N. Dinapoli

Analysis of intraprostatic failures in patients treated with hormonal therapy and radiotherapy: implications for conformal therapy planning

PURPOSE Conformal therapy of prostate cancer is based on high-dose irradiation to the entire prostate gland. The aim of this study was to analyze the pattern of intraprostatic recurrence in patients undergoing external beam radiotherapy (EBRT) at a dose of 65-70 Gy to evaluate whether conventional radiotherapy doses are adequate to control microscopic disease outside the primary tumor and therefore whether high-dose irradiation can be exclusively focused on the macroscopic disease. METHODS AND MATERIALS The clinical and radiologic reports of 118 patients with prostate cancer undergoing EBRT (64.8-70.2 Gy) combined with hormonal therapy were evaluated. In all patients, before and after therapy, the size and site of the primary neoplasm within the prostate were assessed by clinical examination and imaging studies. RESULTS With a median follow-up of 45 months (range 14-119), the 5-year actuarial local control rate was 83.9%. Twelve patients had an intraprostatic recurrence, with the appearance of a new nodule (in 5 patients with a complete response after therapy) or increased nodular size compared with the minimal size (in the 7 other patients). In all patients, on the basis of a semiquantitative evaluation of the site of recurrence, this was shown to originate within the initial tumor volume. CONCLUSION The results of this analysis seem to confirm some histologic findings observed in patients undergoing prostatectomy for local recurrence after radiotherapy that suggest that local recurrence usually originates in the primary tumor rather than in focal prostatic intraepithelial neoplasia. This observation might justify the application of conformal therapy procedures aimed at identifying the gross tumor volume, in the phase of boost, exclusively with the primary tumor.

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.

Single-Arm Phase II Study of Conformal Radiation Therapy and Temozolomide plus Fractionated Stereotactic Conformal Boost in High-Grade Gliomas

Purpose:To assess survival, local control and toxicity using fractionated stereotactic conformal radiotherapy (FSCRT) boost and temozolomide in high-grade gliomas (HGGs).Patients and Methods:Patients affected by HGG, with a CTV1(clinical target volume, representing tumor bed ± residual tumor + a margin of 5 mm) ≤ 8 cm were enrolled into this phase II study. Radiotherapy (RT, total dose 6,940 cGy) was administered using a combination of two different techniques: three-dimensional conformal radiotherapy (3D-CRT, to achieve a dose of 5,040 or 5,940 cGy) and FSCRT boost (19 or 10 Gy) tailored by CTV1diameter (≤ 6 cm and > 6 cm, respectively). Temozolomide (75 mg/m2) was administered during the first 2 or 4 weeks of RT. After the end of RT, temozolomide (150–200 mg/m2) was administered for at least six cycles. The sample size of 41 patients was assessed by the single proportion–powered analysis.Results:41 patients (36 with glioblastoma multiforme [GBM] and five with anaplastic astrocytoma [AA]) were enrolled; RTOG neurological toxicities G1–2 and G3 were 12% and 3%, respectively. Two cases of radionecrosis were observed. At a median follow-up of 44 months (range 6–56 months), global and GBM median overall survival (OS) were 30 and 28 months. The 2-year survival rate was significantly better compared to the standard treatment (63% vs. 26.5%; p < 0.00001). Median progression-free survival (PFS) was 11 months, in GBM patients 10 months.Conclusion:FSCRT boost plus temozolomide is well tolerated and seems to increase survival compared to the standard treatment in patients with HGG.ZusammenfassungZiel:Untersuchung von Uberleben, lokaler Tumorkontrolle und Toxizitat einer fraktionierten stereotaktischen konformalen Strahlentherapie (FSCRT) mit Boostbestrahlung in Kombination mit Temozolomid bei hochmalignen Gliomen (HMG).Patienten und Methodik:Patienten mit HMG und einem CTV1(klinisches Zielvolumen, d. h. Tumorbett ± Resttumor + einem Sicherheitsabstand von 5 mm) ≤ 8 cm wurden in diese Phase-II-Studie eingeschlossen. Die Strahlentherapie (Gesamtdosis 6 940 cGy) wurde als Kombination aus zwei unterschiedlichen Techniken appliziert: dreidimensionale konformale Strahlentherapie (3D-CRT, um eine Strahlendosis von 5 040 oder 5 940 cGy zu erreichen) und lokale Dosisaufsattigung mit FSCRT-Boost (19 oder 10 Gy), die auf den CTV1-Durchmesser (≤ 6 cm bzw. > 6 cm) zugeschnitten war. Temozolomid (75 mg/m2) wurde wahrend der ersten 2 oder 4 Wochen der Strahlentherapie verabreicht. Nach dem Ende der Strahlentherapie erhielten die Patienten Temozolomid (150–200 mg/m2) fur wenigstens sechs Zyklen. Die Fallzahl wurde mit Hilfe eines einfach-proportionalen Testverfahrens („single proportion-powered analysis“) bei 41 Patienten bestimmt.Ergebnisse:41 Patienten (36 mit Glioblastoma multiforme [GBM] und funf mit anaplastischem Astrozytom [AA]) wurden behandelt; Neurotoxizitat gemas RTOG-Skala G1–2 bzw. G3 wurde in 12% bzw. 3% der Patienten beobachtet. Zwei Falle von Radionekrose traten auf. Bei einer mittleren Beobachtungszeit von 44 Monaten (Range 6–56 Monate) lagen die mittlere Gesamt- und die GBM-spezifische Uberlebenszeit (OS) bei 30 und 28 Monaten. Die 2-Jahres-Uberlebensrate war signifikant besser im Vergleich zur Standardbehandlung (63% vs. 26,5%; p < 0.00001). Die mittlere progressionsfreie Uberlebenszeit (PFS) betrug 11 Monate, bei GBM-Patienten 10 Monate.Schlussfolgerung:FSCRT-Boostbestrahlung plus Temozolomid wird gut toleriert und scheint im Vergleich zur Standardbehandlung die Uberlebenszeit von Patienten mit HMG zu verbessern.

