Locoregional Failure Analysis in Head-and-Neck Cancer Patients Treated with IMRT

Purpose:: Purpose: Analysis of locoregional failure in head-and-neck cancer (HNC) following intensity-modulated radiation therapy (IMRT), with focus on the location of locoregional failures in relation to the chosen planning target volumes (PTVs) and dose distributions. Patients and Methods:: Between January 2002 and May 2006, 280 HNC patients were subjected to IMRT at the authors' institution. Mean follow-up was 23.2 months (3-59.3 months). Definitive IMRT was performed in 75% of all patients. In 71%, simultaneous cisplatin-based chemotherapy was given. 70% of patients presented with T3/4, T1-2 N2c/3 or recurred disease. Locoregional failure patterns were analyzed. Results:: 2-year local, nodal, distant, disease-free, and overall survival rates were 80%, 87%, 87%, 73%, and 82%, respectively. 46 local (16%) and 31 nodal (11%) failures have been observed so far. Local tumor persistence was seen in 23/46 cases (50%), and nodal persistence in 12/31 (39%), respectively. One marginal local failure developed in a patient referred for a recurred oral cavity tumor. Three nodal failures developed outside the PTVs at unexpected locations. All other failures have been confirmed "in field”. No failure occurred in level Ib or upper level II. Local failure occurred mainly following definitive IMRT for large tumors, nodal failure only in nodally positive patients with nodal high-risk features. Conclusion:: The dose-volume concept as used here has shown to be adequate, with disease failure developing at the site of the initial gross tumor manifestation inside the boost volum

Prediction of Distant Metastasis in Head Neck Cancer Patients: Implications for Induction Chemotherapy and Pre-treatment Staging?

Background and Purpose: : Intensity modulated radiation therapy (IMRT) combined treatment approaches, surgical and radiodiagnostic advances, respectively, lead to improved local-regional control in head neck cancer (HNC). With increasing local-regional control, distant metastases (DM) become more meaningful. In some trials without concomitant chemotherapy, induction chemotherapy (IC) resulted in an absolute reduction of DM by ~10-15%. In order to define a more efficient selection of patients at risk for DM with respect to IC and M-staging, we analysed our patients treated by contemporary standards. Patients and Methods: : Between 1/2002 to 12/2007, 409 HNC patients were treated with IMRT; 303/409 (74%) underwent definitive, 106 (26%) postoperative IMRT. The mean/median follow-up was 23/20 months (3-72). 70% tolerated 4-7, 9% 1-3 cycles of simultaneous cisplatin. Treatment followed a prospectively designed protocol. In a previous study with 172 HNC IMRT patients, gross tumor volume (GTV) was found the strongest predictor for local-regional control. In the current study, this criterion has been prospectively tested for DM. Numbers needed to treat were calculated for IC. Results: : DM developed in 28/399 (7%) patients; 10 presented initially with DM (total 38/409). In 13/28 (46%), DM remained the only manifestation of disease. GTV was the strongest predictor for DM (p 70 cc; only 6 of them (6/73, 8%) developed isolated DM. Conclusion: : GTV was the most significant predictor for DM, that could guide selective pre-treatment M-staging. The subgroup with isolated DM in the high risk group, that could benefit from IC, is smal

Sclerosing Epithelioid Fibrosarcoma: Case Presentation and a Systematic Review

In sclerosing epithelioid fibrosarcoma (SEF), a rare variant of low-grade fibrosarcoma, treatment results and therapeutic options are poorly characterized. We systematically analyzed the data of all 89 patients (43 female, 46 male; mean age, 47years [range, 14-87years]) reported in the literature concerning clinical presentation, histopathology, differential diagnosis, treatment, survival rates, and prognosis, and we present an additional case. Information detailing treatment, disease control, and followup was available in 60 (67%), 75 (84%), and 68 patients (76%), respectively. Case history was variable with one-third of patients reporting a painful, enlarging mass. Ten patients (13%) presented with metastases, 23 (31%) had metastases develop after diagnosis, and 28 (37%) had local recurrence. Low cellularity, mild pleomorphy, and sclerotic hyaline matrix of SEF suggest a benign clinical behavior, and cell morphology allows for the wide differential diagnosis of benign, pseudosarcomatous, and malignant proliferations. In addition to surgery, 11 patients (15%) had chemotherapy, 22 (29%) had postoperative radiation therapy, and three (4%) had a combination of both. Twenty-three patients (34%) died from their disease after a mean of 46months, 24 (35%) were alive with disease, and 20 (31%) were alive without evidence of disease. Patients with SEF of the head and neck had the worst prognosis. Level of Evidence: Level III, prognostic study. See the Guidelines for Authors for a complete description of levels of evidenc

