Internal Mammary and Medial Supraclavicular Irradiation in Breast Cancer.

BACKGROUND: The effect of internal mammary and medial supraclavicular lymph-node irradiation (regional nodal irradiation) added to whole-breast or thoracic-wall irradiation after surgery on survival among women with early-stage breast cancer is unknown. METHODS: We randomly assigned women who had a centrally or medially located primary tumor, irrespective of axillary involvement, or an externally located tumor with axillary involvement to undergo either whole-breast or thoracic-wall irradiation in addition to regional nodal irradiation (nodal-irradiation group) or whole-breast or thoracic-wall irradiation alone (control group). The primary end point was overall survival. Secondary end points were the rates of disease-free survival, survival free from distant disease, and death from breast cancer. RESULTS: Between 1996 and 2004, a total of 4004 patients underwent randomization. The majority of patients (76.1%) underwent breast-conserving surgery. After mastectomy, 73.4% of the patients in both groups underwent chest-wall irradiation. Nearly all patients with node-positive disease (99.0%) and 66.3% of patients with node-negative disease received adjuvant systemic treatment. At a median follow-up of 10.9 years, 811 patients had died. At 10 years, overall survival was 82.3% in the nodal-irradiation group and 80.7% in the control group (hazard ratio for death with nodal irradiation, 0.87; 95% confidence interval [CI], 0.76 to 1.00; P=0.06). The rate of disease-free survival was 72.1% in the nodal-irradiation group and 69.1% in the control group (hazard ratio for disease progression or death, 0.89; 95% CI, 0.80 to 1.00; P=0.04), the rate of distant disease-free survival was 78.0% versus 75.0% (hazard ratio, 0.86; 95% CI, 0.76 to 0.98; P=0.02), and breast-cancer mortality was 12.5% versus 14.4% (hazard ratio, 0.82; 95% CI, 0.70 to 0.97; P=0.02). Acute side effects of regional nodal irradiation were modest. CONCLUSIONS: In patients with early-stage breast cancer, irradiation of the regional nodes had a marginal effect on overall survival. Disease-free survival and distant disease-free survival were improved, and breast-cancer mortality was reduced. (Funded by Fonds Cancer; ClinicalTrials.gov number, NCT00002851.).

Local control and intermediate-term cosmetic outcome following IMRT for nasal tumors : An update.

OBJECTIVE: This study aims to evaluate local control and intermediate-term cosmetic outcome in patients with cancer of the nose treated with intensity-modulated radiotherapy (IMRT). METHODS: From June 2008 to September 2015, 36 consecutive patients presenting with nasal cavity, ala of the nose, or nasal vestibule tumors were treated at the Department of Radiation Oncology, University Hospital Zurich either postoperatively (n = 14; 3/14 with nasal ablation) or with definitive IMRT (n = 22). Of these 36 patients, 8 presented with recurrent disease after surgery only and 1/36 with N1 disease. Concurrent systemic therapy was administered in 18/36 patients (50%). Nasal follow-up (FU) imaging documentation of 13 patients with preserved organ and >6 months FU offers a pre/post IMRT FU comparison. In addition, these patients' subjective evaluation of cosmesis was assessed. RESULTS: Mean/median FU was 41/33 months (range 5-92 months). Salvage ablation with curative intent was undergone by 3 patients with local relapse after definitive (n = 2) and postoperative (n = 1) IMRT. The 3­year local control, ultimate local control, and overall survival rates were 90, 97, and 90 %, respectively. Subjective and objective cosmetic outcome after IMRT is very satisfying so far. CONCLUSION: IMRT for nasal tumors was found to be effective and well tolerated. Intermediate-term cosmetic results are good. Radical surgical procedures may be saved for curative salvage treatment.

Neutrophil-lymphocyte ratio complements volumetric staging as prognostic factor in patients treated with definitive radiotherapy for oropharyngeal cancer.

