Translational Insights and New Therapeutic Perspectives in Head and Neck Tumors.

Head and neck squamous cell carcinoma (HNSCC) is characterized by a high mortality rate owing to very few available oncological treatments. For many years, a combination of platinum-based chemotherapy and anti-EGFR antibody cetuximab has represented the only available option for first-line therapy. Recently, immunotherapy has been presented an alternative for positive PD-L1 HNSCC. However, the oncologists' community foresees that a new therapeutic era is approaching. In fact, no-chemo options and some molecular targets are on the horizon. This narrative review addresses past, present, and future therapeutic options for HNSCC from a translational point of view.

Comparison of three freeware software packages for 18F-FDG PET texture feature calculation.

PURPOSE: To compare texture feature estimates obtained from 18F-FDG-PET images using three different software packages. METHODS: PET images from 15 patients with head and neck cancer were processed with three different freeware software: CGITA, LIFEx, and Metavol. For each lesion, 38 texture features were extracted from each software package. To evaluate the statistical agreement among the features across packages a non-parametric Kruskal-Wallis test was used. Differences in the features between each couple of software were assessed using a subsequent Dunn test. Correlation between texture features was evaluated via the Spearman coefficient. RESULTS: Twenty-three of 38 features showed a significant agreement across the three software (P < 0.05). The agreement was better between LIFEx vs. Metavol (36 of 38) and worse between CGITA and Metavol (24 of 38), and CGITA vs. LIFEx (23 of 38). All features resulted correlated (ρ > = 0.70, P < 0.001) in comparing LIFEx vs. Metavol. Seven of 38 features were found not in agreement and slightly or not correlated (ρ < 0.70, P < 0.001) in comparing CGITA vs. LIFEx, and CGITA vs. Metavol. CONCLUSION: Some texture discrepancies across software packages exist. Our findings reinforce the need to continue the standardization process, and to succeed in building a reference dataset to be used for comparisons.

Boosting the Immune Response with the Combination of Electrochemotherapy and Immunotherapy: A New Weapon for Squamous Cell Carcinoma of the Head and Neck?

Head and neck squamous cell carcinomas (SCCHN) are not rare malignancies and account for 7% of all solid tumors. Prognosis of SCCHN patients strongly depends on tumor extension, site of onset, and genetics. Advanced disease (recurrent/metastatic) is associated with poor prognosis, with a median overall survival of 13 months. In these patients, immunotherapy may represent an interesting option of treatment, given the good results reached by check-point inhibitors in clinical practice. Nevertheless, only a minor number of patients with advanced disease respond to immunotherapy, and, disease progressions/hyper-progressions are common. The latter could be a very difficult issue, especially in patients having a wide and highly symptomatic head/neck mass. Given the potentiality to boost the immune response of some local modalities, such as electrochemotherapy, a possible future approach may take into account the combination of electrochemotherapy and immunotherapy to treat patients affected by SCCHN, suffering from symptomatic lesions that need rapid debulking.

Management of Ewing Sarcoma Family of Tumors: A Short Description of a Rare Primitive Uterine pPNET and Literature Review.

PURPOSE: To describe the outcome of a patient with a rare primitive uterine pPNET and to perform a review of the available data in literature, leading the clinicians to better face this rare disease. METHODS: We have rescued data regarding the multidisciplinary treatment of pPNET from the PUBMED database, highlighting also issues regarding the pathogenesis and the genetic landscape of the ESFTs (Ewing Sarcoma Family of Tumors). RESULTS: Ewing sarcoma and primitive neuroectodermal tumors (PNETs) are small round cell tumors presenting with different degrees of neuroectodermal differentiation. PNETs are further divided into central PNET and peripheral PNET (pPNET). Since pPNETs share the same genetic background of Ewing Sarcomas, they are considered to belong to the Ewing Sarcoma Family of Tumors (ESFTs). Multimodality treatment currently represents the best choice to offer to the affected patients. CONCLUSION: Although pPNETs are generally diagnosed in children and young adults, an elderly woman aged 85 years came to our attention after a diagnosis of uterine pPNET. Her medical history is presented here, along with a literature review of the subject, highlighting the main biological, pathological and clinical features, with a hypothesis about the possible future therapeutic approaches for these rare malignancies.

