E. Orlandi

Tumor stage, human papillomavirus and smoking status affect the survival of patients with oropharyngeal cancer: an Italian validation study

BACKGROUND Tumor human papillomavirus (HPV) status strongly affects overall survival (OS) of oropharyngeal cancer (OPC) patients. Recently, three groups with different outcomes were identified based on HPV status, smoking history and tumor stage. Our objective was to validate this model using a single-institutional retrospective database. PATIENTS AND METHODS Patients (n=120) diagnosed with OPC at our institution, treated with concomitant cisplatin plus radiotherapy (RT) (n=64), induction chemotherapy followed by concomitant chemoradiation (n=39) or RT alone (n=17), were stratified in three groups with respect to the risk of death (low 26, intermediate 46 and high 49 patients) according to tumor p16 expression as surrogate of HPV status, pack-years of tobacco smoking and nodal/tumor stage. Group-stratified Kaplan-Meier OS curves were estimated and compared using the log-rank test. RESULTS The 2-year OS estimates were 100%, 86% and 70%, respectively. The difference between the survival curves was statistically significant (P=0.009). The Harrells concordance index was 0.70. The calibration plot showed a good concordance between our results and those observed in the original study. CONCLUSIONS This study validates the risk grouping previously identified. Risk-driven clinical decision making and trial designs will help in better defining the most appropriate treatment in OPC patients.

Radiobiological basis and clinical results of the simultaneous integrated boost (SIB) in intensity modulated radiotherapy (IMRT) for head and neck cancer: A review

The simultaneous integrated boost (SIB)-IMRT technique allows the simultaneous delivery of different dose levels to different target volumes within a single treatment fraction. The most significant aspect associated with SIB-IMRT is related to the fractionation strategy, concerning two time-dose parameters: (1) the shortening of the overall treatment time (OTT); (2) the increase of fraction size (FS) to the boost volume. The SIB-IMRT technique represents, therefore, a new way to investigate the accelerated fractionation in definitive treatment of head and neck (H&N) cancers. The aims of this paper are the following: (1) to briefly review the influence of OTT and FS on H&N tumors and on acutely and late responding normal tissues; (2) to review the results of clinical studies of accelerated radiotherapy not employing IMRT in H&N cancer; (3) to review the clinical experiences of the SIB-IMRT technique and to compare the different SIB regimes in terms of radiobiological efficacy.

Oropharyngeal squamous cell carcinoma treated with radiotherapy or radiochemotherapy: prognostic role of TP53 and HPV status.

PURPOSE To study the prognostic value of the TP53 mutation and human papilloma virus (HPV) status in oropharyngeal squamous cell carcinoma (OPSCC). METHODS AND MATERIALS The TP53 mutation and HPV status were analyzed in 78 cases of locoregionally advanced OPSCC. The possible correlation of these factors with locoregiownal control, relapse-free survival, disease-specific survival, and overall survival (OS) was also investigated. RESULTS Of these 78 cases, 22 had disruptive and 22 had non-disruptive (silent) TP53 mutations; the remaining 34 cases had wild-type (WT) TP53. HPV 16 DNA was found in 9 cases (11%), but all HPV-positive (HPV+) cases carried a functional p53 protein, except for 1 case that had a silent mutation. HPV+ patients fared better than HPV-negative (HPV-) patients in terms of all survival parameters, with highly statistically significant differences between the groups. Specifically, no distant metastases were observed in the HPV+ patients, whereas they occurred in 17% of the HPV- patients. However, no difference was observed between the WT TP53 and mutation group, even when this was analyzed in terms of disruptive and non-disruptive mutations. Regardless, treatment with chemotherapy nearly doubled the 5-year OS rates, both in the mutation (42% vs. 22%) and WT (30 vs. 16%) group, but only the mutation group showed improvement in all survival parameters. In addition, the second tumor-free 5-year survival rate was 72% in HPV- cases, but no second tumors were observed in HPV+ and WT p53 cases. CONCLUSIONS Patients with HPV+ OPSCC have an excellent prognosis after radiochemotherapy, but cisplatin-based chemotherapy may not confer a satisfactory outcome, especially in WT cases, thereby justifying the additional or alternative use of taxanes and epidermal growth factor receptors inhibitors. Uncommon distant metastases and second tumors in the HPV+ group may be cause for clinicians to review the follow-up policies in these patients.

