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Falco, Cristina (2015) Exploring the Relationship between Ageing and Cancer: from Translational to Clinical Research. [Ph.D. thesis]

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Abstract (english)

A better understanding of the physiological and functional changes that occur with aging will enable to improve strategies for treating elderly cancer patients. For istance, hemathological toxicity is a major obstacle to the administration of chemotherapy in elderly cancer patients and ageing per sé is a major risk factor for cancer development, but the age-related impairment of immune system has never been studied in cancer patients.
For this reason, the present Doctoral Course has been committed to provide the first description of immune senescence observed in cancer patients. In the context of a prospective, exploratory study, TREC levels, subsets of peripheral naïve/memory T-cells and peripheral cell telomere length have been detected in elderly cancer patients and in age-matched controls.
A further critical issue of geriatric oncology is to uncover clinical problems that may impair the potential benefits and tolerability of anticancer treatments (Balducci, 2003; Extermann, 2003).
Recently, the International Society of Geriatric Oncology released a position paper where the obligatory integration of a comparable form of geriatric assessment is strongly recommended in future studies (Wildiers, 2013). The Multidimensional Prognostic Index (MPI) has been developed from a complete CGA and, differently from it, MPI may be administered and scored in a consistent manner. In order to answer this prioritary issue of geriatric oncology, the second project of this doctoral research program has been devoted to validate the MPI in patients with advanced cancer (Pilotto, 2008) to predict the 6 and 12-months overall mortality risk. In addition to estimate the tumor-independent survival, a CGA is essential when planning a cancer treatment as it uncovers medical conditions that may worsen the chemotherapy toxicity reported in clinical trials involving younger patients (Balducci, 2007). Despite there is strong evidence that any treatment decision in elderly cancer patients should be supported by a CGA, this is still performed in less than 10% of cancer centers because it is highly time-consuming. For this reason various author attempted to summarize the complete CGA in shorter versions. Among these screening tests, the Vulnerable Elders Survey (VES-13), a simple 13-item questionnaire has good sensitivity and acceptable specificity (Luciani, 2010) in comparison with a full CGA, but there is not consistent medical literature regarding its ability to predict chemotherapy toxicity. Therefore, the third chapter of the present Doctoral Research Program reports a joint analysis of 4 prospective studies that evaluated the accuracy of VES-13 in predicting the risk of high grade toxicity in elderly patients undergoing chemotherapy.
Immunesenescence and Cancer. Fifty-two elderly patients with breast or colorectal cancer and 39 age-matched controls without personal history of cancer were enrolled. All patients underwent a Comprehensive Geriatric Assessment (CGA), from which a multidimensional prognostic index (MPI) score was calculated. Peripheral blood samples were collected at the time of enrollment, prior to any oncological medical treatment (endocrine therapy, chemo- therapy, radiotherapy or immune therapy). Peripheral blood samples were studied for naïve and recent thymic emigrant (RTE) CD4+ and C8+ cells by flow cytometry. T-cell receptor rearrangement excision circle (TREC) levels, telomere length and telomerase activity in peripheral blood cells were quantified by real-time PCR. In addition to descriptive analysis through Mann–Whitney U test and Student's t-test, correlations between age and TREC levels, or telomere length in both groups were analyzed with Pearson's χ2 test. TREC levels and telomere length were also analyzed as dichotomous variables (cut-off: ≤median) and Odd Ratios were estimated with a logistic regression model.
Validation of MPI in Cancer Patients. Patients aged 70 yrs and older with a recently-diagnosed metastatic or inoperable cancer were enrolled and received a complete CGA including functional state, comorbidity, cognitive and humoral state, nutritional state, risk of pressure scores, social aspect and medications. The MPI score was calculated for each patient from the results of the various tests (ADL, IADL, SPMSQ, CIRS-CI, MNA, ESS, number of drugs, and social conditions), as reported elsewhere by Pilotto et al (Pilotto, 2007).
Statistical Analysis. The associations between 6- or 12-months mortality and the MPI scores, was analyzed using a Cox’s proportional hazards regression model adjusted for age and gender. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated to estimate the strength of the associations. The discriminatory power of the mortality model at 6 and 12 months of follow-up was assessed by calculating the area under the ROC curves for the MPI (considered as a continuous variable) using logistic regression models.
VES-13 to predict chemotherapy toxicity. The study involved patients aged >70 years with a diagnosis of a solid or hematological tumor. All Patients were administered VES-13. For all patients number of medications, comorbidities, CIRS-G score and index, type of chemotherapy, line of treatment, MMSE and MNA scores were recorded. Grade 3-4 hematological and non hematological toxicities were avaibile for all patients. Regression analysis was performed.