Genetics and management of locally advanced carcinomas of the head and neck: role of altered fractionation radiotherapy.

Squamous cell carcinoma of the head and neck (SCCHN) accounts for 5-7% of all malignancies. About 60% of newly diagnosed SCCHN are detected as locally advanced disease. Chemoradiation is a standard option and response rate to it is variable. Recently, a genetic classification of SCCHN has been proposed by Chung et al., who categorized all SCCHN into four subtypes. The basal-like variant is characterized by high expression of EGFR. Literature data suggest higher efficacy of accelerated and/or hyperfractionated radiotherapy, if compared with conventional radiotherapy in the subgroup of patients with high EGFR expression. In this review, we will describe the genetic factors able to guide treatment choice, with a focus on EGFR expression.

Metastatic HPV-related oropharyngeal carcinoma cured with chemoradiotherapy: importance of pretherapy biomolecular assessment.

Pretherapy assessment has a crucial role in the management of advanced oropharyngeal carcinoma. The case report represents an example of how translational research may help to optimize the therapeutic options and to choose a well-shaped therapy adapted to the tumor and the patient.

Locally advanced paranasal sinus carcinoma: A study of 30 patients.

Sinonasal carcinomas (SNcs) are rare neoplasms arising from the paranasal sinuses and nasal cavity. Although these tumours have a heterogeneous histology, they are commonly diagnosed as a locally advanced disease and are associated with a poor prognosis. The present retrospective study reviewed 30 patients with locally advanced SNc, who were treated with surgery followed by chemoradiotherapy or radiotherapy, or radiotherapy with or without concomitant chemotherapy between January 1999 and January 2013 at the Department of Radiation Therapy, University of Naples 'Federico II' (Naples, Italy). A total of 19 patients were treated with upfront surgery followed by adjuvant radio- or chemoradiotherapy (group A), while the remaining 11 patients received exclusive radiotherapy with or without concomitant chemotherapy (group B). Concurrent cisplatin-based chemotherapy (100 mg/m2, days 1, 22 and 43 for 3 cycles) was administered to 34% of patients in group A and 55% of patients in group B. At a median follow-up of 31 months, 33.3% of patients were alive. Cause-specific survival (CSS) and progression-free survival (PFS) times were 32 and 12 months, respectively. No difference in CSS rate was observed between the two treatment groups. Univariate analysis determined that disease stage was the only factor that significantly affected CSS (P=0.002) and PFS (P=0.0001) rates. Acute and chronic toxicities were mild, with only 23.3% of patients reporting G1-2 side effects and no treatment-related blindness. The present study reported moderate activity and efficacy of surgery followed by adjuvant radio- or chemoradiotherapy, and exclusive radiotherapy with or without chemotherapy in this poor prognosis category of patients.

Dose-surface analysis for prediction of severe acute radio-induced skin toxicity in breast cancer patients.

BACKGROUND: Severe acute radiation-induced skin toxicity (RIST) after breast irradiation is a side effect impacting the quality of life in breast cancer (BC) patients. The aim of the present study was to develop normal tissue complication probability (NTCP) models of severe acute RIST in BC patients. PATIENTS AND METHODS: We evaluated 140 consecutive BC patients undergoing conventional three-dimensional conformal radiotherapy (3D-CRT) after breast conserving surgery in a prospective study assessing acute RIST. The acute RIST was classified according to the RTOG scoring system. Dose-surface histograms (DSHs) of the body structure in the breast region were extracted as representative of skin irradiation. Patient, disease, and treatment-related characteristics were analyzed along with DSHs. NTCP modeling by Lyman-Kutcher-Burman (LKB) and by multivariate logistic regression using bootstrap resampling techniques was performed. Models were evaluated by Spearman's Rs coefficient and ROC area. RESULTS: By the end of radiotherapy, 139 (99%) patients developed any degree of acute RIST. G3 RIST was found in 11 of 140 (8%) patients. Mild-moderate (G1-G2) RIST was still present at 40 days after treatment in six (4%) patients. Using DSHs for LKB modeling of acute RIST severity (RTOG G3 vs. G0-2), parameter estimates were TD50=39 Gy, n=0.38 and m=0.14 [Rs = 0.25, area under the curve (AUC) = 0.77, p = 0.003]. On multivariate analysis, the most predictive model of acute RIST severity was a two-variable model including the skin receiving ≥30 Gy (S30) and psoriasis [Rs = 0.32, AUC = 0.84, p < 0.001]. CONCLUSIONS: Using body DSH as representative of skin dose, the LKB n parameter was consistent with a surface effect for the skin. A good prediction performance was obtained using a data-driven multivariate model including S30 and a pre-existing skin disease (psoriasis) as a clinical factor.