BACKGROUND: Volumetric tumor staging has been shown as superior prognostic tool compared to the conventional TNM system in patients undergoing definitive intensity-modulated radiotherapy (IMRT) for head and neck cancer. Recently, clinical immunoscores such as the neutrophil-lymphocyte ratio (NLR) have been investigated as prognostic markers in several tumor entities. The aim of this study was to assess the combined prognostic value of NLR and tumor volume in patients treated with IMRT for oropharyngeal cancer (OC). METHODS: Data on all consecutive patients treated for locally advanced or inoperable OC with IMRT from 2002-2011 was prospectively collected. Tumor volume was assessed based on the total gross tumor volume (tGTV) calculated by the treatment planning system volume algorithm. The NLR was collected by a retrospective analysis of differential blood count before initiation of therapy. RESULTS: Overall, 187 eligible patients were treated with a median IMRT dose of 69.6 Gy. Three-year recurrence-free survival (RFS) for low, intermediate, high and very high tumor volume groups was 88%, 74%, 62% and 25%, respectively (p = 0.007). Patients with elevated NLR (>4.68) showed a significantly decreased 3-year RFS of 44% vs. 81% (p < 0.001) and 3-year OS of 56% vs. 84% (p < 0.001). The NLR remained a significant prognostic factor for RFS and OS when tested among tumor volume groups. Univariate and multivariate regression analysis confirmed both tumor volume and NLR as independent prognostic factors. The NLR offered further statistically significant prognostic differentiation of the small/intermediate/large tumor volume groups. CONCLUSION: The NLR remains an independent prognostic factor for patients with OC undergoing radiotherapy independent of the tumor volume.

Risk profile for osteoradionecrosis of the mandible in the IMRT era.

BACKGROUND: The risk for osteoradionecrosis (ORN) of the mandible is positively related to bone volume exposed to > ~ 60 Gy. We hypothesized that in combined treatment, surgery may also be a risk factor. PATIENTS AND METHODS: The impact of mandibular surgery on ORN in locally disease-free IMRT cohorts was retrospectively analyzed. RESULTS: Between October 2002 and October 2013, 531 of 715 patients with oral cavity cancer (OCC), mesopharyngeal cancer (MC), or salivary gland tumor were treated with the mandible bone exposed to ~ > 60 Gy (mean follow-up, 38 months; 7-143 months). Of the 531 patients, 36 developed ORN (7 %; 1.5 % with grade 3-4). The ORN rate in definitive IMRT MC (16/227) and in postoperative IMRT OCC patients with no mandibular surgery (3/46) was 7 % each; in OCC patients with mandibular surgery the rate was 29 % (15/60, p = 0.002). Marginal or periosteal bone resection was found to be a high risk factor (39 %, vs. 7 % followed by segmental or no resection, p < 0.0001). CONCLUSION: Marginal or periosteal bone resection of the mandible was identified as the highest ORN risk factor in our IMRT cohort.

IMRT/VMAT for malignancies in the head-and-neck region : Outcome in patients aged 80.

OBJECTIVE: Elderly patients with malignant head-and-neck tumors (HNT) often pose a therapeutic challenge. They frequently have significant comorbidities which may influence their ability to tolerate tumor-specific therapies. Our aim was to investigate the outcome of patients aged 80+ years undergoing curative intent intensity- or volume-modulated radiation therapy (IMRT/VMAT). METHODS: We retrospectively reviewed our HNT patients aged 80+ treated with curative IMRT/VMAT from December 2003 to November 2015. Overall survival (OS), disease-free survival (DFS), local control (LC), and treatment tolerance were assessed. Outcome results were compared with that of a younger HNT patient cohort from our hospital. RESULTS: A total of 140 consecutive patients were included (65 postoperative, 75 definitive). Mean/median age at treatment start was 84.8/84.1 years (range 80-96 years). Mean/median follow-up time was 25/16 months (range 2-92 months). Of the 140 patients, 80 were alive with no evidence of disease when last seen, 28 had died due to the cancer, 12 remained alive with disease, the remaining 20 died intercurrently. Systemic concomitant therapy was administered in 7 %. Late grade 3-4 toxicity was observed in 2 %. All patients completed treatment. Hospitalization and feeding tube rates were 26 % and 11 %, respectively. The 2­/3-year LC, DFS, and OS rates for the entire cohort were 81/80 %, 69/63 %, and 68/66 %, respectively. Squamous cell carcinoma (SCC) patients showed an inferior 3-year OS rate as compared to non-SCC patients (62 % vs 77 %, p = 0.0002), while LC and DFS did not differ. Patients undergoing postoperative radiation attained a higher OS compared to the definitively irradiated subgroup with 74 vs. 60 % at 3 years (p = 0.01); however, DFS rates were similar for both groups (68 vs. 61 %, p = 0.15). Corresponding rates for >1400 HNT patients <80 years treated during the same time interval were 81/80 %, 69/67 %, and 77/72 %, respectively. CONCLUSIONS: Treatment tolerance in our patients aged 80+ was high. These results suggest that elderly HNT patients should not be denied potentially curative treatment strategies.

