Rosa Autorino

HPV infection in squamous cell carcinomas arising from different mucosal sites of the head and neck region. Is p16 immunohistochemistry a reliable surrogate marker

Background:Human papillomavirus 16 infection has been proven to be associated with oropharyngeal squamous cell carcinomas (SCCs) and is probably the main reason of the reported increase in the incidence. The role of high-risk (HR) HPV for carcinogenesis of other sites in the head and neck awaits confirmation. With the aim to evaluate the prevalence of HPV infection and the reliability of different diagnostic tools in SCCs of different sites, 109 consecutive untreated head and neck SCCs were enroled, and fresh tumour samples collected.Methods:Human papillomavirus DNA was detected by Digene Hybrid Capture 2 (HC2). Human papillomavirus E6 and E7 mRNA were detected by NucliSENS EasyQ HPVv1. P16 expression was evaluated by immunohistochemistry.Results:In all, 12.84% of cases were infected by HR genotypes and 1.84% by low-risk genotypes. Human papillomavirus 16 accounted for 87% of HR infections. The overall agreement between DNA and RNA detection is 99.1%. Although p16 expression clearly correlates with HPV infection (P=0.0051), the inter-rater agreement is poor (k=0.27). The oropharynx showed the highest HR HPV infection rate (47.6%) and was also the only site in which p16 immunohistochemistry revealed to be a fair, but not excellent, diagnostic assay (κ=0.61).Conclusion:The prognostic role of HR HPV infection in oropharyngeal oncology, with its potential clinical applications, underscores the need for a consensus on the most appropriate detection methods. The present results suggest that viral mRNA detection could be the standard for fresh samples, whereas DNA detection could be routinely used in formalin-fixed, paraffin-embedded samples.

Whole-brain radiotherapy combined with surgery or stereotactic radiotherapy in patients with brain oligometastases: Long-term analysis

Objective:To verify whether the treatment of brain oligometastases with whole-brain radiotherapy (WBRT) plus stereotactic radiotherapy (SRT) or surgical resection results in different outcomes.Methods:Files of patients affected by brain metastases submitted to surgical resection followed by WBRT (group A) or WBRT + SRT (group B) were retrospectively selected for this study. The two treatment groups were matched for the following potential prognostic factors: WBRT schedule, age, gender, performance status, tumor type, number of brain metastases, extra-cerebral metastases, and recursive partitioning analysis class (RPA). The outcomes of patients in both groups were evaluated in terms of toxicity, local control, and overall survival.Results:Total of 97 patients were selected (56 male; 42 female) who were respectively submitted to surgical resection followed by WBRT (group A, n = 50 patients) or WBRT + SRT (Group B, n = 47 patients). Median follow-up was 95 months (range, 8–171 months). The 1-year local control rates were 46.0% and 69.0% respectively. No significant difference in local tumor control was observed between group A and B (p = 0.10). Median overall survival was 15 and 19 months in group A and B, respectively. One-year survival was 56.0% and 62%, respectively. No difference was observed in the two groups (p = 0.40).Conclusion:Surgery remains the main therapeutic approach in symptomatic patients; nevertheless, our data support the use of WBRT plus SRT in one or two brain metastases smaller than 3 cm.Zielsetzung:Zu untersuchen, ob die Behandlung von Oligohirnmetastasen mit Ganzhirnbestrahlung (whole-brain radiotherapy, WBRT) plus stereotaktischer Radiotherapie (SRT) oder chirurgischer Resektion unterschiedliche Ergebnisse bringt.Methoden:Krankenakten von Patienten mit operativ entfernten Hirnmetastasen und anschließender WBRT (Gruppe A) oder WBRT + SRT (Gruppe B) wurden retrospektiv für diese Studie ausgewählt. Die zwei Beghandlungsarme wurden für folgende prognostische Parameter gematcht: WBRT-Schema. Alter, Geschlecht, Allgemeinzustand, Art des Primärtumors, Anzahl der Hirnmetastasen, extrazerebrale Metastasen, Recursive-Partioning-Analysis-(RPA-)Klasse. Das Behandlungsergebnis für beide Patientengruppen wurde im Hinblick auf Toxizität, lokale Tumorkontrolle und Gesamtüberleben bewertet.Ergebnisse:Insgesamt wurden 97 Patienten ausgewählt (56 m; 42 w), die entweder mit operativer Entfernung und anschließender WBRT (Gruppe A, n = 50 Pat.) oder mit WBRT + SRT (Gruppe B, n = 47 Pat.) behandelt wurden. Die mediane Beobachtungszeit betrug 95 Monate (Spanne 8–171). Die lokale Tumorkontrolle nach 1 Jahr betrug 46,0% (Gruppe A) und 69,0% (Gruppe B), ohne dass dieser Unterschied statistisch signifikant wäre (p = 0,10). Das mediane Gesamtüberleben betrug jeweils 15 und 19 Monate in Gruppe A and B. Die 1-Jahres-Überlebensrate betrug jeweils 56,0% and 62%. Es wurde kein Unterschied zwischen den beiden Gruppen gefunden (p = 0,40).Schlussfolgerung:Die chirurgische Entfernung bleibt die Behandlungsoption bei symptomatischen Patienten. Unsere Daten sprechen für eine Behandlung mit WBRT plus SRT bei Vorliegen von ein oder zwei Hirnmetastasen, die kleiner als 3 cm sind.