Immunesenescence and Cancer. The percentages of CD8+ naïve and CD8+ RTE cells and TREC levels were significantly lower in cancer patients than in controls (p = 0.003, p = 0.004, p = 0.031, respectively). Telomere lengths in peripheral blood cells were significantly shorter in cancer patients than in controls (p = 0.046) and did not correlate with age in patients, whereas it did in controls (r = −0.354, p = 0.031). Short telomere (≤median)/low TREC (≤median) profile was associated with higher risk of cancer (OR = 3.68 [95% CI 1.22–11.11]; p = 0.021). Neither unfitness on CGA nor MPI score were significantly related to thymic output or telomere length in either group.
Validation of MPI in Cancer Patients. A hundred and sixty patients entered the study. The MPI-related hazard ratios were higher at 6 months of follow-up than at 12 months, a high MPI being associated with a HR of 8.094 (95% CI 3.749-17.475, p<0.0001) at 6 months as opposed to 5.655 (95% CI 2.866-11.158, p<0.0001) at 12 months. When the MPI was considered as a continuous variable, any increase by 0.2 units (corresponding to the lower quartile) was associated with a 2.347-fold increase in the mortality risk (95% CI=1.838-2.997) at 6 months and a 2.051-fold increase (95% CI=1.662-2.531) at 12 months. The discriminatory power of the MPI’s predictive performance was statistically significant.
The age- and sex-adjusted area under the ROC curve for MPI score at 6 and 12 months of follow-up were 0.81 (95% CI, 0.74-0.88) and 0.78 (95% CI, 0.71-0.85), respectively.
VES-13 to predict chemotherapy toxicity. 648 patients aged ≥ 66 years old were included, mean age was 76.2 years (SD 4.5, 66 to 90), 336 (51.9%) were female. VES-13 identified 287 of the patients (44.3%) as vulnerable. Grade 3-4 hematological and non-hematological toxicities were more prevalent in the vulnerable subjects (35.2% vs 20.8%, p <0.0001, and 18.5% vs 10.8%, p = 0.0055). Vulnerable patients (OR) had a higher risk of hematological and non hematological toxicity with an OR 2.15, (95% CI 1.46-3.17; p<0.001) and 1.66 (95% CI 1.02-2.72; p = 0.043) respectively.
The study of Immunesenescence provided the first evidence that elderly cancer patients seemed to suffer from a more severe decline in thymic output and had a lower proportion of naïve CD8+ cells than age-matched controls. In addition, cancer patients had significantly shorter telomeres in their peripheral blood cells than age-matched non-cancer patients. This result suggests the unpublished hypothesis – which would need to be tested in a larger study - that elderly people with shorter telomeres are at higher risk of developing cancer. If confirmed, thymic output and telomere length could be widely used in elderly general population to easily identify subjects who run an higher risk of developing cancer and optimize the resources for screening procedures.
The second trial was the first to validate MPI in the oncological setting. The MPI retained in elderly patients with advanced cancer the same reliability and accuracy as reported in the original study by Pilotto et al. The results also suggested the possibility of creating a new, better-performing version of MPI by integrating it with the comorbidity severity index and the geriatric depression scale.
In the third study the patients identified as vulnerable by the VES-13 had a statistically significant higher risk of developing both hematological and non-hematological toxicity. These risk increases progressively with the aging of the population, particularly for haematological toxicity.
With the awareness that geriatric assessment of cancer patients cannot relies on a single test, future studies should be planned with the aim of prospectively identifying which is the most appropriate geriatric instrument for any single aspect of patient management (e.g. toxicity, overall survival, active life expectancy, or the quality of life) and clinical research

Abstract (italian)

Nonostante i casi di neoplasie solide nell’anziano siano in aumento, da decenni gli anziani sono sistematicamente esclusi dagli studi clinici in oncologia e questo implica una notevole difficoltà per gli oncologi a trasferire ai pazienti ultrasettantenni i risultati delle ricerche terapeutiche oncologiche.
Solo una migliore conoscenza delle modificazioni fisiologiche e funzionali che si accompagnano all’invecchiamento consentirebbe di migliorare le strategie di trattamento dei pazienti anziani con tumore. In particolare, nonostante la tossicità ematologica rappresenti il principale ostacolo alla somministrazione di chemioterapia e l’età avanzata sia di per sé un fattore di rischio per l’oncogenesi, non esiste in letteratura alcuno studio che abbia affrontato l’immunosenescenza nel paziente oncologico anziano. Perciò, parte considerevole dell’attività di ricerca svolta nel presente programma di Dottorato è stata dedicata ad uno studio prospettico di ricerca translazionale che ha confrontato l’output timico (livelli di T-cell receptor rearrangement excision circle – TREC- e subset di cellule T naïve e memoria) e la lunghezza dei telomeri in sangue periferico in una coorte di pazienti ultrasettantenni con diagnosi di neoplasia mammaria o colorettale con quelli riportati in anziani di pari età senza anamnesi personale di neoplasia.