Less may be more: nodal treatment in neck positive head neck cancer patients.

Ongoing debates about the need and extent of planned neck dissection (PND), and required nodal radiation doses volumes lead to this evaluation. Aim was to assess nodal control after definitive intensity modulated radiation therapy (IMRT ± systemic therapy) followed by PND in our head neck cancer cohort with advanced nodal disease. Between 01/2005 and 12/2013, 99 squamous cell cancer HNC patients with pre-therapeutic nodal metastasis ≥3 cm were treated with definitive IMRT followed by PND. In addition, outcome in 103 patients with nodal relapse after IMRT and observation only (no-PND cohort) were analyzed. Prior to PND, PET-CT, fine needle aspirations, ultrasound and palpation were assessed regarding its predictive value. Patterns of nodal relapse were assessed in patients with isolated neck failure after definitive IMRT alone. 70/99 (70 %) PND specimens showed histopathological complete response (hCR), which translated into statistically significantly superior survival compared with partial response (hPR) with 4-year overall survival, disease specific survival and nodal control rates of 90/83/96 vs 67/60/78 % (p = 0.002/0.001/0.003). 1/99 patient developed isolated subsequent nodal disease. 64/2147 removed nodes contained viable tumor (3 %). Predictive information of the performed diagnostic investigations was not reliable. 17/70 hCR patients showed true negative findings in available three to four investigations (0/29 hPR). 27/103 no-PND patients developed isolated neck disease (26 %) with successful salvage in 21/24 [88 %, or 21/27 (78 %)]. Nearly all failures occurred in the prior nodal gross tumor volume area. A more restrictive approach regarding PND and/or nodal IMRT dose-volumes may be justified.

Carotid artery disease after head and neck radiotherapy.

Radiation induced atherosclerosis of the carotid artery is a clinically relevant late complication after head and neck radiotherapy. Improved long-term survival after multimodality therapy in neck malignancies result in an increased risk of carotid artery disease in patients after radiotherapy (RT). This review focuses on the current knowledge of occlusive carotid disease after head and neck radiotherapy and highlights the exceeding morphologic post-radiation vessel wall pathologies. More severe and extensive carotid artery atherosclerosis with plaque in all segments including the common carotid artery is a frequent finding after RT. Therefore, colour coded duplex ultrasound surveillance in patients after head and neck RT is recommended. Some histopathological studies indicate differences to “classical” atherosclerosis, and pathogenesis of chronic radiation vasculopathy is still under discussion.

Fluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: long-term results of the EORTC 22921 randomised study.