Multidisciplinary Approach in the Treatment of T1 Glottic Cancer The Role of Patient Preference in a Homogenous Patient Population

AbstractBackground and Purpose:To compare oncological outcome and voice quality among a uniform and well-defined subset of patients with T1 glottic carcinoma.Patients and Methods:Patients, affected by laryngeal glottic carcinoma, treated by laser CO2 surgery or radiotherapy, have been analyzed. Overall survival and disease-free survival were calculated. In order to verify differences in functional outcomes and voice quality, all patients were interviewed during their last follow-up visit during 2009 using the VHI (Voice Handicap Index) questionnaire. The data were analyzed using the MedCalc software.Results:A total of 143 patients were analyzed: 73 underwent surgery and 70 underwent radiotherapy. No statistically significant differences were found between the two groups in terms of overall survival and disease-free survival; dividing patients into stages T1a and T1b also made no difference. In order to evaluate the differences in outcomes for surgery and radiotherapy, patients were interviewed using the VHI questionnaire. Better scores for each category in the VHI were found for patients receiving radiotherapy compared to surgery (physical: p = 0.0023; functional: p < 0.0001; environmental: p < 0.001). The median VHI score for radiotherapy patients was 4, while for surgical patients it was 18 (p < 0.0001).Conclusion:This study confirms the well-known knowledge that results from radiotherapy and surgery in early glottic cancer treatment are equivalent. Furthermore, the role of patient preference in the treatment modality choice and the value of a multidisciplinary approach for a detailed and multi-oriented discussion with the patient are outlined.ZusammenfassungHintergrund und Zielsetzung:Es sollen das onkologische Ergebnis und die Sprachqualität in einer homogenen und gut definierten Gruppe von Patienten mit T1-Stimmbandkarzinomen verglichen werden.Patienten und Methoden:Patienten mit einem Glottiskarzinom, die sich einer CO2-Laser-Operation oder einer Radiotherapie unterzogen hatten, wurden analysiert. Das Gesamtüberleben und die krankheitsfreie Zeit wurden errechnet. Um Unterschiede im funktionellen Ergebnis und bezüglich der Sprachqualität zu quantifizieren, wurden alle Patienten während der letzten Nachsorge im Jahre 2009 dazu angehalten den VHI-(Voice Handicap Index-)Fragebogen auszufüllen. Diese Daten wurden mittels der MedCalc-Software bearbeitet.Ergebnisse:Insgesamt wurden 143 Patienten untersucht: 73 wurden operiert und 70 erhielten eine Strahelentherapie. Es konnte kein statistisch signifikanter Unterschied zwischen den zwei Gruppen bezüglich der Gesamtüberlebenszeit und der krankheitsfreien Zeit festgestellt werden; dies gelang auch nicht, wenn die Gruppen in Stadium T1a und T1b getrennt betrachtet wurden. Um die Unteschiede zwischen Operation und Radiotherapie zu evaluieren, wurde der VHI-Fragebogen verwendet. Es ließ sich zeigen, dass in jeder Kategorie des VHI-Fragebogens die Patienten, die strahlentherapiert wurden, bessere Ergebnisse erzielten als jene, die operiert wurden („physikalisch“: p = 0,0023; „funktionell“: p < 0,0001). Der durchschnittliche VHI-Score für strahlentherapierte Patienten ist 4, im Gegensatz zu 18 für operierte Patienten (p < 0,0001).Zusammenfassung:Diese Studie bestätigt die Erkenntnis, dass Radiotherapie und Operation beim Stimmbandkarzinom im frühen Stadium zu äquivalenten Ergebnissen führen. Weiterhin wird die Bedeutung des Patientenwunsches im Hinblick auf die Therapieoptionen und die Bedeutung eines multidiszplinären Therapieansatzes belegt.

