Francesco Miccichè

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.

Long-Term Results After Neoadjuvant Radiochemotherapy for Locally Advanced Resectable Extraperitoneal Rectal Cancer

PurposeThis study was designed to evaluate long-term outcome in locally advanced resectable extraperitoneal rectal cancer treated by preoperative radiochemotherapy.MethodsEighty-three consecutive patients who developed locally advanced resectable extraperitoneal rectal cancer underwent preoperative concomitant radiochemotherapy followed by surgery, including total mesorectal excision.ResultsMedian follow-up was 108 (range, 10–169) months. The living patients underwent complete follow-up of, at least, nine years. Fourteen patients developed local recurrence. The time to detection was longer than two years in eight cases and longer than five years in four. Twenty-one patients developed metastases, 19 within the first five years from surgery. At the univariate analysis, clinical stage at presentation, lymph node involvement at clinical restaging after neoadjuvant therapy, and pTand pN stage were found positively correlated to the incidence of metastases. At the multivariate analysis, the only factors which confirmed a positive correlation were pT stage and pN stage. The actuarial overall survival at five, seven, and ten years was 75.5, 67.8, and 60.4 percent, respectively. The same figures for cancer-related survival were 77.9, 70, and 65.8 percent. At the univariate analysis, factors directly correlated with worse survival were: TNM stage at clinical restaging after neoadjuvant therapy (in particular lymph node involvement) pTNM, pT, and pN. At the multivariate analysis the only factors that confirmed a correlation with worse survival were pTNM, pT, and pN.ConclusionsLong- term follow-up allows to individuate 28 percent of all local relapses after the first five years from surgery. Postoperative stage is highly predictive of prognosis.

Low-dose fractionated radiotherapy and concomitant chemotherapy in glioblastoma multiforme with poor prognosis: a feasibility study

We explored the feasibility of concurrent palliative chemotherapy and low-dose fractionated radiotherapy (LD-FRT) in glioblastoma multiforme (GBM). Patients with recurrent/progressive GBM at least 3 months after the end of primary radiotherapy received 0.3 Gy twice daily with cisplatin and fotemustine if progressing on temozolomide, or 0.4 Gy twice daily with temozolomide if recurrent 4-6 months later (retreatment group). Newly diagnosed GBM with gross residual mass received 30 Gy with concomitant and adjuvant temozolomide and 0.4 Gy twice daily from the second adjuvant cycle (naive group) for 2-4 cycles. Twenty-six patients were enrolled. In the retreatment group (n = 17; median LD-FRT total dose 7.2 Gy [range 2.4-11.6]), grade 3 or 4 hematological toxicity was observed in 5.9% of patients. Median follow-up time was 20 months (range 4-35). Median progression-free survival (PFS) and overall survival (OS) from the time of recurrence or progression were 4 and 8 months, respectively (OS at 6 months, 69%; at 12 months, 16.7%). In the naive group (n = 9; median LD-FRT total dose 8 Gy [range 3.2-16]), grade 3 or 4 hematological toxicity was observed in 11.1% of patients. Median follow-up time was 17 months (range 8-20)-median PFS was 9 months, with PFS at 6 months and at 1 year of 66.7% and 26.7%, respectively; and median OS was 12 months, with OS at 6 months and at 1 year of 77.8% and 34.6%, respectively. LD-FRT with concurrent chemotherapy was well tolerated.

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.

Technical guidelines for head and neck cancer IMRT on behalf of the Italian association of radiation oncology - head and neck working group.

Performing intensity-modulated radiotherapy (IMRT) on head and neck cancer patients (HNCPs) requires robust training and experience. Thus, in 2011, the Head and Neck Cancer Working Group (HNCWG) of the Italian Association of Radiation Oncology (AIRO) organized a study group with the aim to run a literature review to outline clinical practice recommendations, to suggest technical solutions and to advise target volumes and doses selection for head and neck cancer IMRT. The main purpose was therefore to standardize the technical approach of radiation oncologists in this context. The following paper describes the results of this working group. Volumes, techniques/strategies and dosage were summarized for each head-and-neck site and subsite according to international guidelines or after reaching a consensus in case of weak literature evidence.