BACKGROUND: EORTC trial 22921 examined the addition of preoperative or postoperative chemotherapy to preoperative radiotherapy in patients with rectal cancer. After a median follow-up of 5 years, chemotherapy-irrespective of timing-significantly improved local control. Adjuvant chemotherapy did not improve survival, but the Kaplan-Meier curves diverged, suggesting possible delayed benefit. Here, we report the updated long-term results. METHODS: We randomly assigned patients with clinical stage T3 or T4 resectable rectal cancer to receive preoperative radiotherapy with or without concomitant chemotherapy before surgery followed by either adjuvant chemotherapy or surveillance. Randomisation was done using minimisation with factors of institution, sex, T stage, and distance from the tumour to the anal verge. Study coordinators, clinicians, and patients were aware of assignment. Radiotherapy consisted of 45 Gy to the posterior pelvis in 25 fractions of 1·8 Gy over 5 weeks. Each course of chemotherapy consisted of fluorouracil (350 mg/m(2) per day intravenous bolus) and folinic acid (leucovorin; 20 mg/m(2) per day intravenous bolus). For preoperative chemotherapy, two courses were given (during weeks 1 and 5 of radiotherapy). Adjuvant chemotherapy was given in four cycles, every 3 weeks. The primary endpoint was overall survival. This analysis was done by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00002523. FINDINGS: 1011 patients were randomly assigned to treatment between April, 1993, and March, 2003 (252 to preoperative radiotherapy and 253 to each of the other three groups). After a median follow-up of 10·4 years (IQR 7·8-13·1), 10-year overall survival was 49·4% (95% CI 44·6-54·1) for the preoperative radiotherapy group and 50·7% (45·9-55·2) for the preoperative radiotherapy and chemotherapy group (HR 0·99, 95% CI 0·83-1·18; p=0·91). 10-year overall survival was 51·8% (95% CI 47·0-56·4) for the adjuvant chemotherapy group and 48·4% (43·6-53·0) for the surveillance group (HR 0·91, 95% CI 0·77-1·09, p=0·32). 10-year disease-free survival was 44·2% (95% CI 39·5-48·8) for the preoperative radiotherapy group and 46·4% (41·7-50·9) for the preoperative radiotherapy and chemotherapy group (HR 0·93, 95% CI 0·79-1·10; p=0·38). 10-year disease-free survival was 47·0% (95% CI 42·2-51·6) for the adjuvant chemotherapy group and 43·7% (39·1-48·2) for the surveillance group (HR 0·91, 95% CI 0·77-1·08, p=0·29). At 10 years, cumulative incidence of local relapse was 22·4% (95% CI 17·1-27·6) with radiotherapy alone, 11·8% (7·8-15·8) with neoadjuvant radiotherapy and chemotherapy, 14·5% (10·1-18·9) with radiotherapy and adjuvant chemotherapy and 11·7% (7·7-15·6) with both adjuvant and neoadjuvant chemotherapy (p=0·0017). There was no difference in cumulative incidence of distant metastases (p=0·52). The frequency of long-term side-effects did not differ between the four groups (p=0·22). INTERPRETATION: Adjuvant fluorouracil-based chemotherapy after preoperative radiotherapy (with or without chemotherapy) does not affect disease-free survival or overall survival. Our trial does not support the current practice of adjuvant chemotherapy after preoperative radiotherapy with or without chemotherapy. New treatment strategies incorporating neoadjuvant chemotherapy are required. FUNDING: EORTC, US National Cancer Institute, Programme Hospitalier de Recherche Clinique, Ligue contre le Cancer Comité du Doubs.

Early and Intermediate Treatment Outcome After Postoperative External Beam Accelerated Partial Breast Irradiation in Patients With Early-Stage Breast Cancer.