Human Papillomavirus (HPV) Infection in Squamous Cell Carcinomas Arising From the Oropharynx: Detection of HPV DNA and p16 Immunohistochemistry as Diagnostic and Prognostic Indicators—A Pilot Study

PURPOSE Human papillomavirus (HPV) 16 infection is associated with oropharyngeal carcinogenesis and is likely the cause of the reported increase in disease incidence. We evaluated the prevalence of HPV infection and the reliability of different diagnostic tools using primary tumor samples from a cohort of 50 patients. METHODS AND MATERIALS Formalin-fixed paraffin-embedded (FFPE) tumor samples were collected from all 50 consecutive primary oropharyngeal SCC patients who were enrolled in the study; fresh tumor samples were available in 22 cases. NucliSENS EasyQ HPVv1 was used for RNA, and Digene Hybrid Capture-2(HC2) was used for DNA detection. p16 Expression was evaluated by immunohistochemistry in FPPE specimens. RESULTS Based on the DNA detection assay on FFPE samples, the frequency of high-risk HPV infection was 32%. The agreement rate between HPV RNA and HPV DNA detection in fresh samples was 100%. The agreement rate between p16 immunohistochemistry (IHC) and the detection of HPV DNA in the FFPE samples was fair but not excellent (κ = 0.618). HPV DNA detection was highly significant, as measured by disease-specific survival and determined using a Wilcoxon test (P=.001). p16 IHC also exhibited a prognostic value but with a lower statistical significance (P=.0475). The detection of HPV DNA, but not p16 IHC, was also significantly correlated with locoregional control (P=.0461). CONCLUSION Diagnostic methods based on the detection of HPV nucleic acids appear to be more reliable and objective because they do not require reading by a trained histopathologist. Furthermore, the detection of HPV DNA exhibits an improved correlation with survival, and therefore appears definitely more reliable than p16 IHC for routine use in clinical practice.

Whole-Brain Radiotherapy Combined with Surgery or Stereotactic Radiotherapy in Patients with Brain Oligometastases

