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The majority of patients with glioblastoma (GBM) experience disease progression. At recurrence, treatment options have limited efficacy. Many studies report a limited and short duration response rate. Although clinical trials represent the "gold standard" for providing evidence on efficacy of specific treatment strategies, real-world data can be considered more representative of the "real" GBM population.To describe the management of GBM recurrence in a large real-world sample.We analysed retrospectively the data stored in the database of the Neuro-oncology Unit, IRCCS "Regina Elena" National Cancer Institute, Rome, Italy. We considered only data of patients with histological diagnosis of GBM and disease recurrence during their follow-up. We excluded patients who did not receive treatment after the diagnosis.We analysed 422 patients (64% males, 36% females) with a mean age of 59.6 (range 16-87) years. At GBM recurrence, 135 (32.0%) patients underwent palliative care, and 287 (68.0%) underwent other treatments. Patients on palliative care were older, had a worse performance status, and a shorter time between GBM diagnosis and its recurrence. Patients who received chemotherapy in combination with other treatments (surgery and/or radiation therapy) at GBM recurrence had a longer survival than those in palliative care (p 0.001). Surgery or radiation therapy alone did not have any effect on survival as compared with palliative care (p 0.001).This study confirms the importance of a multidisciplinary approach even at GBM recurrence, suggesting that combination treatments play a key role in management of disease.

Malignant gliomas are brain tumors with dismal prognosis that can affect patients’ neurocognitive status. We performed longitudinal neuropsychological assessments to describe variations due to illness progression and treatment administration. Patients underwent a battery of standardized neuropsychological tests tapping into different cognitive domains (memory, attention, abstract reasoning, executive functions, learning), pre-radiotherapy and at 6, 12 and 24 month follow-up. We enrolled 130 patients, and almost 70% of them had at least one cognitive deficit. The most affected domains were executive function and long- and short-term memory. At follow-up assessments, cognitive status worsened in one-third of patients, whereas it remained unchanged or improved in two-thirds of patients. This is one of few longitudinal studies investigating cognitive function in a large sample of patients to monitor changes along the illness course.

The aim of this paper is to define the pre-treatment radiological characteristics of oropharyngeal squamous cell carcinoma (OPSCC) using morphological and non-morphological magnetic resonance imaging (MRI), based on HPV status, in a single-institution cohort. In total, 100 patients affected by OPSCC were prospectively enrolled in the present study. All patients underwent 1.5T MR with standard sequences, including diffusion-weighted imaging with and intravoxel incoherent motion (IVIM-DWI) technique and a dynamic contrast-enhanced (DCE) MRI. For all patients, human papillomavirus (HPV) status was available. No statistically significant differences in the volume of primary tumors (PTs) and lymph nodes (LNs) were observed based on HPV status. When comparing the two patient groups, no significant differences were found for the PT radiologic characteristics (presence of well-defined borders, exophytic growth, ulceration, and necrosis) and LN morphology (solid/cystic/necrotic). Tumor subsite, smoking status, and alcohol intake significantly differed based on HPV status, as well as ADC and Dt values of both PTs and LNs. We detected no significant difference in DCE-MRI parameters by HPV status. Based on a multivariate logistic regression model, the combination of clinical factors, such as tumor subsite and alcohol habits, with the perfusion-free diffusion coefficient Dt of LNs, may help to accurately discriminate OPSCC by HPV status.

The prognosis of a subset of patients with locally advanced oropharyngeal cancer (LA-OPC) is still poor despite improvements in patient selection and treatment. Identifying specific patient- and tumor-related factors can help to select those patients who need intensified treatment. We aimed to assess the role of historical risk factors and novel magnetic resonance imaging (MRI) biomarkers in predicting outcomes in these patients. Patients diagnosed with LA-OPC were studied with diffusion-weighted imaging (DWI) and dynamic-contrast enhanced MRI at baseline and at the 10th radiotherapy (RT) fraction. Clinical information was collected as well. The endpoint of the study was the development of disease progression, locally or distantly. Of the 97 patients enrolled, 68 were eligible for analysis. Disease progression was recorded in 21 patients (11 had loco-regional progression, 10 developed distant metastases). We found a correlation between N diameter and disease control (p = 0.02); features such as p16 status and extranodal extension only showed a trend towards statistical significance. Among perfusion MRI features, higher median values of Kep both in primary tumor (T, p = 0.016) and lymph node (N, p = 0.003) and lower median values of ve (p = 0.018 in T, p = 0.004 in N) correlated with better disease control. Kep P90 and N diameter were identified by MRMR algorithm as the best predictors of outcome. In conclusion, the association of non-invasive MRI biomarkers and patients and tumor characteristics may help in predicting disease behavior and patient outcomes in order to ensure a more customized treatment.

Cachexia is a complex metabolic syndrome that determines a severe body weight loss characterized by a marked reduction in muscle mass. About 80% of patients with advanced cancer develop cachexia due to both the tumor itself and cancer treatment (radiotherapy and/or chemotherapy), which is associated to a worse prognosis. Despite its clinical relevance, this syndrome is still under-diagnosed and it lacks effective treatments. Radio-chemotherapy treatment is essential in patients with advanced head and neck cancers (HNSCC). Although this treatment has improved patients’ life expectancy, it has also dramatically increased their need for assistance and support. The management of adverse symptoms, including cachexia, is of great importance in order to avoid delays in therapy, reduction of dosages and hospitalizations. MicroRNAs (miRNAs) are small non-coding RNA molecules, which have emerged as powerful biomarkers in stratifying human cancers. Due to their high stability in body fluids, miRNAs might be excellent non-invasive biomarkers for the early detection and follow-up of cancer patients. Here, we will summarize the current knowledge and debate the strong need to identify circulating biomarkers for the early diagnosis of cachexia. We will propose circulating non-coding RNAs as biomarkers for detecting early cachexia and implementing specific treatment. We will also discuss the potential use of circulating miRNAs as biomarkers of cachexia in HNSCC patients’ blood samples collected before and after radio-chemotherapy treatment. Our intent is to pave the way to the identification of specific circulating miRNAs associated to cachexia occurrence and to the design of specific interventions aimed at improving the quality of life of cancer patients.