PURPOSE: To prospectively evaluate early and intermediate outcome after accelerated partial breast irradiation (APBI) in patients early-with stage breast cancer. METHODS AND MATERIALS: Inclusion criteria were defined according to the APBI American Society for Radiation Oncology's ASTRO Evidence-Based Consensus Statement. The prescribed dose was 26 to 28 Gy in 5 fractions on 5 consecutive days. Regular follow-up visits with objective and subjective evaluation of treatment tolerance were performed after 0 and 2 weeks, 6 months, and at annual intervals. RESULTS: Between February 2017 and January 2020, 175 patients with breast conserving surgery met the inclusion criteria for APBI. Mean age was 65.7 years (range, 46-88). Thirteen percent of patients received a diagnosis with carcinoma in situ, 55%, 35%, and 37% with T1a/b/c, and 10% with T2 stages, respectively. The mean volume of planning target volume (PTV) was 119 cc (range, 45-465), the ratio of mean PTV: whole breast volume ratio was 21% (7%-53%). Mean follow-up was 42 months (median, 45, range, 0-67). Acute toxicity after 2 weeks was low with 69%, 26%, and 5% grade 0, 1, and 2. In addition, 1-, 2-, 3-, 4-, and 5-year follow-up data were available from 146, 134, 107, 73, and 25 patients. Patient-reported cosmetic outcomes were assessed excellent or good in 97.9%, 98.5%, 98.1%, 98.6%, and 100%. Regarding grade 2 toxicities, as by now 3%, 2%, 2%, 0%, and 0% G2 fibrosis, 1%, 1%, 0%, 0%, and 0% G2 atrophy, no G2 skin telangiectasia or breast edema occurred. So far, none of the patients have experienced G3 toxicity or higher. The remaining patients had grade 0 or 1 toxicity only. Five ipsilateral breast recurrences (1 marginally to PTV, 4 out-of-field) and 5 distant recurrences were recorded by March 2023. The 4-year in-breast recurrence rate was 2.5%. Eight patients died, with 2 of them from disease. For all patients, the 4-year overall, cancer specific and disease-free survival rates were 97.1%, 99.4%, and 95.3%, respectively. CONCLUSIONS: We showed high early- and intermediate-term treatment tolerance and disease control of APBI using 26 to 28 Gy in five fractions in one week in carefully selected patients with early breast cancer. APBI is highly appreciated by patients and efficient, as an additional advantage for busy centers.

Single-Institution Prospective Evaluation of Moderately Hypofractionated Whole-Breast Radiation Therapy With Simultaneous Integrated Boost With or Without Lymphatic Drainage Irradiation After Breast-Conserving Surgery.

Purpose: We report treatment outcomes for patients who received adjuvant moderate hypofractionated whole-breast radiation therapy with simultaneous integrated boost (SIB-mhWBRT) after breast-conserving surgery. Methods and Materials: SIB-mhWBRT for patients with breast cancer was introduced in our department in July 2017. This prospective evaluation includes 424 consecutive patients treated with SIB-mhWBRT for stage I-III invasive breast cancer (n = 391) and/or ductal carcinoma in situ (n = 33) until December 2021. SIB-mhWBRT was applied with 40 Gy in 15 daily fractions over 3 weeks according to the START B trial, with an SIB dose to the tumor bed of 48 Gy according to Radiation Therapy Oncology Group 1005/UK-IMPORT-HIGH, delivered as 3-dinemsional conformal radiation therapy (RT; n = 402), intensity modulated RT (n = 4), or volumetric modulated arc therapy (n = 18). The mean patient age was 60 years (range, 27-88). Since May 2018, patients with indications for lymphatic pathway RT were included (n = 62). Baseline parameters and follow-up data were recorded and reported, including objective assessment of treatment-related outcomes and subjective patient-reported outcome measures (PROMs). Results: Mean/median follow-up was 29/33 months (range, 2-60). Acute toxicity grade 0, 1, 2, and 3 was observed in 25.0%, 61.4%, 13.3%, and 0%, respectively, at the completion of RT. Data of 281, 266, 243, 172, and 58 patients were available for 6-month and 1-, 2-, 3-, and 4-year follow-up, respectively. Grade 2 late effects were identified in 8.5%, 6.0%, 4.9%, 2.2%, and 10.2% and grade 3 in 2.8%, 1.1%, 1.2%, 0%, and 0% of patients at 6-month and 1-, 2-, 3-, and 4-year follow-up, respectively. Medical treatment of breast edema was the only grade 3 late effect observed. PROM cosmesis results were evaluated as excellent-good, fair, and poor in 97.2%, 2.5%, and 0.4%; 96.5%, 3.1%, and 0.4%; 97.4%, 2.2%, and 0.4%; 97.5%, 2.5%, and 0%; and 96.5%, 3.5%, and 0.0% at 6 months and 1, 2, 3, and 4 years post-RT, respectively. For all patients, the 3-year overall, cancer-specific, and disease-free survival rates were 98.2%, 99.1%, and 95.9%, respectively. Three-year risk of any locoregional recurrence was 0.6%. No mortality or relapse was observed in patients with ductal carcinoma in situ. Conclusions: SIB-mhWBRT demonstrated very favorable side effect profiles and cosmesis/PROMs. Three-year results demonstrate excellent locoregional control. This short-term regimen offers substantial patient comfort and improves institutional efficacy.