A two-variable linear model of parotid shrinkage during IMRT for head and neck cancer.

PURPOSE To assess anatomical, clinical and dosimetric pre-treatment parameters, possibly predictors of parotid shrinkage during radiotherapy of head and neck cancer (HNC). MATERIALS Data of 174 parotids from four institutions were analysed; patients were treated with IMRT, with radical and adjuvant intent. Parotid shrinkage was evaluated by the volumetric difference (DeltaV) between parotid volumes at the end and those at the start of the therapy, as assessed by CT images (MVCT for 40 patients, KVCT for 47 patients). Correlation between DeltaVcc/% and a number of dosimetric, clinical and geometrical parameters was assessed. Univariate as well as stepwise logistic multivariate (MVA) analyses were performed by considering as an end-point a DeltaVcc/% larger than the median value. Linear models of DeltaV (continuous variable) based on the most predictive variables found at the MVA were developed. RESULTS Median DeltaVcc/% were 6.95 cc and 26%, respectively. The most predictive independent variables of DeltaVcc at MVA were the initial parotid volume (IPV, OR: 1.100; p=0.0002) and Dmean (OR: 1.059; p=0.038). The main independent predictors of DeltaV% at MVA were age (OR: 0.968; p=0.041) and V40 (OR: 1.0338; p=0.013). DeltaVcc and DeltaV% may be well described by the equations: DeltaVcc=-2.44+0.076 Dmean (Gy)+0.279 IPV (cc) and DeltaV%=34.23+0.192 V40 (%)-0.2203 age (year). The predictive power of the DeltaVcc model is higher than that of the DeltaV% model. CONCLUSIONS IPV/age and Dmean/V40 are the major dosimetric and clinical/anatomic predictors of DeltaVcc and DeltaV%. DeltaVcc and DeltaV% may be well described by bi-linear models including the above-mentioned variables.

An umbrella protocol for standardized data collection (SDC) in rectal cancer: A prospective uniform naming and procedure convention to support personalized medicine

Predictive models allow treating physicians to deliver tailored treatment moving from prescription by consensus to prescription by numbers. The main features of an umbrella protocol for standardizing data and procedures to create a consistent dataset useful to obtain a trustful analysis for a Decision Support System for rectal cancer are reported.

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.

Effect of whole pelvic radiotherapy for patients with locally advanced prostate cancer treated with radiotherapy and long-term androgen deprivation therapy

PURPOSE To evaluate the effect of whole pelvic radiotherapy (WPRT) in prostate cancer patients treated with RT and long-term (>1 year) androgen deprivation therapy (ADT). METHODS AND MATERIALS Prostate cancer patients with high-risk features (Stage T3-T4 and/or Gleason score≥7 and/or prostate-specific antigen level≥20 ng/mL) who had undergone RT and long-term ADT were included in the present analysis. Patients with bowel inflammatory disease, colon diverticula, and colon diverticulitis were excluded from WPRT and treated with prostate-only radiotherapy (PORT). Patients were grouped according to nodal risk involvement as assessed by the Roach formula using different cutoff levels (15%, 20%, 25%, and 30%). Biochemical disease-free survival (bDFS) was analyzed in each group according to the RT type (WPRT or PORT). RESULTS A total of 358 patients treated between 1994 and 2007 were included in the analysis (46.9% with WPRT and 53.1% with PORT). The median duration of ADT was 24 months (range, 12-38). With a median follow-up of 52 months (range, 20-150), the overall 4-year bDFS rate was 90.5%. The 4-year bDFS rate was similar between the patients who had undergone WPRT or PORT (90.4% vs. 90.5%; p=NS). However, in the group of patients with the greatest nodal risk (>30%), a significant bDFS improvement was recorded for the patients who had undergone WPRT (p=.03). No differences were seen in acute toxicity among the patients treated with WPRT or PORT. The late gastrointestinal toxicity was similar in patients treated with PORT or WPRT (p=NS). CONCLUSIONS Our analysis has supported the use of WPRT in association with long-term ADT for patients with high-risk nodal involvement (>30%), although a definitive recommendation should be confirmed by a randomized trial.

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.