Simple Summary In the present prospective study, we assessed the role of various Magnetic Resonance Imaging biomarkers combined with self-assessed xerostomia questionnaires and patient- and treatment-related factors, in predicting xerostomia at 12 months after chemoradiotherapy for oropharyngeal squamous cell carcinoma. We hypothesized that the integration of pre-treatment imaging biomarkers, which addresses the tissue heterogeneity and individual variations among patients, could improve the accuracy of conventional prediction models that are based only on dose information, ultimately providing a better understanding of the pathophysiological mechanisms underlying radiation induced salivary dysfunction. The implementation of multifactorial models, driven by machine learning algorithms, may improve prediction accuracy of radiation-induced toxicity and tailor individual treatment options for patients. Abstract The advent of quantitative imaging in personalized radiotherapy (RT) has offered the opportunity for a better understanding of individual variations in intrinsic radiosensitivity. We aimed to assess the role of magnetic resonance imaging (MRI) biomarkers, patient-related factors, and treatment-related factors in predicting xerostomia 12 months after RT (XER12) in patients affected by oropharyngeal squamous cell carcinoma (OSCC). Patients with locally advanced OSCC underwent diffusion-weighted imaging (DWI) and dynamic-contrast enhanced MRI at baseline; DWI was repeated at the 10th fraction of RT. The Radiation Therapy Oncology Group (RTOG) toxicity scale was used to evaluate salivary gland toxicity. Xerostomia-related questionnaires (XQs) were administered weekly during and after RT. RTOG toxicity ≥ grade 2 at XER12 was considered as endpoint to build prediction models. A Decision Tree classification learner was applied to build the prediction models following a five-fold cross-validation. Of the 89 patients enrolled, 63 were eligible for analysis. Thirty-six (57.1%) and 21 (33.3%) patients developed grade 1 and grade 2 XER12, respectively. Including only baseline variables, the model based on DCE-MRI and V65 (%) (volume of both glands receiving doses ≥ 65 Gy) had a fair accuracy (77%, 95% CI: 66.5–85.4%). The model based on V65 (%) and XQ-Intmid (integral of acute XQ scores from the start to the middle of RT) reached the best accuracy (81%, 95% CI: 71–88.7%). In conclusion, non-invasive biomarkers from DCE-MRI, in combination with dosimetric variables and self-assessed acute XQ scores during treatment may help predict grade 2 XER12 with a fair to good accuracy.

To investigate the predictive role of Intravoxel Incoherent Motion Diffusion-Weighted Imaging (IVIM-DWI) parameters on cervical nodal response to chemo-radiotherapy (CRT) of head and neck squamous cell carcinoma (HNSCC).Patients with pathologically confirmed HNSCC were included in the present prospective study, having at least one positive cervical lymph node (LN). They received concomitant CRT and underwent three serial IVIM-DWI investigations: before, at mid-treatment and after treatment completion. Tissue diffusion coefficient D, perfusion-related diffusion coefficient D* and perfusion fraction f were calculated by a bi-exponential fit. The two-sided Mann-Whitney rank test was used to compare the imaging parameters of patients with regional failure (RF) and regional control (RC). A p value lower than 0.05 was considered to be statistically significant.Thirty-four patients were accrued. Twenty-four out of 34 LN (70.6%) showed persistent RC after a median follow-up time of 27.6 months (range: 12.0-50.2 months), while ten cases of RF (29.4%) were confirmed with a median time of 6.8 months (range: 1.5-19.5 months). Patients with RC showed significantly lower pre-treatment D values compared to the RF patients (p=0.038). At mid-treatment, the patients with RF showed significantly higher D values (p=0.025), and exhibited larger percent reductions in f and the product D*×f from the baseline (p=0.008 and0.001, respectively). No additional information was provided by the examination at the end of treatment.Pre-treatment and mid-treatment IVIM-DWI showed potential for prediction of treatment response of cervical LN in HNSCC patients.

Background There is no widely accepted intervention in the prevention of acute mucositis during chemoradiotherapy for head and neck carcinoma. In the present double-blind study, we tested 4 natural agents, propolis, aloe vera, calendula, and chamomile versus placebo. Methods Patients undergoing concomitant chemo-intensity-modulated radiotherapy (IMRT) were given natural agent or matched placebo; grade 3 mucositis on physical examination according to Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 was the primary endpoint. Various covariates were tested at logistic regression, including the individual amount of mucosa receiving at least 9.5 Gy per week (V9.5w). Results One hundred seven patients were randomized from January 2011 to July 2014, and 104 were assessable (51%-49% were assigned to the placebo group and 53%-51% were assigned to the natural agent). Overall, 61 patients developed peak grade 3 mucositis with no difference between arms (P = .65). Conversely, V9.5w (P = .007) and primary site (P = .037) were independent predictors. Conclusion The selected natural agents do not prevent mucositis, whereas the role of V9.5w is confirmed.

To compare long-term late local toxicity after either concomitant or sequential chemoradiation therapy after breast-conserving surgery.From 1997 to 2002, women aged 18 to 75 years who underwent breast-conserving surgery and axillary dissection for early breast cancer and in whom CMF (cyclophosphamide, methotrexate, and 5-fluorouracil) chemotherapy was planned were randomized between concomitant and sequential radiation therapy. Radiation therapy was delivered to the whole breast through tangential fields to 50 Gy in 20 fractions over a period of 4 weeks, followed by an electron boost. Surviving patients were tentatively contacted and examined between March and September 2014. Patients in whom progressive disease had developed or who had undergone further breast surgery were excluded. Local toxicity (fibrosis, telangiectasia, and breast atrophy or retraction) was scored blindly to the treatment received. A logistic regression was run to investigate the effect of treatment sequence after correction for several patient-, treatment-, and tumor-related covariates on selected endpoints. The median time to cross-sectional analysis was 15.7 years (range, 12.0-17.8 years).Of 206 patients randomized, 154 (74.8%) were potentially eligible. Of these, 43 (27.9%) refused participation and 4 (2.6%) had been lost to follow-up, and for 5 (3.2%), we could not restore planning data; thus, the final number of analyzed patients was 102. No grade 4 toxicity had been observed, whereas the number of grade 3 toxicity events was low (8%) for each item, allowing pooling of grade 2 and 3 events for further analysis. Treatment sequence (concomitant vs sequential) was an independent predictor of grade 2 or 3 fibrosis according to both the National Cancer Institute Common Terminology Criteria for Adverse Events (odds ratio [OR], 4.05; 95% confidence interval [CI], 1.34-12.2; P=.013) and the SOMA (Subjective, Objective, Management and Analytic) scale (OR, 3.75; 95% CI, 1.19-11.79; P=.018), as well as grade 2 or 3 breast atrophy or retraction (OR, 3.87; 95% CI, 1.42-10.56; P=.008). No effect on telangiectasia was detected.At long-term follow-up, concomitant chemoradiation therapy has a detrimental effect on both fibrosis and retraction with an approximately 4-fold increase in the odds of grade 2 or 3 toxicity.