Un’altra criticità dell’Oncologia Geriatrica è quella di standardizzare la valutazione geriatrica multidimensionale (CGA), strumento fondamentale per identificare possibili ostacoli all’efficacia ed alla tollerabilità dei trattamenti oncologici, per poterla utilizzare negli studi clinici.
Per rispondere a tale richiesta il secondo progetto di questo programma di Dottorato è stato finalizzato a validare per la prima volta nel setting oncologico il Multidimensional Prognostic Index (MPI), uno strumento codificato che deriva dalla CGA tradizionale. Nell’ambito di uno studio di Ricerca Ministeriale Finalizzata è stata valutata la capacità del MPI di predire la mortalità a 6 e 12 mesi in una coorte di pazienti anziani con neoplasia solida avanzata.
Terza priorità dell’oncologia geriatrica è di diffondere maggiormente l’uso della valutazione geriatrica. Attualmente infatti meno del 10% dei centri oncologici applica la CGA, che richiede oltre 2 ore a paziente per la corretta esecuzione, mentre invece qualsiasi scelta terapeutica nel paziente anziano dovrebbe tenere conto di una CGA basale, anche allo scopo di identificare i pazienti a rischio di tossicità da chemioterapia. Per risolvere questa criticità negli ultimi anni sono stati introdotti dei test di screening fnializzati ad identificare i pazienti che meritano una valutazione geriatrica. Tra questi, la Vulnerable Elders Survey – 13 (VES-13) presenta una buona sensibilità e specificità rispetto alla CGA completa ma non era mai stata testata per predire la tossicità da chemioterapia. Pertanto, nel terzo studio riportato nella presente tesi sono stati analizzati i risultati di 4 studi prospettici che hanno valutato l’accuratezza della VES-13 nel predire il rischio di tossicità di alto grado in pazienti oncologici anziani in trattamento antiblatico.
Immunesenescenza e Cancro. Cinquantadue pazienti con neoplasia mammaria o colorettale in stadio I-III e 39 controlli senza storia personale di tumore e di pari età sono stati arruolati nel presente studio e sottoposti inizialmente a CGA. Dopo la chirurgia e prima di iniziare qualsiasi trattamento medico adiuvante è stato prelevato sangue periferico per la determinazione citofluorimetrica di CD4+ and C8+ naïve e memoria e per la determinazione in real-time PCR dei livelli di TREC, della lunghezza dei telomeri nelle cellule periferiche e dell’attività telomerasica.
Validazione del MPI in pazienti oncologici. Pazienti ultrasettantenni e con recente diagnosi di neoplasia solida metastatica o inoperabile sono stati arruolati e sottoposti ad una CGA completa, comprendente lo stato funzionale, cognitive, umorale, le comorbidità, le medicazioni a domicilio, lo stato nutrizionale, il rischio di piaghe da decubito, gli aspetti sociali, da cui è stato calcolato il MPI come riportato da Pilotto et al (Pilotto, 2007). Per definire il valore prognostico di MPI sono stati utilizzati modelli di regressione Cox aggiustati per età e genere. Sono state inoltre calcolate le curve ROC attraverso modelli di regression logistica.
VES-13 e rischio di tossicità da chemioterapia. Quest’analisi combinata ha coinvolto pazienti ultrasettantenni con diagnosi di neoplasia solida o ematologica. Tutti i pazienti hanno compilato il questionario VES-13. Sono stati riportati infine I dati relative al tipo di chemioterapia ricevuta, la linea di trattamento, la tossicità ematologica e non ematologica di grado 3-4 secondo I common toxicity criteria for adverse events (CTCAE). A questi dati è stata applicata un’analisi di regressione.