Further Improvement in Outcomes of Nasopharyngeal Carcinoma With Optimized Radiotherapy and Induction Plus Concomitant Chemotherapy: An Update of the Milan Experience

PURPOSE To report the outcome of a consecutive series of patients with nonmetastatic nasopharyngeal carcinoma (NPC), focusing on the impact of treatment-related factors. METHODS AND MATERIALS Between 2000 and 2006, 87 patients with NPC were treated with either conventional (two- or three-dimensional) radiotherapy (RT) or with intensity-modulated RT (IMRT). Of these patients, 81 (93%) received either concomitant CHT (24%) or both induction and concomitant chemotherapy (CHT) (69%). Stage was III in 36% and IV in 39% of patients. Outcomes in this study population were compared with those in the previous series of 171 patients treated during 1990 to 1999. RESULTS With a median follow-up of 46 months, actuarial rates at 3 years were the following: local control, 96%; local-regional control, 93%; distant control (DC), 90%; disease-free survival (DFS), 82%; overall survival, 90%. In Stage III to IV patients, distant control at 3 years was 56% in patients treated with concomitant CHT only and 92% in patients treated with both induction and concomitant CHT (p = 0.014). At multivariate analysis, histology, N-stage, RT technique, and total RT dose had the strongest independent impact on DFS (p < 0.05). Induction CHT had a borderline effect on DC (p = 0.07). Most dosimetric statistics were improved in the group of patients treated with IMRT compared with conventional 3D technique. All outcome endpoints were substantially better in the study population compared with those in the previous series. CONCLUSIONS Outcome of NPC has further improved in the study period compared with the previous decade, with a significant effect of RT technique optimization. The impact of induction CHT remains to be demonstrated in controlled trials.

Treatment-related outcome of oropharyngeal cancer patients differentiated by HPV dictated risk profile: a tertiary cancer centre series analysis

BACKGROUND To date, no treatment modality has been identified as more effective for oropharyngeal cancer (OPC), and no predictive factors are known to guide treatment decision for this disease. This retrospective study evaluates the differential effects of diverse treatment options for OPC according to patient risk profiles. PATIENTS AND METHODS We considered two series of locally advanced squamous cell OPC patients treated with either surgery followed by radiotherapy (surgical series) or chemoradiation (CRT) with/without induction docetaxel, cisplatin and 5-fluorouracil (TPF) chemotherapy (CRT series). Smoking habits, tumor p16 expression/human papillomavirus (HPV) status and T and N stage were analyzed to stratify the patients according to Angs risk profile (low, intermediate and high risk). Overall survival (OS) and disease-free survival were calculated with the Kaplan-Meier method. RESULTS Globally, 171 patients were considered, 56 in surgical and 115 in CRT series. Patients were stratified in low- (20% of surgical and CRT groups), intermediate- (23% and 41%) and high-risk (57% and 39%) groups. In the surgical series, 5-year OS was 54.5%, 46.9% and 40.0% in low, intermediate and high Angs risk profiles, respectively, whereas in the CRT series those were 100%, 78.9% and 46.7%, respectively. In the multivariable analyses, adjusting for inhomogeneity between the treatment group, the CRT effect was significantly higher in the low- and intermediate-risk groups (P-value for the interaction treatment risk group = 0.034 in the OS analysis). CONCLUSIONS In this retrospective analysis, low- and intermediate-risk OPC patients had a better survival when treated with CRT compared with open surgery followed by radiation therapy. These data suggest that different treatment approaches might be essential in determining outcome results.BACKGROUND To date, no treatment modality has been identified as more effective for oropharyngeal cancer (OPC), and no predictive factors are known to guide treatment decision for this disease. This retrospective study evaluates the differential effects of diverse treatment options for OPC according to patient risk profiles. PATIENTS AND METHODS We considered two series of locally advanced squamous cell OPC patients treated with either surgery followed by radiotherapy (surgical series) or chemoradiation (CRT) with/without induction docetaxel, cisplatin and 5-fluorouracil (TPF) chemotherapy (CRT series). Smoking habits, tumor p16 expression/human papillomavirus (HPV) status and T and N stage were analyzed to stratify the patients according to Angs risk profile (low, intermediate and high risk). Overall survival (OS) and disease-free survival were calculated with the Kaplan-Meier method. RESULTS Globally, 171 patients were considered, 56 in surgical and 115 in CRT series. Patients were stratified in low- (20% of surgical and CRT groups), intermediate- (23% and 41%) and high-risk (57% and 39%) groups. In the surgical series, 5-year OS was 54.5%, 46.9% and 40.0% in low, intermediate and high Angs risk profiles, respectively, whereas in the CRT series those were 100%, 78.9% and 46.7%, respectively. In the multivariable analyses, adjusting for inhomogeneity between the treatment group, the CRT effect was significantly higher in the low- and intermediate-risk groups (P-value for the interaction treatment risk group = 0.034 in the OS analysis). CONCLUSIONS In this retrospective analysis, low- and intermediate-risk OPC patients had a better survival when treated with CRT compared with open surgery followed by radiation therapy. These data suggest that different treatment approaches might be essential in determining outcome results.