Obiettivo dello studio è stato quello di valutare la sicurezza, l’efficacia e i risultati funzionali della radioterapia intraoperatoria (IORT) seguita dalla radioterapia a intensità modulata (IMRT) nel trattamento di tumori maligni avanzati estesi all’orecchio medio. Sono stati inclusi nello studio in modo retrospettivo 13 pazienti consecutive affetti da tumore dell’orecchio esterno esteso all’orecchio medio. Il follow-up è stato in media di 33 mesi (range 6-133). Cinque pazienti (38%) erano di stadio III e 8 pazienti (62%) erano di stadio IV secondo la classificazione dell’Università di Pittsburgh. Una petrosectomia laterale (LTBR) è stata eseguita in tutti i pazienti, la LTBR è stata associata a parotidectomia in 5 (38%) casi e a svuotamento latero-cervicale associato a parotidectomia in 6 (46%) casi. In tutti i casi si è effettuata asportazione della malattia macroscopicamente evidente. Il trattamento chirurgico è stato completato da IORT (12 Gy) e IMRT (50Gy). Chemioterapia adiuvante è stata eseguita in 4 (30%) casi. Test audiometrici pre- e post-operatori sono stati eseguiti per valutare la perdita uditiva. Il tasso di controllo di malattia locale (LC) a 5 anni, di metastasi a distanza (DM) a 5 anni, la sopravvivenza libera da malattia (DFS) e la sopravvivenza globale (OS) a 5 anni sono state calcolate con il metodo di Kaplan-Meyer. Variazioni significative nella conduzione per via ossea sono state osservate dopo trattamento. Una necrosi parziale del lembo di ricostruzione è stata l’unica complicanza precoce osservata in 3(23%) casi, mentre una fistola meningea è stata osservata in un solo caso (7,6%) come complicanza tardiva. Il tasso di LC è stato del 68%. Il tasso di DM è stato del 90%. Il tasso di DFS è stato del 61%. Il tasso di OS è stato del 69%. La IORT seguita dalla IMRT nel trattamento dei tumori maligni avanzati dell’orecchio esterno e medio sembra essere sicuro. Nel nostro studio non sono riportati morti. La IORT può ridurre la dose di radioterapia postoperatoria a livello del tessuto residuo ottenendo la medesima dose a livello della sede del tumore. Non abbiamo osservato alcuna complicanza a livello dell’orecchio esterno residuo, mentre si è notato un peggioramento dell’udito anche a livello neurosensoriale. Sono necessari studi prospettici al fine di confermare quanto da noi osservato.

Background Functional magnetic resonance imaging may provide several quantitative indices strictly related to distinctive tissue signatures with radiobiological relevance, such as tissue cellular density and vascular perfusion. The role of Intravoxel Incoherent Motion Diffusion Weighted Imaging (IVIM-DWI) and Dynamic Contrast-Enhanced (DCE) MRI in detecting/predicting radiation-induced volumetric changes of parotids both during and shortly after (chemo)radiotherapy of oropharyngeal squamous cell carcinoma (SCC) was explored. Methods Patients with locally advanced oropharyngeal SCC were accrued within a prospective study offering both IVIM-DWI and DCE-MRI at baseline; IVIM-DWI was repeated at the 10th fraction of treatment. Apparent diffusion coefficient (ADC), tissue diffusion coefficient Dt, perfusion fraction f and perfusion-related diffusion coefficient D* were estimated both at baseline and during RT. Semi-quantitative and quantitative parameters, including the transfer constant Ktrans, were calculated from DCE-MRI. Parotids were contoured on T2-weighted images at baseline, 10th fraction and 8th weeks after treatment end and the percent change of parotid volume between baseline/10th fr (∆Vol10fr) and baseline/8th wk. (∆Volpost) computed. Correlations among volumetric changes and patient-, treatment- and imaging-related features were investigated at univariate analysis (Spearman’s Rho). Results Eighty parotids (40 patients) were analyzed. Percent changes were 18.2 ± 10.7% and 31.3 ± 15.8% for ∆Vol10fr and ∆Volpost, respectively. Among baseline characteristics, ∆Vol10fr was correlated to body mass index, patient weight as well as the initial parotid volume. A weak correlation was present between parotid shrinkage after the first 2 weeks of treatment and dosimetric variables, while no association was found after radiotherapy. Percent changes of both ADC and Dt at the 10th fraction were also correlated to ∆Vol10fr. Significant relationships were found between ∆Volpost and baseline DCE-MRI parameters. Conclusions Both IVIM-DWI and DCE-MRI can help to detect/predict early (during treatment) and shortly after treatment completion the parotid shrinkage. They may contribute to clarify the correlations between volumetric changes of parotid glands and patient−/treatment-related variables by assessing individual microcapillary perfusion and tissue diffusivity. Electronic supplementary material The online version of this article (10.1186/s13014-018-1137-4) contains supplementary material, which is available to authorized users.