Risk-adapted dental care prior to intensity-modulated radiotherapy (IMRT).

BACKGROUND: At the Clinic for Radiation Oncology at the Zurich University Hospital (UniversitätsSpital Zürich [USZ]), head-and-neck tumor (HNT) patients have been treated with intensity-modulated radiotherapy (IMRT) since 01/2002 (n 〉 800). This method causes less damage to normal tissues adjacent to the tumor, and thus it was possible in the head/neck region to markedly reduce the rate of osteoradionecrosis (ORN), in addition to reducing the rate of severe xerostomia. Based on these results, risk-adapted dental care (RaDC) was adopted by our clinic as the standard mode of pre-IMRT dental treatment. The guidelines as formulated by Grötz et al. were respected. ORN prophylaxis is one of the most important goals of pre-radiotherapy dental care, and the ORN rate is a measurable parameter for the efficacy of dental care, given a certain radiation technique. The aim of the present study was therefore to evaluate the efficacy of RaDC as reflected by the ORN rate of our IMRT patients. MATERIALS AND METHODS: IN August 2006, RaDC was clinically implemented and has been used for all HNT patients prior to IMRT since then. Before that (01/2002-07/2006), dental restorations were performed according to the usual procedure. RESULTS: The rate of grade-2 ORN was similar in the conventionally treated and RaDC groups (2% and 1%, resp.); grade-3 ORN had not occurred by the time the analysis was conducted. As expected, fewer extractions were performed in the RaDC cohort (no extractions in 47% of the RaDC/IMRT cohort vs. 27% in the IMRT cohort receiving conventional dental care). CONCLUSION: After considerably less invasive dental treatment, no higher-grade ORN occurred and no ORN-related jaw resections were required. Based on the present data, risk-adapted minimally invasive dental care is recommended before IMRT.

[Radiation Oncology - Recent Status]. / Krebsbehandlung: aktueller Stand der perkutanen Strahlentherapie.

Radiation Oncology - Recent Status Abstract. We summarize the most important developments and innovations in the field over the past years and illustrate resulting external radiation treatment schedules and related treatment tolerance, focusing on hypofractionation.

Simultaneous integrated boost intensity-modulated radiotherapy (SIB­IMRT) in nasopharyngeal cancer.

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 radio-responsive WHO type 1, was equally effective. Treatment tolerance was excellent.

Consolidation cetuximab after concurrent triplet radiochemotherapy+cetuximab in patients with advanced head and neck cancer: A randomized phase II study.

BACKGROUND AND PURPOSE: Preclinical data suggest that cetuximab should be continued after end of concurrent radiotherapy+cetuximab due to its efficacy against residual tumor cells in the irradiated tumor bed. Based on this concept the phase II add-on cetuximab (AOC) study was designed. MATERIALS AND METHODS: Altogether 63 patients with advanced head and neck cancer were treated with radiochemotherapy (70 Gy, cisplatin 40 mg/m2 weekly) in combination with concurrent cetuximab (loading dose 400 mg/m2, then 250 mg/m2 weekly). Thereafter patients were randomized to cetuximab consolidation (500 mg/m2 biweekly × 6) or no further treatment. The primary endpoint was the 2-year locoregional control (LRC) rate. As translational research endpoints serum markers were analyzed before and during treatment and CT-based quantitative image analysis (radiomics) was performed. RESULTS: Median follow-up was 24 months. The 2-year LRC rates were 67.9% and 67.7% in the treatment arms with and without consolidation cetuximab, respectively. Higher than median levels of three serum markers were negatively associated with the 2-year LRC rate in the overall patient cohort: Osteopontin, IL8 and FasL2 (p ≤ 0.05). A radiomics model consisting of two radiomics features could be built showing that higher entropy and higher complexity of tumor Hounsfield unit distribution indicates worse LRC (concordance index 0.66). No correlation was found between biological and imaging markers. CONCLUSIONS: There was no evidence that consolidation cetuximab would improve the 2-year LRC rate. Prognostic biological and imaging markers could be identified for the overall patient cohort. Studies with larger patient numbers are needed to correlate biological and imaging markers.

