastroretentive drug delivery systems (GRDDS). Due to the description of movement provided in the PhEur, the movement velocity of the basket-rack assembly follows a sinusoidal profile. Therefore, hydrodynamic conditions are changing continually throughout the movement cycle. CFD simulations revealed that the dosage form is exposed to a wide range of fluid velocities and shear forces during the test. The hydrodynamic conditions in the compendial device are highly variable and cannot be controlled. A new, modified disintegration test device based on computerized numerical control (CNC) technique was developed. The modified device can be moved in all three dimensions and radial movement is also possible. Simple and complex moving profiles can be developed and the influence of the hydrodynamic conditions on oral solid dosage form performance can be evaluated. Furthermore, a modified basket was designed that allows two-sided fluid flow. CFD simulations of the hydrodynamics and forces in the modified device revealed significant differences in the fluid flow field and forces when compared to the compendial device. Due to the CNC technique moving velocity and direction are arbitrary and hydrodynamics become controllable. The modified disintegration test device was utilized to examine the influence of moving velocity on disintegration times of IR tablets. Insights into the influence of moving speed, medium viscosity and basket design on disintegration times were obtained. An exponential relationship between moving velocity of the modified basket and disintegration times was established in simulated gastric fluid. The same relationship was found between the disintegration times and the CFD predicted average shear stress on the tablet surface. Furthermore, a GRDDS was developed based on the approach of an in situ polyelectrolyte complex (PEC). Different complexes composed of different grades of chitosan and carrageenan and different ratios of those were investigated for their swelling behavior, mechanical stability, and in vitro drug release. With an optimized formulation the influence of changing hydrodynamic conditions on the swelling behavior and the drug release profile was demonstrated using the modified disintegration test device. Both, swelling behavior and drug release, were largely dependent on the hydrodynamic conditions. Concluding, it has been shown within this thesis that the application of the modified disintegration test device allows for detailed insights into the influence of hydrodynamic conditions on solid oral dosage form disintegration and dissolution. By the application of appropriate test conditions, the predictive power of in vitro disintegration testing can be improved using the modified disintegration test device. Furthermore, CFD has proven a powerful tool to examine the hydrodynamics and forces in the compendial as well as in the modified disintegration test device. rn

A method for automated generation of radiotherapy treatment plans for lung cancer

La radioterapia è una tecnica molto impiegata per la cura del cancro. Attualmente la somministrazione avviene principalmente attraverso la intensity modulated radiotherapy (IMRT, sovrapposizione di campi ad intensità modulata), un cui sviluppo recente è la volumetric modulated arc therapy (VMAT, irradiazione continua lungo un arco ininterrotto). La generazione di piani richiede esperienza ed abilità: un dosimetrista seleziona cost functions ed obiettivi ed un TPS ottimizza la disposizione dei segmenti ad intensità modulata. Se il medico giudica il risultato non soddisfacente, il processo riparte da capo (trial-and-error). Una alternativa è la generazione automatica di piani. Erasmus-iCycle, software prodotto presso ErasmusMC (Rotterdam, The Netherlands), è un algoritmo di ottimizzazione multicriteriale di piani radioterapici per ottimizzazione di intensità basato su una wish list. L'output consiste di piani Pareto-ottimali ad intensità modulata. La generazione automatica garantisce maggiore coerenza e qualità più elevata con tempi di lavoro ridotti. Nello studio, una procedura di generazione automatica di piani con modalità VMAT è stata sviluppata e valutata per carcinoma polmonare. Una wish list è stata generata attraverso una procedura iterativa su un gruppo ristretto di pazienti con la collaborazione di fisici medici ed oncologi e poi validata su un gruppo più ampio di pazienti. Nella grande maggioranza dei casi, i piani automatici sono stati giudicati dagli oncologi migliori rispetto ai rispettivi piani IMRT clinici generati manualmente. Solo in pochi casi una rapida calibrazione manuale specifica per il paziente si è resa necessaria per soddisfare tutti i requisiti clinici. Per un sottogruppo di pazienti si è mostrato che la qualità dei piani VMAT automatici era equivalente o superiore rispetto ai piani VMAT generati manualmente da un dosimetrista esperto. Complessivamente, si è dimostrata la possibilità di generare piani radioterapici VMAT ad alta qualità automaticamente, con interazione umana minima. L'introduzione clinica della procedura automatica presso ErasmusMC è iniziata (ottobre 2015).