Objective To investigate the ability of neck ultrasounds (US), magnetic resonance imaging (MRI) and positron emission tomography (FDG-PET/TC) in detecting residual nodal disease after chemoradiotherapy in patients with advanced oropharyngeal squamous cell carcinoma (OPSCC). Methods From 2006 to 2009, 36 consecutive patients affected by OPSCC with bulky nodal disease (>3 cm), treated with primary concurrent chemoradiotherapy, were enrolled prospectively. Nodal response to treatment was assessed by using US, MRI and FDG-PET/CT. Planned neck dissection (ND) was performed in all the patients, and the histopathological node status was compared to the imaging findings in order to establish sensitivity, specificity, accuracy and predictive values of each technique. Results Metastatic disease was assessed in 18/37 (48.6%) hemi-necks, always localized in levels II–IV. US showed greater sensitivity (77.8%) and, combined with FDG-PET/TC, produced the highest negative predictive value (93.3%). US, MRI and FDG-PET/TC scans showed the highest specificity (100%), accuracy (93.8%) and positive predictive values (100%). Conclusions In the presence of advanced OPSCC with bulky nodal disease, US combined with FDG-PET/TC could be a reliable and cost-effective strategy to identify patients with complete nodal response to chemoradiotherapy that might not require post-treatment ND but only observation. When residual disease in the neck was detected, selective ND was recommended.

Purpose To investigate the potential of intravoxel incoherent motion (IVIM) MRI for early evaluation of irradiated major salivary glands. Materials and Methods Thirty-four patients with head-neck cancer were included in a prospective study. All patients underwent three serial IVIM-MRI: before, half-way through, and at the end of radiotherapy (RT). Apparent diffusion coefficient (ADC), ADClow derived in the low b-value range, perfusion fraction f, and pure diffusion coefficient D were estimated. Pretreatment values and early changes of diffusion parameters were correlated with parotid mean dose (Dmean) and volume reduction after RT. Results Changes in diffusion parameters over time were all significant (P < 0.001 for ADC, ADClow, and D, P = 0.003 for f). Variations of ADC, ADClow, and f were not correlated with Dmean (P = 0.089, P = 0.252 and P = 0.884, respectively), whereas a significant relationship was found between changes in D and Dmean (r = 0.197 with CI95% = 0.004–0.375, P = 0.046). Pretreatment f and Dmean were the best independent predictors for the percentage shrinkage (P = 0.0003 and 0.0597 respectively; R2 = 0.391). Conclusion Early changes of irradiated major salivary glands can be noninvasively evaluated by IVIM-MRI. Perfusion-related coefficients in conjunction with dosimetric information increase our capability to predict the change in parotid volume and hence, if further validated, guide treatment strategy in RT. J. Magn. Reson. Imaging 2015;41:974–982. © 2014 Wiley Periodicals, Inc.

Purpose To investigate the relationships between imaging parameters derived from intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) and HPV status in oropharyngeal squamous cell carcinoma (OPSCC). Materials and Methods 73 patients with a new diagnosis of OPSCC were enrolled in the present study. MRI including IVIM-DWI with nine b value (range 0–800 s/mm2) was acquired in all patients. Primary tumor (PT) and the largest metastatic lymph node (LN), if present, were volumetrically contoured and the tissue diffusion coefficient Dt, perfusion fraction f and perfusion-related diffusion coefficient D* were estimated by a bi-exponential fit. The apparent diffusion coefficient (ADC) was also estimated by a mono-exponential fit. The predictive power of the most relevant patient/tumor characteristics and image-based features in determining the HPV status was assessed. Results 67 PTs and 67 metastatic LNs were analyzed. Significant differences in ADC and Dt values among HPV-positive and HPV-negative patients were found for PTs (p = 0.003 and p Conclusion Significant correlations were found between IVIM-DWI and HPV status in OPSCCs. The perfusion-free diffusion coefficient, Dt, may better reflect the HPV-related tumor differences compared to ADC, whereas the perfusion-related parameters were not able to reliably discriminate HPV-positive from HPV-negative OPSCC.

There is no widely accepted intervention in the prevention of acute mucositis during chemoradiotherapy for head and neck carcinoma. In the present double-blind study, we tested 4 natural agents, propolis, aloe vera, calendula, and chamomile versus placebo.Patients undergoing concomitant chemo-intensity-modulated radiotherapy (IMRT) were given natural agent or matched placebo; grade 3 mucositis on physical examination according to Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 was the primary endpoint. Various covariates were tested at logistic regression, including the individual amount of mucosa receiving at least 9.5 Gy per week (V9.5w).One hundred seven patients were randomized from January 2011 to July 2014, and 104 were assessable (51%-49% were assigned to the placebo group and 53%-51% were assigned to the natural agent). Overall, 61 patients developed peak grade 3 mucositis with no difference between arms (P = .65). Conversely, V9.5w (P = .007) and primary site (P = .037) were independent predictors.The selected natural agents do not prevent mucositis, whereas the role of V9.5w is confirmed.

Purpose One of the worst radiation-induced acute effects in treating head-and-neck (HN) cancer is grade 3 or higher acute (oral and pharyngeal) mucosal toxicity (AMT), caused by the killing/depletion of mucosa cells. Here we aim to testing a predictive model of the AMT in HN cancer patients receiving different radiotherapy schedules. Methods and Materials Various radiotherapeutic schedules have been reviewed and classified as tolerable or intolerable based on AMT severity. A modified normal tissue complication probability (NTCP) model has been investigated to describe AMT data in radiotherapy regimens, both conventional and altered in dose and overall treatment time (OTT). We tested the hypothesis that such a model could also be applied to identify intolerable treatment and to predict AMT. This AMT NTCP model has been compared with other published predictive models to identify schedules that are either tolerable or intolerable. The area under the curve (AUC) was calculated for all models, assuming treatment tolerance as the gold standard. The correlation between AMT and the predicted toxicity rate was assessed by a Pearson correlation test. Results The AMT NTCP model was able to distinguish between acceptable and intolerable schedules among the data available for the study (AUC = 0.84, 95% confidence interval=0.75-0.92). In the equivalent dose at 2 Gy/fraction (EQD2) vs OTT space, the proposed model shows a trend similar to that of models proposed by other authors, but was superior in detecting some intolerable schedules. Moreover, it was able to predict the incidence of ≥G3 AMT. Conclusion The proposed model is able to predict ≥G3 AMT after HN cancer radiotherapy, and could be useful for designing altered/hypofractionated schedules to reduce the incidence of AMT.