Objective:To verify whether the treatment of brain oligometastases with whole-brain radiotherapy (WBRT) plus stereotactic radiotherapy (SRT) or surgical resection results in different outcomes.Methods:Files of patients affected by brain metastases submitted to surgical resection followed by WBRT (group A) or WBRT + SRT (group B) were retrospectively selected for this study. The two treatment groups were matched for the following potential prognostic factors: WBRT schedule, age, gender, performance status, tumor type, number of brain metastases, extra-cerebral metastases, and recursive partitioning analysis class (RPA). The outcomes of patients in both groups were evaluated in terms of toxicity, local control, and overall survival.Results:Total of 97 patients were selected (56 male; 42 female) who were respectively submitted to surgical resection followed by WBRT (group A, n = 50 patients) or WBRT + SRT (Group B, n = 47 patients). Median follow-up was 95 months (range, 8–171 months). The 1-year local control rates were 46.0% and 69.0% respectively. No significant difference in local tumor control was observed between group A and B (p = 0.10). Median overall survival was 15 and 19 months in group A and B, respectively. One-year survival was 56.0% and 62%, respectively. No difference was observed in the two groups (p = 0.40).Conclusion:Surgery remains the main therapeutic approach in symptomatic patients; nevertheless, our data support the use of WBRT plus SRT in one or two brain metastases smaller than 3 cm.Zielsetzung:Zu untersuchen, ob die Behandlung von Oligohirnmetastasen mit Ganzhirnbestrahlung (whole-brain radiotherapy, WBRT) plus stereotaktischer Radiotherapie (SRT) oder chirurgischer Resektion unterschiedliche Ergebnisse bringt.Methoden:Krankenakten von Patienten mit operativ entfernten Hirnmetastasen und anschließender WBRT (Gruppe A) oder WBRT + SRT (Gruppe B) wurden retrospektiv für diese Studie ausgewählt. Die zwei Beghandlungsarme wurden für folgende prognostische Parameter gematcht: WBRT-Schema. Alter, Geschlecht, Allgemeinzustand, Art des Primärtumors, Anzahl der Hirnmetastasen, extrazerebrale Metastasen, Recursive-Partioning-Analysis-(RPA-)Klasse. Das Behandlungsergebnis für beide Patientengruppen wurde im Hinblick auf Toxizität, lokale Tumorkontrolle und Gesamtüberleben bewertet.Ergebnisse:Insgesamt wurden 97 Patienten ausgewählt (56 m; 42 w), die entweder mit operativer Entfernung und anschließender WBRT (Gruppe A, n = 50 Pat.) oder mit WBRT + SRT (Gruppe B, n = 47 Pat.) behandelt wurden. Die mediane Beobachtungszeit betrug 95 Monate (Spanne 8–171). Die lokale Tumorkontrolle nach 1 Jahr betrug 46,0% (Gruppe A) und 69,0% (Gruppe B), ohne dass dieser Unterschied statistisch signifikant wäre (p = 0,10). Das mediane Gesamtüberleben betrug jeweils 15 und 19 Monate in Gruppe A and B. Die 1-Jahres-Überlebensrate betrug jeweils 56,0% and 62%. Es wurde kein Unterschied zwischen den beiden Gruppen gefunden (p = 0,40).Schlussfolgerung:Die chirurgische Entfernung bleibt die Behandlungsoption bei symptomatischen Patienten. Unsere Daten sprechen für eine Behandlung mit WBRT plus SRT bei Vorliegen von ein oder zwei Hirnmetastasen, die kleiner als 3 cm sind.

Chemoradiation With Concomitant Boosts Followed by Radical Surgery in Locally Advanced Cervical Cancer: Long-term Results of the ROMA-2 Prospective Phase 2 Study

PURPOSE This prospective, phase 2 study aimed at assessing the efficacy of accelerated fractionation radiation therapy by concomitant boosts (CBs) associated with chemoradiation therapy (CRT) of the whole pelvis, in improving the rate of pathological complete response (pCR) to treatment in patients with International Federation of Gynaecology and Obstetrics (FIGO) stage IB2-IVA locally advanced cervical cancer. METHODS AND MATERIALS Neoadjuvant CRT included conformal irradiation of the whole pelvis with a total dose of 39.6 Gy (1.8 cGy/fraction, 22 fractions), plus additional irradiation of primary tumor and parametria with 10.8 Gy administered with CBs (0.9 cGy/fraction, 12 fractions, every other day). Concomitant chemotherapy included cisplatin (20 mg/m(2), days 1-4 and 26-30 of treatment), and capecitabine (1300 mg/m(2)/daily, orally) during the first 2 and the last 2 weeks of treatment. Radical hysterectomy plus pelvic with or without aortic lymphadenectomy was performed within 6 to 8 weeks from CRT. Toxicity was recorded according to Radiation Therapy Oncology Group toxicity criteria and Chassagne grading system. Based on the Simon design, 103 cases were required, and the regimen would be considered active if >45 pCR were registered (α error = 0.05; β error = 0.1). RESULTS pCR was documented in 51 cases (50.5%), and the regimen was considered active, according to the planned statistical assumptions. At median follow-up of 36 months (range: 7-85 months), the 3-year local failure rate was 7%, whereas the 3-year disease-free and overall survival rates were 73.0% and 86.1%, respectively. Grade 3 leukopenia and neutropenia were reported in only 1 and 2 cases, respectively. Gastrointestinal toxicity was always grade 1 or 2. CONCLUSIONS Addition of CBs in the accelerated fractionation modality to the whole pelvis chemoradiation followed by radical surgery results in a high rate of pathologically assessed complete response to CRT and a very encouraging local control rate, with acceptable toxicity.