Radiotherapy with scanning carbon ion beams: biological dose analysis for partial treatment delivery

L’uso di particelle cariche pesanti in radioterapia prende il nome di adroterapia. L’adroterapia permette l’irraggiamento di un volume bersaglio minimizzando il danno ai tessuti sani circostanti rispetto alla radioterapia tradizionale a raggi X. Le proprietà radiobiologiche degli ioni carbonio rappresentano un problema per i modelli radiobiologici a causa della non linearità della loro efficacia biologica. In questa tesi presenteremo gli algoritmi che possono essere usati per calcolare la dose fisica e biologica per un piano di trattamento del CNAO (Centro Nazionale Adroterapia Oncologica). Un caso di particolare interesse è l’eventualità che un piano di trattamento venga interrotto prima del dovuto. A causa della non linearità della sopravvivenza cellulare al variare della quantità di dose ricevuta giornalmente, è necessario studiare gli effetti degli irraggiamenti parziali utilizzando algoritmi che tengano conto delle tante variabili che caratterizzano sia i fasci di ioni che i tessuti irraggiati. Nell'ambito di questa tesi, appositi algoritmi in MATLAB sono stati sviluppati e implementati per confrontare la dose biologica e fisica assorbita nei casi di trattamento parziale.

Quantitative analysis of extracapsular extension of metastatic lymph nodes and its significance in radiotherapy planning in head and neck squamous cell carcinoma

We performed a histopathologic analysis to assess the extent of the extracapsular extension (ECE) beyond the capsule of metastatic lymph nodes (LN) in head and neck cancer to determine appropriate clinical target volume (CTV) expansions.

Intensity-modulated radiotherapy for a rendu-osler-weber disease patient with recurrent severe epistaxis: a case report

We present a case of a Rendu-Osler-Weber disease patient with recurrent life threatening epistaxis demanding multiple blood transfusions despite of repetitive endoscopic laser and electrocoagulations, endovascular embolisation, septodermoplasty, and long-term intranasal dressings. As alternative treatment modalities repeatedly failed and the patient became almost permanently dependent on nasal dressing, we performed a highly conformal intensity-modulated radiotherapy of the nasal cavity; a total dose of 50 Gy in 2 Gy single fractions was applied. The therapy was very well tolerated, no acute toxicities occurred. Two weeks after the last radiation dose had been applied, the nasal dressing could be removed without problems. Endoscopical control revealed an almost avascular white mucosa without any trace of bleeding spots; previously existing hemangiomas and crusts had disappeared. After a 1-year-follow up, the patient had no significant recurrent epistaxis.

Concomitant Cisplatin and Hyperfractionated Radiotherapy in Locally Advanced Head and Neck Cancer: 10-Year Follow-up of a Randomized Phase III Trial (SAKK 10/94)

To compare the long-term outcome of treatment with concomitant cisplatin and hyperfractionated radiotherapy versus treatment with hyperfractionated radiotherapy alone in patients with locally advanced head and neck cancer.

Preliminary Experience in Treatment of Papillary and Macular Retinoblastoma: Evaluation of Local Control and Local Complications After Treatment with Linear Accelerator-Based Stereotactic Radiotherapy with Micromultileaf Collimator as Second-Line or Salvage Treatment after chemotherapy

To determine the local control and complication rates for children with papillary and/or macular retinoblastoma progressing after chemotherapy and undergoing stereotactic radiotherapy (SRT) with a micromultileaf collimator.