Cardiac involvement in Erdheim- Chester disease: MRI findings and literature revision.

Erdheim-Chester disease (ECD) is a rare form of non-Langerhans cell histiocytosis, characterized by the involvement of several organs. The lesions may be skeletal or extra-skeletal: in particular, long bones, skin, lungs, and the cardiovascular and the central nervous systems can be affected. In this report, we describe a case of a 34-year-old man, who came to our observation with symptomatic ECD, for a correct assessment of the degree of cardiac involvement through magnetic resonance imaging (MRI).

Optimal management of a patient with recurrent nasopharyngeal carcinoma.

Nasopharyngeal carcinoma is rare in western countries, accounting for less than 1% of all malignancies. Despite prognosis is satisfactory for newly diagnosed, non-metastatic disease, management of recurrent disease is challenging, with a survival expectancy of approximately 6 mo with the use of chemotherapy as the sole salvage treatment. We report a case of recurrent nasopharyngeal carcinoma treated with a combination of chemotherapy, radiotherapy and surgery in the context of a multidisciplinary approach. A durable complete response was achieved.

Pulmonary damage in Hodgkin's lymphoma patients treated with sequential chemo-radiotherapy: Predictors of radiation-induced lung injury.

BACKGROUND: Our aim was to define predictors of late radiation-induced lung injury (RILI) in Hodgkin's lymphoma (HL) survivors treated with bleomycin-containing chemotherapy and radiotherapy. MATERIAL AND METHODS: Eighty consecutive patients treated with chemotherapy and subsequent supradiaphragmatic radiation therapy for HL were retrospectively reviewed for symptoms and/or radiological signs of RILI. Median patient age was 26 years (range 14-55). Left, right, and total lung dosimetric parameters along with clinical, disease, and treatment-related characteristics were analyzed. Multivariate logistic regression analyses were performed. A receiver operator characteristic (ROC) curve analysis was performed to find possible cutoff values dividing patients into high- and low-risk groups. RESULTS: Seven of 80 (9%) patients had lung disease at baseline. Four of 80 (5%) had toxicity after chemotherapy and before the beginning of radiotherapy. These patients were excluded from further evaluation. At a median time of 10 months (range 9-18), 9/69 patients (13%) developed lung radiological changes on computed tomography (CT) after treatment. Four of nine patients were diagnosed RTOG grade ≥ 2. On multivariate analyses, left-lung V30 (p = 0.004, OR = 1.108 95% CI 1.033-1.189) and total-lung V30 (p = 0.009, OR = 1.146 95% CI 1.035-1.270) resulted to be predictors of lung CT changes with a cutoff value of 16% and 15%, respectively. When only symptomatic RILI was considered a left-lung V30 cutoff value of 32% was estimated. CONCLUSION: Bleomycin and RT may cause lung injury in a small, but significant fraction of HL patients. Left-lung V30 predicts the risk of developing asymptomatic or symptomatic RILI after sequential chemo-radiotherapy.

Radiation therapy following surgery for localized breast cancer: outcome prediction by classical prognostic factors and approximated genetic subtypes.