Aims To quantify the changes in dose as well as in the prediction of parotid gland toxicity due to anatomical changes during therapy of head and neck cancer patients. Materials and methods Fifteen patients with advanced locoregional head and neck cancer, with no evidence of distant metastasis, were enrolled in a prospective study. All patients were treated with intensity-modulated radiotherapy. Multiple computed tomography scans were repeated at the end of each treatment week. The original treatment plans were copied to the per-treatment scans to create hybrid plans. The normal tissue complication probability (NTCP) was calculated assuming the end point to be grade ≥3 xerostomia according to the Radiation Therapy Oncology Group late toxicity scale. Results The gross tumour volume dose coverage was slightly affected by the anatomical changes, whereas the mean dose (D mean ) to the parotids changed from 26.1 ± 6.0 to 27.4 ± 7.4 Gy, with a mean increase of 0.22 Gy/treatment week. Consequently, the mean NTCP increased from 0.15 ± 0.06 to 0.18 ± 0.10, primarily due to a few patients exhibiting a marked increase. The absolute gross tumour volume shrinkage and the percentage parotids shrinkage were the best independent predictors for the NTCP variations. Conclusions On average, the increase in the parotids D mean as well as in NTCP during treatment is limited, and the observed variations were strongly patient-dependent.

Purpose To retrospectively compare survival in recurrent uveal melanoma, between patients treated by enucleation or by a second course of fractionated proton beam therapy (PBT). Methods and Materials Tumor recurrence was documented in 73 patients treated with PBT for uveal melanoma. Of the patients, 31 received a second course of PBT and 42 underwent enucleation. The mean patient age was 56 and 61 years for those undergoing enucleation and those undergoing reirradiation, respectively. Both primary and recurrent tumors were larger in patients undergoing enucleation. Tumor location and the presence or absence of ciliary body involvement did not differ significantly between the groups. The median follow-up after enucleation and after re-treatment was 79 and 59 months, respectively. Cumulative rates of outcomes and differences in rates between the reirradiated and enucleation groups were calculated by the Cox proportional hazards model and the log-rank test, respectively. Results The median survival duration in the enucleated and reirradiated groups was 42 and 90 months, respectively. The median time free of metastases was 38 months in enucleated patients and 97 months in reirradiated patients. At 5 years after enucleation and after reirradiation, the probability of overall survival was 36% and 63%, respectively ( p = 0.040, log-rank test); the probability of freedom from metastases was 31% and 66%, respectively ( p = 0.028, log-rank test). These differences persisted after adjustment for recurrent tumor largest diameter and volume at the time of reirradiation or enucleation. Conclusions This retrospective analysis suggests that survival in reirradiated patients is not compromised by administration of a second course of PBT for recurrent uveal melanoma.

Purpose To investigate the predictors of incidence and duration of xerostomia (XT) based on parotid glands (PG), submandibular glands (SMG), and both glands taken as a whole organ (TG) in head-and-neck cancer patients treated with intensity-modulated radiotherapy. Methods and Materials A prospective study was initiated in May 2003. Sixty-three head-and-neck patients (44 with nasopharynx cancer) were included in the analysis. Using the dose–volume histogram the PG, SMG, and TG mean doses were calculated. Unstimulated and stimulated salivary flow were measured and XT-related questionnaires were compiled before and at 3, 6, 12, 18, and 24 months after radiotherapy. Salivary gland toxicity was evaluated using the Radiation Therapy Oncology Group scale, and Grade ≥3 toxicity was used as the endpoint. The XT incidence was investigated according to descriptive statistics and univariate and multivariate analysis. The Bonferroni method was used for multiple comparison adjustment. Results After a reduced flow at 3 months after radiotherapy, recovery of salivary flow was observed over time. Primary site and salivary gland mean doses and volumes were identified in univariate analysis as prognostic factors. Multivariate analysis confirmed that TG mean dose ( p = 0.00066) and pretreatment stimulated salivary flow ( p = 0.00420) are independent factors for predicting XT. Conclusion The TG mean dose correlates with XT as assessed by Radiation Therapy Oncology Group criteria, salivary output, and XT-related questionnaires. Our results suggest that TG mean dose is a candidate dose constraint for reducing XT, requiring considerably more validation in non–nasopharyngeal cancer patients.

This is a retrospective study to evaluate the outcomes and complications of combined treatment, surgery with or without adjunctive intraoperative radiotherapy, of locally advanced temporal bone squamous cell carcinoma. A series of 17 patients with locally advanced squamous cell carcinoma of the temporal bone were treated between September 2002 and February 2007. Eleven patients had primary tumors, and 6 patients had recurrences. According to the University of Pittsburgh staging system, 5 patients were stage II (T2 N0), 6 patients were stage III (5, T3 N0 and 1, T1 N1), and 6 patients were stage IV (5, T3 N2b and 1, T4 N0). All patients underwent lateral temporal bone resection and pedicle flap reconstruction. Eight patients received intraoperative and postoperative radiotherapies, 4 patients underwent postoperative radiation alone, whereas 5 patients did not receive any adjunctive treatment. Median follow-up was 29.5 months. No major complications were observed. No patients were found to have residual gross tumor. Disease-free survival was 73.3%, and overall survival was 75.6%. Radical external auditory canal and/or middle ear canal resection is of utmost importance to obtain a good surgical outcome. Postoperative radiotherapy is necessary to obtain good local control; no major adverse effects were observed in the intraoperative radiotherapy patients. The incidence of major complication is minimal after pedicle flap reconstruction.

To investigate dose-volume effects of salivary flow and the functional recovery over time, using salivary function data and different models of normal tissue complication probability (NTCP).A total of 59 patients with head-and-neck cancer treated with intensity-modulated radiotherapy (IMRT) were analyzed in the present study. The toxicity was evaluated using the Radiation Therapy Oncology Group (RTOG) scale and salivary flows, both unstimulated (USF) and stimulated (SSF). The assessments were done before radiotherapy (RT) and at 3, 6, 12, 18, and 24 months after RT. Grade 3 toxicity was the primary endpoint. Analyses of toxicity incidence at 3, 6, and 12 months after RT were performed by both the Lyman-Kutcher-Burman (LKB) and relative seriality (S) models.A significant correlation was found between the incidence of Grade 3 toxicity and the incidence of patients with a reduction in SSF to25% of the pre-RT value. Better correlations resulted between the RTOG toxicity score and the dosimetric parameters, compared with USF/SSF. The TD(50), assessed by the LKB model, was 21.4, 27.8, and 41.6 Gy at 3, 6, and 12 months after RT, respectively. The TD(50), assessed by the S model, was 20.0, 26.3, and 40.0 Gy at 3, 6, and 12 months after RT, respectively.Recovery of salivary gland function vs. time after RT took place mostly within 1 year after RT. The RTOG Grade 3 was a reliable score to perform the NTCP modeling. The choice of NTCP model had no influence on the accuracy of predictions.