Docetaxel, cisplatin and 5-fluorouracil-based induction chemotherapy followed by intensity-modulated radiotherapy concurrent with cisplatin in locally advanced EBV-related nasopharyngeal cancer

BACKGROUND This monocentric study evaluates the activity and tolerability of docetaxel (Taxotere), cisplatin and 5-fluorouracil (5-FU) (TPF) induction chemotherapy followed by intensity-modulated radiotherapy (IMRT) concurrent with high-dose cisplatin in Epstein-Barr virus -related locally advanced undifferentiated nasopharyngeal cancer. PATIENTS AND METHODS We retrospectively reviewed the records of patients who received induction docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2) on day 1, and 5-FU 750 mg/m(2)/day (96-h continuous infusion). Following induction, patients received full doses of IMRT concurrently with cisplatin 100 mg/m(2) every 21 days for three cycles. RESULTS Thirty patients received three TPF cycles (median). Induction was well tolerated; the main toxicity was neutropenia (33%, grade 3-4). During chemoradiotherapy, neutropenia (40%) and mucositis (43%) were the most frequent grade 3-4 adverse events. Mean dose of IMRT was 68.8 Gy. Worst late toxicity was xerostomia. Complete response rate was 93%. At 35 months, two patients had locoregional recurrence, three had distant metastases, and one had both. Three-year progression-free survival and overall survival were 79% [95% confidence interval (CI) 64% to 94%] and 87% (95% CI 74%- to 100%), respectively. CONCLUSIONS In this high-stage nonendemic cancer population, TPF followed by high-dose cisplatin IMRT was promising; this treatment approach deserves evaluation in randomized trials.

Set-up errors analyses in IMRT treatments for nasopharyngeal carcinoma to evaluate time trends, PTV and PRV margins

Abstract Introduction. The aims of this study were to analyze the systematic and random interfractional set-up errors during Intensity Modulated Radiation Therapy (IMRT) in 20 consecutive nasopharyngeal carcinoma (NPC) patients by means of Electronic Portal Images Device (EPID), to define appropriate Planning Target Volume (PTV) and Planning Risk Volume (PRV) margins, as well as to investigate set-up displacement trend as a function of time during fractionated RT course. Material and methods. Before EPID clinical implementation, an anthropomorphic phantom was shifted intentionally 5 mm to all directions and the EPIs were compared with the digitally reconstructed radiographs (DRRs) to test the systems capability to recognize displacements observed in clinical studies. Then, 578 clinical images were analyzed with a mean of 29 images for each patient. Results. Phantom data showed that the system was able to correct shifts with an accuracy of 1 mm. As regards clinical data, the estimated population systematic errors were 1.3 mm for left-right (L-R), 1 mm for superior-inferior (S-I) and 1.1 mm for anterior-posterior (A-P) directions, respectively. Population random errors were 1.3 mm, 1.5 mm and 1.3 mm for L-R, S-I and A-P directions, respectively. PTV margin was at least 3.4, 3 and 3.2 mm for L-R, S-I and A-P direction, respectively. PRV margins for brainstem and spinal cord were 2.3, 2 and 2.1 mm and 3.8, 3.5 and 3.2 mm for L-R, A-P and S-I directions, respectively. Set-up error displacements showed no significant changes as the therapy progressed (p>0.05), although displacements >3 mm were found more frequently when severe weight loss or tumor nodal shrinkage occurred. Discussion. These results enable us to choose margins that guarantee with sufficient accuracy the coverage of PTVs and organs at risk sparing. Collected data confirmed the need for a strict check of patient position reproducibility in case of anatomical changes.