The purpose of this study was to evaluate the outcome prediction power of classical prognostic factors along with surrogate approximation of genetic signatures (AGS) subtypes in patients affected by localized breast cancer (BC) and treated with postoperative radiotherapy. We retrospectively analyzed 468 consecutive female patients affected by localized BC with complete immunohistochemical and pathological information available. All patients underwent surgery plus radiotherapy. Median follow-up was 59 months (range, 6-132) from the diagnosis. Disease recurrences (DR), local and/or distant, and contralateral breast cancer (CBC) were registered and analyzed in relation to subtypes (luminal A, luminal B, HER-2, and basal), and classical prognostic factors (PFs), namely age, nodal status (N), tumor classification (T), grading (G), estrogen receptors (ER), progesterone receptors and erb-B2 status. Bootstrap technique for variable selection and bootstrap resampling to test selection stability were used. Regarding AGS subtypes, HER-2 and basal were more likely to recur than luminal A and B subtypes, while patients in the basal group were more likely to have CBC. However, considering PFs along with AGS subtypes, the optimal multivariable predictive model for DR consisted of age, T, N, G and ER. A single-variable model including basal subtype resulted again as the optimal predictive model for CBC. In patients bearing localized BC the combination of classical clinical variables age, T, N, G and ER was still confirmed to be the best predictor of DR, while the basal subtype was demonstrated to be significantly and exclusively correlated with CBC.

Thyroid V30 predicts radiation-induced hypothyroidism in patients treated with sequential chemo-radiotherapy for Hodgkin's lymphoma.

PURPOSE: Hypothyroidism (HT) is a frequent late side effect of Hodgkin's lymphoma (HL) therapy. The purpose of this study is to determine dose-volume constraints that correlate with functional impairment of the thyroid gland in HL patients treated with three-dimensional radiotherapy. METHODS AND MATERIALS: A total of 61 consecutive patients undergoing antiblastic chemotherapy and involved field radiation treatment (median dose, 32 Gy; range, 30-36 Gy) for HL were retrospectively considered. Their median age was 28 years (range, 14-70 years). Blood levels of thyroid-stimulating hormone (TSH), free triiodo-thyronine (FT3), free thyroxine (FT4), and thyroglobulin antibody (ATG) were recorded basally and at different times after the end of therapy. For the thyroid gland, normal tissue complication probability (NTCP), dosimetric parameters, and the percentage of thyroid volume exceeding 10, 20, and 30 Gy (V10, V20, and V30) were calculated in all patients. To evaluate clinical and dosimetric factors possibly associated with HT, univariate and multivariate logistic regression analyses were performed. RESULTS: Eight of 61 (13.1%) patients had HT before treatment and were excluded from further evaluation. At a median follow-up of 32 months (range, 6-99 months), 41.5% (22/53) of patients developed HT after treatment. Univariate analyses showed that all dosimetric factors were associated with HT (p < 0.05). On multivariate analysis, the thyroid V30 value was the single independent predictor associated with HT (p = 0.001). This parameter divided the patients into low- vs. high-risk groups: if V30 was ≤ 62.5%, the risk of developing HT was 11.5%, and if V30 was >62.5%, the risk was 70.8% (p < 0.0001). A Cox regression curve stratified by two levels of V30 value was created (odds ratio, 12.6). CONCLUSIONS: The thyroid V30 predicts the risk of developing HT after sequential chemo-radiotherapy and defines a useful constraint to consider for more accurate HL treatment planning.

Dosimetric predictors of asymptomatic heart valvular dysfunction following mediastinal irradiation for Hodgkin's lymphoma.

PURPOSE: To identify dose-heart-volume constraints that correlate with the risk of developing asymptomatic valvular defects (VD) in Hodgkin's lymphoma (HL) patients treated with three-dimensional radiotherapy (RT). PATIENTS AND METHODS: Fifty-six patients undergoing cytotoxic chemotherapy (CHT) and involved-field radiation treatment for HL were retrospectively analyzed. Electro-echocardiography was performed before CHT, after CHT, and after RT. For the entire heart, for right and left ventricle (RV, LV), right and left atrium (RA, LA) percentage of volume exceeding 5-30Gy in increment of 5Gy (V(x)), and dosimetric parameters were calculated using 1.6Gy fraction as reference. To evaluate clinical and dosimetric factors possibly associated with VD, univariate and multivariate logistic regression analyses were performed. RESULTS: At a median follow up of 70.5 months, 32.1% of patients developed VD (regurgitation and/or stenosis): 25.0% developed mitral, 5.4% developed aortic, and 14.3% tricuspid VD. In particular the percentage of LA exceeding 25Gy (LA-V(25)) and the percentage of LV exceeding 30Gy (LV-V(30)) correlated with mitral and aortic VD with an odds ratio (OR) of 5.7 (LA-V(25)>63.0% vs. LA-V(25)≤63.0%) and OR of 4.4 (LV-V(30)>25% vs. LV-V(30)≤25%), respectively. RV-V(30) correlated with tricuspid VD (OR=7.2, RV-V(30)>65% vs. RV-V(30)≤65%). CONCLUSION: LA-V(25), LV- and RV-V(30) prove to be predictors of asymptomatic alteration of valve functionality.