IMRT in Hypopharyngeal Tumors

Background and Purpose:: Intensity-modulated radiation therapy (IMRT) data on hypopharyngeal cancer (HC) are scant. In this study, the authors report on early results in an own HC patient cohort treated with IMRT. A more favorable outcome as compared to historical data on conventional radiation techniques was expected. Patients and Methods:: 29 consecutive HC patients were treated with simultaneous integrated boost (SIB) IMRT between 01/2002 and 07/2005 (mean follow-up 16 months, range 4-44 months). Doses of 60-71 Gy with 2.0-2.2 Gy/fraction were applied. 26/29 patients were definitively irradiated, 86% received simultaneous cisplatin-based chemotherapy. 60% presented with locally advanced disease (T3/4 Nx, Tx N2c/3). Mean primary tumor volume measured 36.2 cm3 (4-170 cm3), mean nodal volume 16.6 cm3 (0-97 cm3). Results:: 2-year actuarial local, nodal, distant control, and overall disease-free survival were 90%, 93%, 93%, and 90%, respectively. In 2/4 patients with persistent disease (nodal in one, primary in three), salvage surgery was performed. The mean dose to the spinal cord (extension of > 5-15 mm) was 26 Gy (12-38 Gy); the mean maximum (point) dose was 44.4 Gy (26-58.9 Gy). One grade (G) 3 dysphagia and two G4 reactions (laryngeal fibrosis, dysphagia), both following the schedule with 2.2 Gy per fraction, have been observed so far. Larynx preservation was achieved in 25/26 of the definitively irradiated patients (one underwent a salvage laryngectomy); 23 had no or minimal dysphagia (G0-1). Conclusion:: Excellent early disease control and high patient satisfaction with swallowing function in HC following SIB IMRT were observed; these results need to be confirmed based on a longer follow-up period. In order to avoid G4 reactions, SIB doses of < 2.2 Gy/fraction are recommended for large tumors involving laryngeal structure

Osteoradionecrosis of the Mandible: Minimized Risk Profile Following Intensity-Modulated Radiation Therapy (IMRT)

Background and Purpose:: Osteoradionecrosis (ON) of the mandible is a serious late complication of high-dose radiation therapy for tumors of the oropharynx and oral cavity. After doses between 60 and 72 Gy using standard fractionation, an incidence of ON between 5% and 15% is reported in a review from 1989, whereas in more recent publications using moderately accelerated or hyperfractionated irradiation and doses between 69 and 81 Gy, the incidence of ON is between 60 Gy for oropharyngeal or oral cavity cancer). 21/73 patients were treated in a postoperative setting, 52 patients underwent primary definitive irradiation. In 56 patients concomitant cisplatin-based chemotherapy was applied. Mean follow-up time was 22 months (12-46 months). Oral cavity including the mandible bone outside the planning target volume was contoured and dose-volume constraints were defined in order to spare bone tissue. Dose-volume histograms were obtained from contoured mandible in each patient and were analyzed and related to clinical mandible bone tolerance. Results:: Using IMRT with doses between 60 and 75 Gy (mean 67 Gy), on average 7.8, 4.8, 0.9, and 0.3 cm3 were exposed to doses > 60, 65, 70, and 75 Gy, respectively. These values are substantially lower than when using three-dimensional conformal radiotherapy. The difference has been approximately quantified by comparison with a historic series. Additional ON risk factors of the patients were also analyzed. Only one grade 3 ON of the lingual horizontal branch, treated with lingual decortication, was observed. Conclusion:: Using IMRT, only very small partial volumes of the mandibular bone are exposed to high radiation doses. This is expected to translate into a further reduction of ON and improved osseointegration of dental implant

Bidirectional silencing of RNA polymerase I transcription by a strand switch region in Trypanosoma brucei

