Patrizia Olmi

High-Risk Human Papillomavirus Affects Prognosis in Patients With Surgically Treated Oropharyngeal Squamous Cell Carcinoma

PURPOSE Human papillomavirus (HPV) DNA tumors actively integrating the E6 and E7 oncogenes have a distinct biologic behavior resulting in a more favorable prognosis. To which extent the viral integration by itself, and/or the associated wild-type (wt) TP53 status, and/or a functional p16 contribute to prognosis is unclear. PATIENTS AND METHODS To clarify how the presence of high-risk (HR) -HPV, TP53, and p16INK4a status interact with clinical outcome, we considered a retrospective series of 90 consecutive oropharyngeal cancer patients treated primarily with surgery. RESULTS Seventeen (19%) patients showed integrated HPV 16 DNA (HPV positive), wt TP53 in all but two patients, normal p16INK4a in 15 assessable patients, and p16 expression in all 17 patients. Thirty-five patients (39%), two of whom were HPV positive, harbored TP53 mutations. p16INK4a deletion and p16 null immunophenotype occurred in 28 and 58 patients, respectively, and was similarly distributed in both patients with mutated TP53 (48% and 82%, respectively) and in patients with wt TP53 (46% and 77%, respectively). Statistical analysis showed that HPV-positive status significantly affects all investigated end points: overall survival (P = .0018), incidence of tumor relapse (P = .0371), and second tumor (P = .0152), whereas TP53 and p16INK4a status and p16 expression were not prognostic by themselves. CONCLUSION Our molecular and clinical results are in agreement with previous findings but provide additional information into the biologic mechanisms involved in HR-HPV oropharyngeal cancer in comparison to HPV-negative tumors. According to the reduced risk of relapse and second tumors associated with HR-HPV positivity of oropharyngeal cancer, the therapeutic strategy and follow-up procedures should be reviewed.

Malignant peripheral nerve sheath tumors: Prognostic factors and survival in a series of patients treated at a single institution

The authors explored the prognostic factors and clinical outcomes of patients who had malignant peripheral nerve sheath tumors (MPNST) with and without neurofibromatosis type 1 (NF‐1).

Dermatofibrosarcoma Protuberans Treated at a Single Institution: A Surgical Disease With a High Cure Rate

PURPOSE Dermatofibrosarcoma protuberans (DFSP) is a rare, low-grade, cutaneous sarcoma with autocrine overproduction of the platelet-derived growth factor (PDGF) beta-chain from gene rearrangement as a key pathogenetic factor, now susceptible of molecular-targeted therapy. The aim of this retrospective analysis was to explore the outcome of patients with primary or recurrent DFSP. PATIENTS AND METHODS Two hundred eighteen patients surgically treated at the Istituto Nazionale per lo studio e la cura dei Tumori (Milan, Italy) over 20 years were reviewed. Local relapse, distant metastasis, and survival were studied. RESULTS One hundred thirty-six patients (62.4%) presented with a primary DFSP, while 82 patients (37.6%) had a recurrent disease. In the primary group, margins were microscopically positive in 11.8%, while in the recurrent group they were positive in 14.6% (P =.613). In the primary group, patients undergoing re-excision after inadequate previous surgery had residual disease in 62% of cases. Reconstructive surgery was needed in 30%, significantly more frequently in patients with a recurrence or a head and neck tumor. The crude cumulative incidence of local relapses was 4% at 10 years, and 2% at 10 years for distant metastases. No significant difference was found between primary and recurrent patients, as well as between positive and negative margins. CONCLUSION This being one of the largest mono-institutional series of DFSP, we confirm that long-term outcome is excellent, in terms of both local and distant control, after a wide excision with negative margins. Reconstructive surgery is often needed. Novel medical therapies will be of use in a limited subgroup of patients.

Retroperitoneal soft tissue sarcomas: patterns of recurrence in 167 patients treated at a single institution.

The objective of this study was to assess long‐term prognosis and patterns of failure in patients with retroperitoneal soft tissue sarcoma who underwent surgery with curative intent at a single institution. Several series of patients with retroperitoneal sarcoma were reported, providing widely variable data regarding local and distant failure.