Fractionated stereotactic radiation therapy for orbital optic nerve sheath meningioma - a single institution experience and a short review of the literature.

Optic nerve sheath meningioma (ONSM) is a rare orbital tumor that generally induces a slow progressive visual loss in affected patients. Radiotherapy (RT) has currently become the first choice to treat ONSM. In this study our experience in ONSM treatment with fractionated stereotactic radiotherapy (FSRT) is reported. Five patients with diagnosis of orbital ONSM were treated between April 2007 and December 2009 at the Radiation Oncology department of our institution. All patients underwent history and physical, and ophthalmic examinations. Orbital MRI was performed before and 6 weeks after treatment; thereafter every 6 months for the first 2 years. By previous stereotactic localization of the target, RT was delivered with 28 daily fraction of 1.8 Gy by multiple non coplanar arcs dynamically conformed by a micro multileaf-collimator. At diagnosis, in all 5 patients, visual acuity limitations of different degrees were found, while exophthalmos was present in 2, diplopy in 2, orbital pain in 1, and proptosis in 1. In all patients pre-treatment MRI showed an orbital mass involving the optic nerve. After radiotherapy, previous symptoms improved in all patients. However, after RT the MRI consistently showed a stationary status compared to the MRI before RT. At a median follow up of 26 months (range 9-37) all patients had a subjective and/or objective better visual performance than before RT without any evidence of disease progression. No late side effects were recorded. Accordingly to the current literature, our experience confirms the efficacy and the safety of FSRT in patients with orbital ONSM.

Radiation therapy in primary orbital lymphoma: a single institution retrospective analysis.

BACKGROUND: Primary orbital lymphoma is a rare disease that accounts for 10% of all orbital tumors. Radiotherapy on the orbital cavity is the treatment of choice for this unusual presentation of localized non-Hodgkin's lymphoma (NHL). The aim of this study is to retrospectively evaluate the effectiveness and the toxicity of radiation treatment in patients with primary orbital lymphoma. METHODS: Forty-seven consecutive patients having primary orbital lymphoma treated in our department between May 1983 and September 2006 were investigated in a retrospective study. Either 60Co gamma rays or 6 MV X rays were used to deliver daily fractions of 1.8 or 2.0 Gy, 5 times/week, with total doses ranging from 34.2 to 50 Gy. Forty-three patients had stage IE, three had stage II and one stage IV disease. Thirty-eight patients had marginal zone B-cell lymphoma, 5 diffuse large B cell lymphoma, 3 mantle cell lymphoma and 1 Burkitt lymphoma. Local control (LC), disease free survival (DFS), overall survival (OS) and late side effects were evaluated in all patients. RESULTS: With a median follow up of 45 months, LC was obtained in 100% of patients. The estimated 5- and 7-year DFS rates were 75.8% and 55.3%, and the 5- and 7-year OS rates were 88.7% and 79.9% respectively. Acute toxicity was minimal. Late toxicity such as cataract, keratitis, retinopathy and xerophthalmia occurred respectively in 12 (25.5%), 5 (10.6%), 1 (2.1%), and 9 (19.1%) patients. CONCLUSION: Radiotherapy is an effective and at the same time well tolerated treatment for primary orbital lymphoma.

Preoperative radiation treatment for rectal cancer: comparison of target coverage and small bowel NTCP in conventional vs. 3D-conformal planning.