The procyclin genes in Trypanosoma brucei are transcribed by RNA polymerase I as part of 5-10 kb long polycistronic transcription units on chromosomes VI and X. Each procyclin locus begins with two procyclin genes followed by at least one procyclin-associated gene (PAG). In procyclic (insect midgut) form trypanosomes, PAG mRNA levels are about 100-fold lower than those of procyclins. We show that deletion of PAG1, PAG2 or PAG3 results in increased mRNA levels from downstream genes in the same transcription unit. Nascent RNA analysis revealed that most of the effects are due to increased transcription elongation in the knockouts. Furthermore, transient and stable transfections showed that sequence elements on both strands of PAG1 can inhibit Pol I transcription. Finally, by database mining we identified 30 additional PAG-related sequences that are located almost exclusively at strand switch regions and/or at sites where a change of RNA polymerase type is likely to occu

Simultaneous Integrated Boost Intensity‑Modulated Radiotherapy (SIB‑IMRT) in Nasopharyngeal Cancer

Abstract : Purpose: : To assess the efficacy and safety of using simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) to treat nasopharyngeal cancer (NPC) in a Caucasian cohort. Outcome was analyzed with respect to dose-volume histogram (DVH) values. Patients and Methods: : Between 03/2002 and 01/2008, 39 NPC patients underwent SIB-IMRT (37 Caucasians; 31 males; mean age 53 years [16-78 years]). 41% presented with WHO (World Health Organization) type 1 unfavorable histology, 85% with stage III/IV disease. 19 patients had total gross tumor volume (GTV) 16-70 cm3 (mean 36 cm3), while 16 had GTV > 70 cm3 (73-217 cm3; mean 115 cm3). All patients with stage II-IV disease received concomitant cisplatin. The prescribed SIB dose delivered to the planning target volume (PTV) was 70 Gy (2.00 Gy/fraction) in 17, 69.6 Gy (2.11 Gy/fraction) in 19, and 66 Gy (2.20 Gy/fraction) in three patients. Results: : 3-year local relapse-free, nodal relapse-free, distant metastases-free, disease-free rates and overall survival were 86%, 89%, 85%, 72%, and 85% (median follow-up 30 months [8-71 months]). Histology was a significant prognostic factor concerning overall survival, with worst prognosis in WHO type 1 compared to type 2/3 (75% vs. 93%; p = 0.03). There was a trend in favor of WHO type 2/3 regarding local control (74% vs. 94%; p = 0.052). The PTV DVHs showed a slight left shift compared to reported series. Three patients developed grade 3 late effects (xerostomia [n = 2], dysphagia [n = 1], hearing loss [n = 1]). Conclusion: : In comparison with predominantly Asian NPC IMRT series in the literature, chemo-IMRT in the own Caucasian cohort, characterized by less radioresponsive WHO type 1, was equally effective. Treatment tolerance was excellen

Dysphagia in head and neck cancer patients following intensity modulated radiotherapy (IMRT)

BACKGROUND: To evaluate the objective and subjective long term swallowing function, and to relate dysphagia to the radiation dose delivered to the critical anatomical structures in head and neck cancer patients treated with intensity modulated radiation therapy (IMRT, +/- chemotherapy), using a midline protection contour (below hyoid, ~level of vertebra 2/3). METHODS: 82 patients with stage III/IV squamous cell carcinoma of the larynx, oropharynx, or hypopharynx, who underwent successful definitive (n = 63, mean dose 68.9Gy) or postoperative (n = 19, mean dose 64.2Gy) simultaneous integrated boost (SIB) -IMRT either alone or in combination with chemotherapy (85%) with curative intent between January 2002 and November 2005, were evaluated retrospectively. 13/63 definitively irradiated patients (21%) presented with a total gross tumor volume (tGTV) >70cc (82-173cc; mean 106cc). In all patients, a laryngo-pharyngeal midline sparing contour outside of the PTV was drawn. Dysphagia was graded according subjective patient-reported and objective observer-assessed instruments. All patients were re-assessed 12 months later. Dose distribution to the swallowing structures was calculated. RESULTS: At the re-assessment, 32-month mean post treatment follow-up (range 16-60), grade 3/4 objective toxicity was assessed in 10%. At the 32-month evaluation as well as at the last follow up assessment mean 50 months (16-85) post-treatment, persisting swallowing dysfunction grade 3 was subjectively and objectively observed in 1 patient (1%). The 5-year local control rate of the cohort was 75%; no medial marginal failures were observed. CONCLUSIONS: Our results show that sparing the swallowing structures by IMRT seems effective and relatively safe in terms of avoidance of persistent grade 3/4 late dysphagia and local disease control