Can Elderly Patients With Newly Diagnosed Glioblastoma be Enrolled in Radiochemotherapy Trials

Objectives:Age is an unfavorable prognostic factor in glioblastoma multiforme (GBM). To assess the possibility and the advantage of radiotherapy (RT) plus concomitant/sequential temozolomide (TMZ) in patients over 65 years with GBM, we analyzed 4 prospective trials in terms of compliance and outcomes. Methods:Elderly patients with histologically proven GBM, included in 4 prospective phase II studies with a Karnofsky Performance Status (KPS) >70 and a Charlson Comorbidity Index (CCI) <3, were selected for these analyses. Patients were treated by 3D-conformal RT (60 Gy), fractionated stereotactic conformal-RT (69.4 Gy), or intensity-modulated RT with simultaneous integrated boost (63 Gy). Concomitant (standard modality, first and last week, or from the Monday to Friday) and adjuvant chemotherapy with TMZ was administered. To stratify patients, recursive partitioning analysis was used. Safety and tolerability were measured by the National Cancer Institute Common Criteria. Progression-free survival (PFS) and overall survival (OS) were calculated by Kaplan-Meier method. Results:From 2001 to 2011, 201 patients were enrolled in 4 trials and 111 elderly patients were recruited for this analysis. Compliance was 96.4%: 4/111 patients discontinued treatment, prevalently for disease progression. During radiochemotherapy, acute toxicity was mild. At a median follow-up of 64 months (range, 9 to 122 mo), median PFS and OS were 10 and 13 months, respectively. Extent of surgery (P=0.009) and radiation dose (P=0.01) significantly improved survival. Conclusions:Radiochemotherapy is effective and well tolerated by elderly patients when KPS >70 and CCI <3; therefore these criterions should be considered to enroll elderly patients in combined prospective study.

Chemoradiation and brachytherapy in extrahepatic bile duct carcinoma.

BACKGROUND To explore the role of radiotherapy in the extrahepatic bile duct carcinoma, and to understand if and when radiotherapy could be effective for this group of patients. METHODS A systematic review of recently published literature was completed. Recent studies using radiotherapy with survival data, resection rates and quality of life data have been analyzed. RESULTS There are no randomized trials regarding the treatment of extrahepatic cholangiocarcinoma. The bulk of available studies suggest that in some cases radio-chemotherapy can be used as adjuvant therapy. Radiotherapy could also have a role in unresectable cholangiocarcinoma: external radiotherapy or intraluminal brachytherapy--alone or in combination--could improve the outcome in selected patients. Finally, radiotherapy, and in particular intraluminal brachytherapy, could be used as a palliative treatment to improve the quality of life and in controlling symptoms. CONCLUSION The role of radiotherapy in extrahepatic cholangiocarcinoma remains undefined due to the lack of randomized trials or otherwise properly controlled studies.