A prospective study was undertaken to evaluate the improvement in rectal cancer radiation treatment achieved with the implementation of target delineation for conformal radiotherapy, replacing conventional technique using standard radiological anatomy for target volume definition. In 10 patients receiving preoperative pelvic irradiation for rectal cancer, a 3-field technique was designed by a 3-dimensional (3D) planning system. Two plans were simulated for each patient, one with the fields designed in the conventional way based on radiological anatomy, and the other with the fields designed on the basis of a computed tomography (CT) delineated planning target volume (PTV). A total dose of 45 Gy in 25-daily fractions of 1.8 Gy in 5 weeks was planned. Dose-volume histograms (DVHs) of PTV, small bowel, anal sphincter, and urinary bladder were analyzed to compare plans. The minimum, maximum, and mean dose in the PTV and in critical organs were also evaluated. The inhomogeneity coefficient (IC) and the target coverage (TC) were calculated. The normal tissue complication probability (NTCP) for each organ at risk (OAR) was determined. NTCP for small bowel and urinary bladder was not statistically different, while the PTV coverage was significantly lower with conventional treatment relative to conformal treatment (median IC=7.2, median TC=0.91 vs. median IC=0.14 and median TC=1, p<0.005). The 3D conformal treatment plan in preoperative radiotherapy for rectal cancer improves target coverage without significantly affecting small bowel and urinary bladder NTCP.

A phase I/II trial of gefitinib and radiotherapy in patients with locally advanced inoperable squamous cell carcinoma of the head and neck.

Two different doses of gefitinib, administered along with standard radiation therapy, were tested in locally advanced inoperable head and neck cancer with the aim of finding the maximum tolerated dose and assessing the toxicity and activity of the combination. The standard '3+3' design was used for the phase I study. Radiation therapy was given according to conventional dose and schedule. Gefitinib dose escalation was stopped if more than one-third of patients of a given cohort had dose-limiting toxicity. Dose-limiting toxicity was observed in three of four patients treated at the dose of 500 mg, and included grade 3 stomatitis in three patients and grade 3 liver toxicities in one patient. The dose level of 250 mg was recommended for the phase II study. Six confirmed objective responses were observed among 16 patients. Our results do not support further trials with gefitinib and radiation therapy, according to our schedule, in this patient population. Integration of gefitinib within chemoradiotherapy regimens and combination with other biological therapies may represent the next challenge.

Lymph nodes in the irradiated field influence the yield of radiation-induced chromosomal aberrations in lymphocytes from breast cancer patients.

PURPOSE: To measure chromosomal aberrations in blood lymphocytes from breast cancer patients treated with radiotherapy after quadrantectomy or tumorectomy. METHODS AND MATERIALS: Twenty-two breast cancer patients treated with breast-conserving surgery and radiation were evaluated. Adjuvant chemotherapy was also given to 9 patients. Blood samples were obtained before radiotherapy, after about one-half of the fractions, and at the end of the treatment of the whole breast (50 Gy). Chromosome aberrations in peripheral blood lymphocytes were measured using chemical-induced premature chromosome condensation combined with fluorescence in situ hybridization. RESULTS: Radiation treatment produced a significant increase in the yield of chromosomal aberrations. A large interindividual variability was observed. The variability was not related to field size, previous chemotherapy, or treatment morbidity. Chromosome aberrations in lymphocytes at the end of the treatment were significantly higher in the group of patients with no lymph nodes surgically removed before the treatment than in the group of patients with more than 10 lymph nodes removed. CONCLUSION: The number of lymph nodes within the radiation field is an important factor affecting the yield of radiation-induced chromosomal aberrations in breast cancer patients.

Primary non-Hodgkin's lymphoma of the lacrimal sac: a case report.

Primary non-Hodgkin's lymphoma of the lacrimal sac is an extremely rare presentation of orbital localization of lymphoma. We present a 45-year-old male patient with primary NHL of the lacrimal sac, stage IE, who was treated with surgery and radiotherapy. Fourteen months after the end of radiotherapy the patient is free of disease and does not show any treatment-related toxicity.