The management of elderly glioblastoma (GBM) remains controversial for under-representation in controlled trials, for modest tolerance of treatments, and higher rate of side effects. Age was identified as an important prognostic factor for survival, mainly in patients with poor performance status. The presence of co-morbidities (CM) represents an important issue in elderly because the correlation with frailty, and the role as predictor of disability and mortality. The aim of this study was to evaluate the impact of CM on outcome of elderly GBM. METHODS: Patients affected by GBM with age ≥ 65 years have been enrolled in a prospective study. For each patient, CM were identified with the Cumulative Illness Rating Scale (CIRS). RESULTS: Sixty-six elderly patients affected by GBM were enrolled into the study. The average age at diagnosis was 73 years (range 65-87). The median PFS at 12 months has been 8 months, with a rate of 29.1% patients free of progression at 1 year. The median OS has been 18 months (95% CI 13-23), with a survival rate of 35% at 2 years. The univariate analysis showed that the severity of CM is a strong predictor of disease progression (HR = 1.24, 95% CIs from 1.11 to 1.38, p = 0.000). Multivariate analysis confirmed that the severity of CM (HR = 1.24 for each increase of CIRS score, 95% CIs from 1.11 to 1.38, p = 0.000) is an independent predictor of disease progression. In addition, higher score of CM and age higher than 75 years are associated with short survival. DISCUSSION: We observed that high CM score is an independent predictor of disease progression and shorter survival. The evaluation of CM should drive therapeutic decisions in elderly GBM. In subgroups of elderly GBM without high score of CM, standard treatments should be considered. Further studies on elderly GBM are warranted to confirm these data.

Purpose To evaluate cervical spinal cord tolerance using equivalent uniform dose (EUD) and dose volume histogram (DVH) analysis after proton-photon radiotherapy. Methods and material The 3D dose distributions were analyzed in 85 patients with cervical vertebral tumors. Mean follow-up was 41.3 months. The mean prescribed dose was 76.3 Cobalt Gray Equivalent (CGE = proton dose × RBE 1.1). Dose constraints to the center and the surface of the cervical cord were 55–58 CGE and 67–70 CGE, respectively. Dose parameters, DVH and EUD, were calculated for each patient. The spinal cord toxicity was graded using the European Organization for Research and Treatment of Cancer (EORTC) and Radiation Therapy Oncology Group (RTOG) late effects scoring system. Results Thirteen patients experienced Grade 1–2 toxicity. Four patients had Grade 3 toxicity. For the dose range used in this study, none of the dosimetric parameters was found to be associated with the observed distribution of cord toxicities. The only factor significantly associated with cord toxicity was the number of surgeries before irradiation. Conclusion The data and our analysis suggest that the integrity of the normal musculoskeletal supportive tissues and vascular supply may be important confounding factors of toxicity at these dose levels. The results also indicate that the cervical spinal cord dose constraints used in treating these patients are appropriate for conformal proton-photon radiotherapy.

Background and purpose Three-dimensional conformal radiotherapy and intensity modulated radiotherapy allow accurate dose delivery on target volumes. Due to the different background among specialists involved in target volume definition, the contouring emerges as one of the most questionable steps in treatment planning procedures. A software tool devoted to contouring training, named tutorial for image guided external radiotherapy (‘TIGER'), based on the Visible Human Project images data-set, is described. Materials and methods TIGER is addressed to facilitate the learning of axial anatomical images, to promote the training and reproducibility in contouring process, to allow the availability of a tool to enhance the ‘drill and practice' approach in training programs. TIGER includes three different environments: Anatomic tutorial devoted to facilitate a self-learning approach to axial body sections; Contouring tutorial addressed to practice contouring process of anatomical structures and to undergo a test program prepared by tutors; Teacher's tools to offer to tutors the opportunity to insert new outlines in TIGER-database, according to local needs or conventions, and to use them in tutorial programs. TIGER-database is grouped in six main anatomical sections: head and neck, male thorax, female thorax, abdomen, male pelvis, and female pelvis. Overall 432 corresponding CT-VH images and 1189 contours of 134 different anatomical structures and lymphatic drainage areas are available. The access to the TIGER software is allowed by ESTRO web site (http://www.estro.be). Conclusions TIGER provides an interactive human anatomy cross-sectional oriented source to facilitate the interpretation of CT scan images usually contoured in daily practice. It offers a drill tool to facilitate the learning of a reproducible contouring procedure.

Background. No established chemotherapeutic regimen exists for the treatment of recurrent malignant gliomas (rMGs). Herein, we report the activity and safety results of the bevacizumab (B) plus fotemustine (FTM) combination for the treatment of rMGs.Patients and Methods. An induction phase consisted of B 10 mg/kg days 1, 15 plus FTM 65 mg/m2days 1, 8, and 15. Nonprogressive patients entered the maintenance phase with B 10 mg/kg plus FTM 75 mg/m2every 3 weeks. The primary endpoint was response rate; secondary endpoints included safety, progression free survival (PFS), and overall survival (OS).Results. Twenty-six patients affected by recurrent MGs (50% glioblastoma) were enrolled. Eight partial responses (31%) were observed. Median PFS and OS were 4 (95% C.I.: 2.8–5.1) and 6 months (95% C.I.: 4.2–7.8), respectively. Responses were significantly associated with both improved PFS and OS (P=0.002andP=0.001, resp.). Treatment adverse events were mostly mild to moderate in intensity. Bevacizumab-related adverse events included grade 3 venous thromboembolic event (8%), grade 2 epistaxis (4%), hypertension (8%), and gastrointestinal perforation (4%).Conclusions. Bevacizumab plus FTM showed activity and good tolerability in pretreated MGs. Further investigations are needed in order to verify the benefits deriving from the addition of B to a cytotoxic in this clinical setting of patients.