Multidisciplinary Approach in the Treatment of T1 Glottic Cancer

AbstractBackground and Purpose:To compare oncological outcome and voice quality among a uniform and well-defined subset of patients with T1 glottic carcinoma.Patients and Methods:Patients, affected by laryngeal glottic carcinoma, treated by laser CO2 surgery or radiotherapy, have been analyzed. Overall survival and disease-free survival were calculated. In order to verify differences in functional outcomes and voice quality, all patients were interviewed during their last follow-up visit during 2009 using the VHI (Voice Handicap Index) questionnaire. The data were analyzed using the MedCalc software.Results:A total of 143 patients were analyzed: 73 underwent surgery and 70 underwent radiotherapy. No statistically significant differences were found between the two groups in terms of overall survival and disease-free survival; dividing patients into stages T1a and T1b also made no difference. In order to evaluate the differences in outcomes for surgery and radiotherapy, patients were interviewed using the VHI questionnaire. Better scores for each category in the VHI were found for patients receiving radiotherapy compared to surgery (physical: p = 0.0023; functional: p < 0.0001; environmental: p < 0.001). The median VHI score for radiotherapy patients was 4, while for surgical patients it was 18 (p < 0.0001).Conclusion:This study confirms the well-known knowledge that results from radiotherapy and surgery in early glottic cancer treatment are equivalent. Furthermore, the role of patient preference in the treatment modality choice and the value of a multidisciplinary approach for a detailed and multi-oriented discussion with the patient are outlined.ZusammenfassungHintergrund und Zielsetzung:Es sollen das onkologische Ergebnis und die Sprachqualität in einer homogenen und gut definierten Gruppe von Patienten mit T1-Stimmbandkarzinomen verglichen werden.Patienten und Methoden:Patienten mit einem Glottiskarzinom, die sich einer CO2-Laser-Operation oder einer Radiotherapie unterzogen hatten, wurden analysiert. Das Gesamtüberleben und die krankheitsfreie Zeit wurden errechnet. Um Unterschiede im funktionellen Ergebnis und bezüglich der Sprachqualität zu quantifizieren, wurden alle Patienten während der letzten Nachsorge im Jahre 2009 dazu angehalten den VHI-(Voice Handicap Index-)Fragebogen auszufüllen. Diese Daten wurden mittels der MedCalc-Software bearbeitet.Ergebnisse:Insgesamt wurden 143 Patienten untersucht: 73 wurden operiert und 70 erhielten eine Strahelentherapie. Es konnte kein statistisch signifikanter Unterschied zwischen den zwei Gruppen bezüglich der Gesamtüberlebenszeit und der krankheitsfreien Zeit festgestellt werden; dies gelang auch nicht, wenn die Gruppen in Stadium T1a und T1b getrennt betrachtet wurden. Um die Unteschiede zwischen Operation und Radiotherapie zu evaluieren, wurde der VHI-Fragebogen verwendet. Es ließ sich zeigen, dass in jeder Kategorie des VHI-Fragebogens die Patienten, die strahlentherapiert wurden, bessere Ergebnisse erzielten als jene, die operiert wurden („physikalisch“: p = 0,0023; „funktionell“: p < 0,0001). Der durchschnittliche VHI-Score für strahlentherapierte Patienten ist 4, im Gegensatz zu 18 für operierte Patienten (p < 0,0001).Zusammenfassung:Diese Studie bestätigt die Erkenntnis, dass Radiotherapie und Operation beim Stimmbandkarzinom im frühen Stadium zu äquivalenten Ergebnissen führen. Weiterhin wird die Bedeutung des Patientenwunsches im Hinblick auf die Therapieoptionen und die Bedeutung eines multidiszplinären Therapieansatzes belegt.

ENT COBRA (Consortium for Brachytherapy Data Analysis): Interdisciplinary standardized data collection system for head and neck patients treated with interventional radiotherapy (brachytherapy)

Purpose Aim of the COBRA (Consortium for Brachytherapy Data Analysis) project is to create a multicenter group (consortium) and a web-based system for standardized data collection. Material and methods GEC-ESTRO (Groupe Européen de Curiethérapie – European Society for Radiotherapy & Oncology) Head and Neck (H&N) Working Group participated in the project and in the implementation of the consortium agreement, the ontology (data-set) and the necessary COBRA software services as well as the peer reviewing of the general anatomic site-specific COBRA protocol. The ontology was defined by a multicenter task-group. Results Eleven centers from 6 countries signed an agreement and the consortium approved the ontology. We identified 3 tiers for the data set: Registry (epidemiology analysis), Procedures (prediction models and DSS), and Research (radiomics). The COBRA-Storage System (C-SS) is not time-consuming as, thanks to the use of “brokers”, data can be extracted directly from the single centers storage systems through a connection with “structured query language database” (SQL-DB), Microsoft Access®, FileMaker Pro®, or Microsoft Excel®. The system is also structured to perform automatic archiving directly from the treatment planning system or afterloading machine. The architecture is based on the concept of “on-purpose data projection”. The C-SS architecture is privacy protecting because it will never make visible data that could identify an individual patient. This C-SS can also benefit from the so called “distributed learning” approaches, in which data never leave the collecting institution, while learning algorithms and proposed predictive models are commonly shared. Conclusions Setting up a consortium is a feasible and practicable tool in the creation of an international and multi-system data sharing system. COBRA C-SS seems to be well accepted by all involved parties, primarily because it does not influence the centers own data storing technologies, procedures, and habits. Furthermore, the method preserves the privacy of all patients.