Nutritional counselling and oral nutritional supplements in head and neck cancer patients undergoing chemoradiotherapy

BACKGROUND The role of nutritional counselling (NC) with or without oral nutritional supplements (ONS) in patients receiving chemoradiotherapy (CRT) for head and neck cancer (HNC) still remains to be clearly defined, particularly with regard to CRT-related toxicity. METHODS Patients undergoing CRT for HNC received NC by the dietitian within the first 4 days of radiotherapy and weekly for the course of radiotherapy (approximately 6 weeks). A weekly supply of oral nutrition supplements [1560 kJ (373 kcal) per 100 g] for up to 3 months was provided to all patients. RESULTS Twenty-one patients completed CRT. Mucositis G3 developed in seven (33.3%) patients, whereas mucositis G4 was absent. Dysphagia was present before the start of treatment in four patients. In the remaining 17 patients, dysphagia G3 developed during/at the end of treatment in five cases. The percentage of patients interrupting anti-neoplastic treatment for was 28% for ≥6 days, 28% for 3-5 days and 44% for 0-2 days. Mucositis G3 frequency was lower in patients with a baseline body mass index (BMI, kg m(-2) ) ≥25 (two out of 12; 16.6%) than in patients with BMI <25 (five out of nine; 55.5%) (P = 0.161) and in patients with a baseline mid arm circumference >30 cm than in those with a mid arm circumference in the range 28.1-30 cm and <28 cm, and higher in patients with a greater weight loss and a greater reduction of serum albumin and mid arm circumference. CONCLUSIONS Nutritional counselling and ONS are associated with relatively low CRT-related toxicity and with mild deterioration of nutritional parameters.

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.

Comparison of total laryngectomy with surgical (cricohyoidopexy) and nonsurgical organ-preservation modalities in advanced laryngeal squamous cell carcinomas: A multicenter retrospective analysis

Functional outcome and quality of life (QOL) have become relevant endpoints in the field of laryngeal oncology, leading to the emergence of organ‐preserving strategies.

Oncologic outcomes in advanced laryngeal squamous cell carcinomas treated with different modalities in a single institution: A retrospective analysis of 65 cases

Treatment for laryngeal squamous cell carcinoma (SCC) has been predominantly surgical for decades, but in the last 20 years nonsurgical modalities (radiotherapy), with the aim of organ preservation, also became predominant among advanced stages. Retrospectively evaluating our series of stage III and stage IV laryngeal SCCs, we compared the 2 main therapeutic modalities.

Low-Dose Hyperradiosensitivity: Is There a Place for Future Investigation in Clinical Settings?

BACKGROUND AND PURPOSE In vitro radiation doses of below 0.5 Gy have been shown to be more effective than higher doses per unit dose in killing clonogenic cells of many epithelial tumor cell lines. This phenomenon is known as low-dose hyperradiosensitivity. Preclinical studies have now suggested that there is synergism between chemotherapy and low-dose fractionated radiotherapy (LD-FRT). To test the clinical efficacy of this approach, we prospectively evaluated concurrent palliative chemotherapy and LD-FRT in patients with various types of epithelial tumors. METHODS AND MATERIALS Patients suffering from relapses or metastases of epithelial tumors were scheduled to receive concurrent LD-FRT (two fractions of 0.4 Gy per day) and chemotherapy. Radiologic assessments were performed after three cycles of chemotherapy plus LD-FRT. RESULTS Between June 2006 and October 2007, 12 patients with lung cancer, 7 patients with head-and-neck tumors, 2 patients with breast cancer, and 1 patient with esophageal carcinoma, for a total patient population of 22, underwent concomitant LD-FRT and chemotherapy. All patients but 3 (86%) had received previous treatments for their cancer. The median total dose of LD-FRT delivered was 800 cGy (range, 320-1280 cGy). The overall response rate was 45% (42% in previously treated patients). Grade 3-4 hematologic toxicities (Radiation Therapy Oncology Group ratings) were observed in 2 patients. At a median follow-up of 6.5 months, however, no local toxicity was observed. CONCLUSION In our experience, concurrent LD-FRT and chemotherapy was well tolerated. Because the response rate seems promising, prospective Phase II studies of the strategy are now under way.