Locoregionally advanced carcinoma of the oropharynx: conventional radiotherapy vs. accelerated hyperfractionated radiotherapy vs. concomitant radiotherapy and chemotherapy--a multicenter randomized trial.

PURPOSE To compare conventional fractionation radiation therapy (RT), Arm A, vs. split-course accelerated hyperfractionated RT (S-AHF), Arm B, vs. conventional fractionation RT plus concomitant chemotherapy (CT), Arm C, in terms of survival and toxicity for advanced, unresectable epidermoid tumors of oropharynx. METHODS AND MATERIALS Between January 1993 and June 1998, 192 previously untreated patients affected with Stage III and IV oropharyngeal carcinoma (excluding T1N1 and T2N1) were accrued in a multicenter, randomized Phase III trial (ORO 93-01). For Arms A and C, 66-70 Gy in 33-35 fractions, 5 days a week, were administered in 6.5-7 weeks to tumor and positive nodes. In Arm B, the dose delivered to tumor and involved nodes was 64-67.2 Gy, giving 2 fractions of 1.6 Gy every day with an interfraction interval of at least 4 h and preferably 6 h, 5 days a week. At 38.4 Gy, a 2-week split was planned; after the split, RT was resumed with the same modality. In Arm C, CT regimen consisted of carboplatin and 5-fluorouracil (CBDCA 75 mg/m(2), Days 1-4; 5-FU 1,000 mg/m(2) i.v. over 96 h, Days 1-4, recycling every 28 days (at 1st, 5th, and 9th week). RESULTS No statistically significant difference was detected in overall survival (p = 0.129): 40% Arm A vs. 37% Arm B vs. 51% Arm C were alive at 24 months. Similarly, there was no statistically significant difference in terms of event-free survival (p = 0.196): 20% for Arm A, 19% for Arm B, and 37% for Arm C were event free at 24 months. On the contrary, the 2-year disease-free survival was significantly different among the three arms (p = 0.022), with a superiority for Arm C. At 24 months, the proportion of patients without relapse was 42% for Arm C vs. 23% for Arm A and 20% for Arm B. Patients in Arm A less frequently developed G3+ acute mucositis than their counterparts in Arm B or C (14.7% vs. 40.3% vs. 44%). Regarding the CT-related acute toxicity, apart from 1 case of fatal nephrotoxicity, only hematologic G3+ (Grade 3 or higher) acute sequelae were observed (World Health Organization scale), most commonly leukopenia (22.7%). Arm C showed slightly more G3+ skin, s.c. tissue, and mucosal late side effects (RTOG scale), although significant sequelae were relatively uncommon, and mucosal sequelae were most commonly transient. The occurrence of persistent G3 xerostomia was comparable in all three treatment arms. CONCLUSIONS The combination of simultaneous CT and RT with the regimen of this trial is better than RT alone in advanced oropharyngeal squamous-cell carcinomas, by increasing disease-free survival. This improvement, however, did not translate into an overall survival improvement, and was associated with a higher incidence of acute morbidity.

Staging and follow-up of nasopharyngeal carcinoma: magnetic resonance imaging versus computerized tomography.