Clinical outcome after treatment with a brachytherapy boost versus external beam boost for anal carcinoma.

PURPOSE: To evaluate the outcome after definitive whole pelvis external beam radiotherapy (EBRT) followed by brachytherapy (BT) boost after treatment break vs. external beam boost without break in the treatment of anal carcinoma. METHODS AND MATERIALS: Eighty-one consecutive patients with invasive anal carcinoma were analyzed retrospectively. Patients treated with an interstitial (192)Ir high-dose-rate (HDR) implant boost of 14Gy/7 fractions/3d given 3 weeks after completion of whole pelvis 45Gy EBRT were compared with those treated with external beam boost of 14.4Gy, started immediately after completion of whole pelvis 45Gy EBRT. Concomitant chemotherapy (CT) with mitomycin C was applied during whole pelvis EBRT depending on tumor stage. Pattern of care, local disease control (LC), cancer-specific survival (CSS), overall survival (OS), toxicity, and quality of life (QOL) were assessed. RESULTS: Radiotherapy with or without concomitant CT achieved clinical complete response in 93.4% of patients. In early stage tumors, (192)Ir-HDR BT boost with CT resulted in a 5-year LC and CSS of 100%. In all patients, BT boost did not result in improved LC, OS, and CSS compared with EBRT boost, despite stage and treatment bias favoring small tumors to be treated with BT. The 5-year and 10-year OS were 66% and 44% (BT boost) and 66% and 52% (EBRT boost), respectively. Subgroup analysis of Stages I and II disease revealed no significant improvement after BT boost compared with EBRT boost. Acute skin toxicity was less common in the BT boost group (whole cohort: p=0.14; Stages I-IIIa: p=0.05), but long-term morbidity and QOL were similar. No local necrosis was seen after BT boost and the 10-year sphincter preservation rate was 87% in these patients. CONCLUSIONS: Interstitial (192)Ir-HDR implant boost with break and EBRT boost without break yield similar results. Acute skin toxicity is reduced with BT boost but long-term morbidity and QOL are identical. BT boost is most beneficial in early stage tumors but the advantage of BT seems to be limited due to its invasiveness, doctor dependence, and logistic circumstances.

[Recommendations for dental care prior to intensity-modulated radiotherapy (IMRT). Adaptation of the University Hospital Zurich (USZ) guidelines]. / Empfehlung für die Zahnsanierung vor intensitäts-modulierter Radiotherapie (IMRT). UniversitätsSpital Zürich (USZ)-Richtlinien-Anpassung.

This article is aimed to inform about the recently performed adjustments of the established standard procedures for pre-radiotherapeutic dental care (GROTZ 2003; Shaw et al. 2000) on intensity modulated radiation therapy (IMRT) at the Department of Radiation Oncology, University Hospital Zurich (USZ). The adjustments described base on prospectively assessed results and clinical observations of more than 300 head and neck cancer patients treated with definitive or postoperative IMRT at the own institution. In order to explain the clinical differences between conventional radiation techniques and IMRT, a brief introduction section addresses characteristics of IMRT delivery, optimization of normal tissue sparing, and resulting improved normal tissue tolerance (Fig. 1a-c). In conclusion, careful adjustments of pre-treatment dental care as proposed (Tab. I) are recommended for IMRT patients. This requires close case-related interdisciplinary cooperation between the referring radiation oncologist and the dentist or dental care centre, respectively. The depicted sketches (Fig. 2) are thought to get completed by the radiation oncologist, in order to inform the dentist about topographic risk areas/levels for radiation-induced late effects.

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 cm(3) (4-170 cm(3)), mean nodal volume 16.6 cm(3) (0-97 cm(3)). 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 structures.