Tp53 status as guide for the management of ethmoid sinus intestinal-type adenocarcinoma

OBJECTIVE Intestinal-type adenocarcinoma (ITAC) of the ethmoid sinus is a rare, occupational-related tumor. Optimal treatment consists of surgery and radiotherapy, while chemotherapy is still investigational. The molecular profile of ITAC is characterized by the occurrence of TP53 mutations associated with genotoxic agents such as wood dust. We investigated the role of p53 functionality in relation to the primary treatment. MATERIALS AND METHODS We retrospectively reviewed 100 medical charts of consecutive patients with a first diagnosis of ITAC treated at our Institute; 74 patients were evaluable for TP53 analysis. Thirty (41%) were treated from 1991 to 2006 with craniofacial resection followed by radiotherapy (Group A), compared with 44 patients (59%) treated from 1996 to 2006 with cisplatin-based induction chemotherapy (PFL) followed by standard treatment (Group B). RESULTS Five-year OS in Group A was 42%, while in Group B it was 70% (p = 0.041); 5-year DFS in Group A was 40%, while in Group B it was 66%, (p = 0.009) (p = 0.061 and 0.003 at Cox multivariable OS and DFS analyses). Analyzing each group according to p53 functional status, only for Group B patients (who received preoperative chemotherapy) both OS and DFS were in favor of functional p53 (p = 0.023 and p = 0.010, respectively). No impact of p53 functional status as a biomarker was observed in Group A. CONCLUSIONS Functional p53 may predict PFL-chemotherapy efficacy, offering a possible increase in survival when induction chemotherapy is given to a selected population. On the other hand, upcoming innovative approaches should be explored in the presence of non-functional p53.

Preoperative chemotherapy in advanced resectable OCSCC: long-term results of a randomized phase III trial

BACKGROUND Data on preoperative chemotherapy in resectable oral cavity cancer are conflicting. We present the long-term results of a randomized trial of induction chemotherapy in resectable oral cavity cancer. PATIENTS AND METHODS A randomized, parallel, multicentre trial evaluated the impact of three cycles of cisplatin 100 mg/m2 and fluorouracil 1000 mg/m2 (120-h infusion administered every 21 days) in stage T2-T4, N0-N2, previously untreated patients with advanced disease. Control group received upfront surgery. Postoperative radiation was offered to both arms when pathologic risk features were identified. The co-primary end points were the occurrence of locoregional or distant tumour relapse, and death. RESULTS Among the 198 enrolled patients, with a median follow-up of 11.5 years, there was no difference in the incidence of locoregional relapse between chemotherapy and control group (P=0.6337), nor in distant metastasis development (P=0.1527). There was also no difference between groups in overall survival (P=0.3402). Patients with a pathological complete response (pCR) had higher probability of survival than those without (10-year OS: 76.2% versus 41.3%, P=0.0004). Late toxicities in patients with a minimum follow-up of 60 months (42 in each group) were similar between arms, except from fibrosis (cumulative incidence 40% versus 22% in chemotherapy arm) and grade 2 dysphagia (14% versus 5%). CONCLUSIONS Long-term follow-up of this randomized trial confirmed the absence of survival benefit with preoperative chemotherapy in oral cavity cancer. Late toxicity was similar in the two arms except for fibrosis and dysphagia, which were less in the chemotherapy arm. The survival benefit for patients achieving a pCR was maintained.

Paranasal sinus cancer

Paranasal sinus cancers are rare diseases, accounting for about 5% of all head and neck malignancies. The variety of histological types and the overlapping pathological features with other entities constitute difficulties in pathologic interpretation, often requiring a skilled interpretation or a second opinion. Treatment of locally advanced disease relies on surgery and radiation therapy for operable disease, with a possible role for systemic treatment in selected histologies within a multimodal approach; unresectable paranasal sinus cancers are generally treated with a combination of radiotherapy and chemotherapy. The employment of high conformal radiation techniques, such as Intensity Modulated Radiation Therapy orcharged particle therapy, proton or carbon ion therapy may improve outcome and reduce late effects. Surgical treatment has evolved due to the progressive application of transnasal endoscopic techniques for naso-ethmoidal malignancies and due to innovative reconstructive techniques after resection of cancers of the maxillary sinus. Because of the rarity and complexity of this disease, multicenter trials represent an urgent need to improve prognosis and to reduce treatment-related effects.