Immunosenescenza e Cancro. La percentuale di cellule CD8+ naïve, CD8+ RTE ed i livelli di TREC sono risultati significativamente più bassi nei pazienti oncologici rispetto ai controlli (p = 0.003, p = 0.004, p = 0.031, rispettivamente). La lunghezza dei telomeri nelle cellule di sangue periferico era significativamente inferiore nei pazienti oncologici rispetto ai controlli (p = 0.046) e non correlava con l’età, come avveniva invece nei controlli (r = −0.354, p = 0.031). Il profilo con telomero corto (inferiori alla mediana) e bassi livelli di TREC (inferiori alla mediana) era significativamente associato con la diagnosi di neoplasia (OR = 3.68 [95% CI 1.22–11.11]; p = 0.021) mentre non vi era alcuna correlazione tra l’esito della CGA ed il punteggio MPI da un lato ed i marcatori di immunosenescenza dall’altro in entrambi i gruppi.
Validazione del MPI in pazienti oncologici. Lo studio ha coinvolto 160 pazienti. Gli hazard ratio correlati a MPI sfavorevole sono risultati significativamente più alti per la mortalità a 6 mesi rispetto a 12 mesi, più precisamente 8.094 (95% CI 3.749-17.475, p<0.0001) a 6 mesi e 5.655 (95% CI 2.866-11.158, p<0.0001) a 12 mesi. Quando MPI è stato valutato come una variabile continua, ogni incremento di 0.2 unità era associato ad un aumento di 2.347-volte del rischio di mortalità (95% CI=1.838-2.997) a 6 mesi e 2.051-volte (95% CI=1.662-2.531) a 12 mesi. Il valore prognostico di MPI è risultato statisticamente significativo. L’area delle curve ROC a 6 e 12 mesi, aggiustate per genere ed età era 0.81 (95% CI, 0.74-0.88) e 0.78 (95% CI, 0.71-0.85), rispettivamente.
VES-13 e rischio di tossicità da chemioterapia. Seicentoquarantotto pazienti di età ≥ 66 anni sono stati considerati nella presente analisi. Attraverso la VES-13 sono stati identificati 287 pazienti vulnerabili. Gli eventi di tossicità ematologica e non ematologica di grado 3-4 sono risultati prevalenti nei soggetti vulnerabili (35.2% vs 20.8%, p <0.0001, e 18.5% vs 10.8%, p = 0.0055). Gli odd ratios per la tossicità ematologica e non ematologica nei pazienti vulnerabili sono risultati pari a 2.15, (95% CI 1.46-3.17; p<0.001) e 1.66 (95% CI 1.02-2.72; p = 0.043) rispettivamente.
Lo studio sull’immunosenescenza e cancro ha fornito la prima evidenza che i pazienti anziani oncologici, rispetto ai controlli sani, presentano una severa riduzione dell’output timico e della lunghezza dei telomeri in cellule di sangue periferico. Tali risultati suggeriscono l’ipotesi che i soggetti anziani con sistema immunitario senescente e telomeri più corti abbiano un rischio più alto di sviluppare neoplasie. Se tale associazione fosse confermata in una popolazione più ampia, i marcatori di immunosenescenza potrebbero essere impiegati per identificare gli anziani a rischio più elevato di neoplasia, sui quali concentrare le risorse per la diagnosi precoce.
Il secondo studio riportato è stato il primo a dimostrare che nei pazienti oncologici MPI mantiene il suo valore prognostico, con la stessa affidabilità ed accuratezza riportate nello studio originale di Pilotto et al. I risultati dello studio suggeriscono infine la possibilità di migliorare le prestazioni di MPI in oncologia integrandolo con l’indice di comorbidità e lo stato umorale.
Il terzo studio ha dimostrato che i pazienti giudicati vulnerabili alla VES-13 hanno un rischio significativamente più alto di sviluppare tossicità ematologica e non ematologica di alto grado. Tale rischio aumenta progressivamente con l’età, soprattutto per la tossicità eamtologica.
Con la consapevolezza che la valutazione geriatrica del paziente oncologico anziano non può essere esaustivamente svolta con un unico test, ulteriori studi dovranno essere condotti per identificare i test più appropriati per altri aspetti rilevanti per la gestione del paziente con neoplasia, ovvero la l’aspettativa di vita tumore-indipendente e la qualità di vita. Parallelamente vi è la necessità di studiare il processo di invecchiamento nell’anziano oncologico per identificare dei marcatori molecolari di età biologica, che guidino in maniera oggettiva la scelta terapeutica in questa popolazione

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EPrint type:Ph.D. thesis
Tutor:Manzato, Enzo
Data di deposito della tesi:28 January 2015
Anno di Pubblicazione:28 January 2015
Key Words:Senescenza, oncogenesi, rischio, mortalità, tossicità; ageing, cancer, risk, mortality, toxicity
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/06 Oncologia medica
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze Cardiologiche, Toraciche e Vascolari
Codice ID:7671
Depositato il:09 Nov 2015 11:36
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