Background and purpose: Irradiation of the Pharyngeal Superior Constrictor Muscle (PSCM) seems to play a crucial role in radiation-related swallowing dysfunctions. Purpose of our study was to quantify operator-related variability in the contouring of PSCM on Computed Tomography (CT) scans and adherence with contours derived from MR images. Materials and methods: Three sets of treatment planning CT and their corresponding MR images were selected. Contouring of the PSCM was performed using both a literature-based method, derived from literature review, and an optimized method, derived from Magnetic Resonance (MR) images thus obtaining ‘‘literature-based’’ and ‘‘optimized’’ contours. Each operator contoured the PSCM on CT scans according to both methods for three times in three different days. Inter- and intra-operator variability and adherence to a contour obtained from MR images (named ‘‘MR-derived’’ contour) were analyzed. Results: Thirty-four operators participated and 612 contours were obtained. Both intra- and inter-operator variability and adherence to the ‘‘MR-derived’’ contour were significantly different between the two methods (p 6 0.05). The ‘‘optimized’’ method showed a lower intra- and inter-operator variability and a higher adherence to the ‘‘MR-derived’’ contour. Conclusions: The ‘‘optimized’’ method ameliorates both operator-related variability and adherence with MR images.

To investigate the potential of intravoxel incoherent motion (IVIM) MRI for early evaluation of irradiated major salivary glands.Thirty-four patients with head-neck cancer were included in a prospective study. All patients underwent three serial IVIM-MRI: before, half-way through, and at the end of radiotherapy (RT). Apparent diffusion coefficient (ADC), ADClow derived in the low b-value range, perfusion fraction f, and pure diffusion coefficient D were estimated. Pretreatment values and early changes of diffusion parameters were correlated with parotid mean dose (Dmean ) and volume reduction after RT.Changes in diffusion parameters over time were all significant (P0.001 for ADC, ADClow , and D, P = 0.003 for f). Variations of ADC, ADClow , and f were not correlated with Dmean (P = 0.089, P = 0.252 and P = 0.884, respectively), whereas a significant relationship was found between changes in D and Dmean (r = 0.197 with CI95% = 0.004-0.375, P = 0.046). Pretreatment f and Dmean were the best independent predictors for the percentage shrinkage (P = 0.0003 and 0.0597 respectively; R(2) = 0.391).Early changes of irradiated major salivary glands can be noninvasively evaluated by IVIM-MRI. Perfusion-related coefficients in conjunction with dosimetric information increase our capability to predict the change in parotid volume and hence, if further validated, guide treatment strategy in RT.

Sterotactic radiosurgery (SRS) is an effective and commonly employed therapy for metastatic brain tumors. Among complication of this treatment, symptomatic focal cerebral radionecrosis (RN) occurs in 2–10 % of cases. The large diffusion of combined therapies as SRS followed by WBRT and/or CHT, has significantly amplified the number of patients who potentially might be affected by this pathology and neurosurgeons are increasingly called to treat suspected area of RN. Results of surgery of RN in patients with brain metastases are rarely reported in literature, a standardization of diagnostic work-up to correctly identify RN is still lacking and the timing and indications in favour of surgical therapy over medical treatments are not clear as well. In this retrospective study, we review current concept related to RN and analyze the outcome of surgical treatment in a series of 15 patients previously submitted to SRS for brain metastases and affected by suspected radionecrotic lesions. After surgery, all patients except one neurologically improved. No intra-operative complications occurred. Brain edema improved in all patients allowing a reduction or even suspension of corticosteroid therapy. Pure RN was histologically determined in 7 cases; RN and tumor recurrence in the other 8. Overall median survival was 19 months. An aggressive surgical attitude may be advisable in symptomatic patients with suspected cerebral RN, to have histologic confirmation of the lesion, to obtain a long-lasting relief from the mass effect and brain edema and to improve the overall quality of life, sparing a prolonged corticosteroid therapy.

Background The purpose of this study was to compare 5-field and 7-field intensity-modulated radiation therapy (IMRT) techniques in terms of xerostomia and related quality of life in patients with nasopharyngeal cancer. Methods Eight and 23 patients were treated with 5-field (group I) and 7-field (group II) techniques, respectively. The xerostomia was evaluated using the Radiation Therapy Oncology Group (RTOG) scale, stimulated and unstimulated salivary flow (SSF/USF), and xerostomia-related questionnaires (XQs). The assessments were done before and at 3, 6, 12, 18, and 24 months after radiotherapy. Results The mean parotid dose was 45.7 Gy and 29.9 Gy and the ≥G3 toxicity at 24 months was 25% and 19% in group I and II, respectively. Sixty-three percent and 93% of patients recovered at least 25% of SSF pretherapy values. The XQ scores of both groups improved over time but more so in group II. Conclusion The 7-field technique decreases the mean parotid dose, reducing xerostomia assessed by the RTOG/XQ score. © 2011 Wiley Periodicals, Inc. Head Neck, 2012

Background Accelerated hypofractionation is an attractive approach for adjuvant whole breast radiotherapy. In this study we evaluated the adverse effects at least 3 years post an accelerated hypofractionated whole breast radiotherapy schedule. Methods From October 2004 to March 2006, 39 consecutive patients aged over 18 years with pTis, pT1-2, pN0-1 breast adenocarcinoma who underwent conservative surgery were treated with an adjuvant accelerated hypofractionated radiotherapy schedule consisting of 34 Gy in 10 daily fractions over 2 weeks to the whole breast, followed after 1 week by an electron boost dose of 8 Gy in a single fraction to the tumour bed. Skin and lung radiation toxicity was evaluated daily during therapy, once a week for one month after radiotherapy completion, every 3 months for the first year and from then on every six months. In particular lung toxicity was investigated in terms of CT density evaluation, pulmonary functional tests, and clinical and radiological scoring. Paired t-test, Chi-square test and non-parametric Wilcoxon test were performed. Results After a median follow-up of 43 months (range 36-52 months), all the patients are alive and disease-free. None of the patients showed any clinical signs of lung toxicity, no CT-lung toxicity was denoted by radiologist on CT lung images acquired about 1 year post-radiotherapy, no variation of pulmonary density evaluated in terms of normalised Hounsfield numbers was evident. Barely palpable increased density of the treated breast was noted in 9 out of 39 patients (in 2 patients this toxicity was limited to the boost area) and teleangectasia (2) limited to the boost area was evident in 2 out of 39 patients. The compliance with the treatment was excellent (100%). Conclusion The radiotherapy schedule investigated in this study (i.e 34 Gy in 3.4 Gy/fr plus boost dose of 8 Gy in single fraction) is a feasible and safe treatment and does not lead to adjunctive acute and late toxicities. A longer follow up is necessary to confirm these favourable results.