PURPOSE To compare computerized tomography (CT) and magnetic resonance (MR) in relation to their accuracy in the staging of nasopharyngeal carcinoma (NPC); to compare CT and MR in postirradiation follow-up of NPC. METHODS AND MATERIALS Staging: From 1985 to 1993, 53 patients affected with NPC were studied with MR and CT. All cases were biopsy-proved epithelial carcinoma. Plain and contrast-enhanced CT scans were performed with third-generation scanners. Magnetic resonance were obtained with 0.5 and 1.5 Tesla units in sagittal, axial, and coronal planes. Computerized tomography was chosen as reference method and findings obtained with MR were compared to those obtained with CT. FOLLOW-UP From 1985 to 1993, 53 patients irradiated with radical intent were followed up with both CT and MR; 71 examinations were performed in all. The baseline follow-up scan was performed, in general, no sooner than 2 months after the end of radiotherapy. All patients were submitted to unlimited clinical follow-up. RESULTS Staging: Magnetic resonance showed retropharyngeal adenopathies in 6 of 14 cases in which oropharyngeal involvement had been reported after CT; in 3 other patients, adenopathies were recognized on MR, while primary extent to parapharyngeal space had been diagnosed on CT initially. Infiltration of long muscles of the neck was revealed with MR in 14 cases. On the other hand, CT showed bone invasion in 12 patients vs. 8 on MR. Upstaging to T4 occurred in four cases on the basis of CT; no upstaging occurred after MR. FOLLOW-UP Findings on CT were uncertain in 10 out of 53 patients, disease recurrence was excluded by MR in nine cases, whereas progressive disease was confirmed in one patient. CONCLUSION Staging: Our series shows that either CT and MR can provide essential information in the staging of NPC. Magnetic resonance, however, seems to provide the most detailed imaging of soft tissue invasion outside the nasopharynx and of retropharyngeal node involvement. Nonetheless, its limitations in evaluating bone details suggest that CT should be always performed when the status of base of skull is uncertain on MR. General reasons and our data indicate that CT can still be considered a valuable tool in routine NPC staging. Follow up: Magnetic resonance may be the modality of choice because it seems to solve, more often than CT, the problems of differentiation between postradiation changes and recurring tumor, apart from those cases showing subtle bone erosions on initial CT scan.

Accelerated fractionation in advanced head and neck cancer: results and analysis of late sequelae

From 1975 to 1985, 161 patients affected by head and neck cancer (58 oropharynx, 67 oral cavity, 36 paranasal sinuses) were treated with radiotherapy using an accelerated fractionation (AF) schedule at the University and Hospital Radiotherapy Departments of Florence. Most cases, classified with U.I.C.C. and A.J.C. TNM (1978) were advanced (137/161 = 85%). Five-year actuarial local control and survival was 38% for the oropharynx, 18% and 20% for the oral cavity, and 38% and 31% for the paranasal sinuses. Results were analysed according to T and N stage as well. Severe late sequelae were evaluated in 53 patients without local disease and with a minimum follow-up of one year: 8 patients developed osteonecrosis; there were 3 cases of trismus, 2 cases of laryngeal oedema, one case of blindness and one case of ophthalmitis.

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.

Epithelioid sarcoma: Prognostic factors and survival in a series of patients treated at a single institution

BackgroundEpithelioid sarcoma (ES) is a rare subtype of soft-tissue sarcoma of unknown histogenesis. Typically, it occurs superficially as single/multiple nodules (nodular ES), or in deeper tissues as a mass. The correlation between initial presentation and clinical outcome was investigated.MethodsFifty-four consecutive patients surgically treated at a single referral center were retrospectively reviewed. Thirty-six patients presented with a primary and 18 with a recurrent tumor. Potential prognostic clinicopathological variables, including macroscopic features at first presentation, were tested by univariable and multivariable analysis with respect to overall (OS), metastasis-free (MFS), and local recurrence-free survival (LRFS).ResultsThe 10-year OS was 61.8% for the whole series. Thirty patients relapsed; in detail, local and distant failure occurred in 14 (25.9%) and 24 (44.4%) patients, respectively. The lymph node involvement rate was 16/54 (29.6%). In both the whole series and the subset of patient with primary ES, single localized tumor correlated with increased OS at multivariable analysis; occurrence of nodal involvement during postoperative follow-up correlated to worse OS and MFS. Nodular ES was an independent predictor of worse LRFS. In univariable analysis, nodular ES was associated with smaller tumor size, distal limb locations, earlier classification of malignant tumor (TNM) stage, and higher amputation rate. A statistical difference in the pattern of failure between nodular and mass ES was found.ConclusionsPrimary tumor macroscopic features seem to correlate to different local aggressiveness and failure patterns. Better prognosis is associated with single localized disease stage and no occurrence of locoregional spread.

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.