Background The acute toxicity of intraoperative radiation therapy (IORT) delivered as an “early boost” after tumor resection in patients with locally advanced head and neck cancer was evaluated. Methods Twenty-five patients were enrolled in the study. All patients underwent surgery with radical intent, and 17 had microvascular flap reconstruction. The IORT was delivered in the operating room. Twenty patients received adjuvant external beam radiation therapy (EBRT). Results Five patients experienced various degrees of complications in the postoperative period, all of which were treated conservatively. One patient had a partial flap necrosis after EBRT that was treated with flap removal. Six deaths were recorded during the mean follow-up period of 8 months; none of the deaths were related to radiation treatment. Conclusion This feasibility study shows that the use of IORT as an early boost is feasible with no increase in acute toxicity directly attributable to radiation. © 2008 Wiley Periodicals, Inc. Head Neck, 2008

Purpose: To evaluate the outcomes of a second course of proton beam radiation therapy (PBRT) in patients with recurrent uveal melanoma. Methods and Materials: Thirty-one patients received a second course of PBRT. The mean interval between the first and the second PBRT course was 50.2 months (range, 8–165 months). Most patients (87%) received 70 cobalt Gray equivalent (CGE) for both courses. Visual acuity was 20/200 or better in 30 patients initially and in 22 patients at the second treatment. The mean follow-up time after the second treatment was 50 months (range, 6–164 months). Results: At the time of the last follow-up, 20 patients were classified as having no evidence of disease, defined as tumor regression or an absence of tumor progression. Nine eyes (29%) were enucleated because of local recurrence (n = 5) or intractable pain (n = 4). The 5-year eye retention rate was 55% (95% confidence interval: 25.2–77.4). Six of the 22 patients who retained the eye (27%) had useful vision (20/200 or better). Conclusions A second course of PBRT for recurrent uveal melanoma to total doses between 118 and 140 CGE was associated with a relatively good probability of local control and a low enucleation rate. Although most patients lost vision, the majority were able to retain the reirradiated eye. Further evaluation is needed to assess metastasis-free survival of additional proton irradiation vs. enucleation after local recurrence.

BACKGROUND: Advances in surgical approaches, radiotherapy, and chemotherapy are contributing to incremental improvements in survival of the patients with High Grade Gliomas (HGG) but few options exist for the management of recurrent or resistant disease. Long survivors are often treated with more lines of chemotherapy (CT) after failure of second line treatment but no data are available about the real impact of third line of CT. METHODS: We retrospectively analyzed the clinical records of HGG patients treated with third line CT at the Regina Elena Cancer Institute in the last 10 years (2003-2013) with the aim to evaluate the benefit in term of time to treatment failure (TTF) and overall survival (OS). RESULTS: 62 HGG (31 GBM, 31 Anaplastic gliomas) were included in this analysis. Mean age was 43 y; 47 male, 15 female; all patients received in their previous history surgery (2 biopsy) radiotherapy and at least 2 line of chemotherapy (temozolomide and nitrosurea based CT). Third line treatment included bevacizumab (alone or in combination with citotoxic drugs) in 47% of cases and citotoxic drugs alone in 53% of cases. Median TTS was 3 months in both group of patients. TTF was significantly longer in patients with previous history higher than 3 years (5 months p 0.015) respect to patients with previous history shorter than 3 y (TTF 2 months). MGMT methilation status was obtained ony in 17 patients and was not significantly correlated to TTF or OS. OS after third line treatment resulted significantly longer in patients with histology different than GBM and in patients with less than 50 y at diagnosis. Clinical benefit with stable or improved Karnoky performance status after third line treatment was observed in 37% of patients. CONCLUSION: The role of third line chemotherapy in HGG progressing after second line treatment failure requires to be better defined in order to avoid futile treatment in HGG patients with short life expectancy.

Purpose: The purpose of this study was to examine the potential benefit of proton therapy for abdominal tumors. Extensive comparative planning was conducted investigating the most up-to-date photon and proton irradiation technologies. Methods and Materials: A number of rival plans were generated for four patients: two inoperable pancreatic tumors, one inoperable and one postoperative biliary duct tumor. The dose prescription goal for these large targets was 50 Gy, followed by a boost dose up to 20 Gy to a smaller planning target volume (PTV). Photon plans were developed using "forward" planning of coplanar and noncoplanar conformal fields and "inverse" planning of intensity-modulated (IM) fields. Proton planning was simulated as administered using the so called spot-scanning technique. Plans were evaluated on the basis of normal tissues' dose–volume constraints (Emami B, Lyman J, Brown A, et al. Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys 1990;21:109–122) and coverage of treatment volumes with prescribed doses. Results: For all cases, none of the forward calculated photon plans was able to deliver 50 Gy to large PTVs at the same time respecting the dose–volume constraints on all critical organs. Nine evenly spaced IM fields achieved or nearly achieved all maximum dose constraints to critical structures for two out of three inoperable patients. IM plans also obtained good results for the postoperative patient, even though the dose to the liver was very close to the maximum allowed. In all cases, photon irradiation of large PTV1s to 50 Gy followed by a 20 Gy boost entailed a risk very close to or higher than 5% for serious complications to the kidneys, liver, or bowel. Simple arrangements of 2, 3, and 4 proton fields obtained better dose conformation to the target, allowing the delivery of planned doses including the boost to all patients, without excessive risk of morbidity. Dose homogeneity inside the targets was also superior with protons. Conclusion: For the irradiation of large PTVs located in the abdominal cavity, where multiple, parallel structured organs surround the target volumes, proton therapy, delivered with a sophisticated isocentric technique, has the potential to achieve superior dose distributions compared with state-of-the-art photon irradiation techniques. IM photon plans obtain better results in the postoperative case, because the reduced volume lessens the effect of the unavoidable increase of integral dose to surrounding tissues.