Differential activation of the phosphatidylinositol 3'-kinase/Akt survival pathway by ionizing radiation in tumor and primary endothelial cells.

Ionizing radiation induces an intracellular stress response via activation of the phosphatidylinositol 3'-kinase (PI3K)/Akt survival pathway. In tumor cells, the PI3K/Akt pathway is induced through activation of members of ErbB receptor tyrosine kinases. Here, we investigated the receptor dependence of radiation-induced PI3K/Akt activation in tumor cells and in endothelial cells. The integrity of both the ErbB and the vascular endothelial growth factor (VEGF) ligand-activated PI3K/Akt pathway in endothelial cells was demonstrated using specific ErbB and VEGF receptor tyrosine kinase inhibitors. Irradiation of endothelial cells resulted in protein kinase B (PKB)/Akt activation in a similar time course as observed in response to VEGF. More importantly, radiation-induced PKB/Akt phosphorylation in endothelial cells was strongly down-regulated by the VEGF receptor tyrosine kinase inhibitor, whereas the ErbB receptor tyrosine kinase inhibitor did not affect PKB/Akt stimulation in response to irradiation. An opposite receptor dependence for radiation-induced PKB/Akt phosphorylation was observed in ErbB receptor-overexpressing A431 tumor cells. Furthermore, direct VEGF receptor phosphorylation was detected after irradiation in endothelial cells in absence of VEGF, which was almost completely inhibited after irradiation in presence of the VEGF receptor tyrosine kinase inhibitor. These data demonstrate that ionizing radiation induces VEGF ligand-independent but VEGF receptor-dependent PKB/Akt activation in endothelial cells and that PI3K/Akt pathway activation by radiation occurs in a differential cell type and receptor-dependent pattern.

Hypofractionated Radiotherapy for Breast Cancer Including Risk-adapted Boost: Update on Tolerance and Efficacy of an Accelerated START A Regime.

AIM: To present an update of a prospective study evaluating an accelerated hypofractionated whole breast irradiation (WBI) schedule of the START A trial plus hypofractionated boost in breast cancer patients. PATIENTS AND METHODS: One hundred and forty consecutive patients ≥55 years were included in this study. Patients received postoperative WBI with 13×3.2 Gy to 41.6 Gy plus a boost of 3.0 Gy/fraction to 9-12 Gy applied in <3.5 weeks, depending on the resection margin. Prospectively planned follow-up (FU) visits, including objective and subjective assessment of treatment tolerance, were performed at 0 and 8 weeks, as well as one, two, four or more years following radiotherapy (RT). RESULTS: The 3-year rates of local control, nodal control, disease-free and overall survival were 99%, 100%, 96% and 91%, respectively. Cosmetic outcome was very good with 99% (n=110/111), 98% (n=99/101) and 100% (n=59/59) of the patients being satisfied or very satisfied one, two and four years after RT, respectively. CONCLUSION: Acceleration of the START A regime with 41.6 Gy WBI plus additional boost of 9-12 Gy remained effective and well-tolerated.

Concomitant cisplatin significantly improves locoregional control in advanced head and neck cancers treated with hyperfractionated radiotherapy.

PURPOSE: To determine whether the application of two courses of cisplatin simultaneously with hyperfractionated radiotherapy improves the outcome in locally advanced and/or node-positive nonmetastatic carcinomas of the head and neck, compared with hyperfractionated radiotherapy alone. PATIENTS AND METHODS: From July 1994 to July 2000, 224 patients with squamous cell carcinomas of the head and neck (excluding nasopharynx and paranasal sinus) were randomly assigned to hyperfractionated radiotherapy (median dose, 74.4 Gy; 1.2 Gy twice daily) or the same radiotherapy combined with two cycles of concomitant cisplatin (20 mg/m2 on 5 days of weeks 1 and 5). The primary end point was time to any treatment failure; secondary end points were locoregional failure, metastatic relapse, overall survival, and late toxicity. RESULTS: There was no difference in radiotherapy between both treatment arms (74.4 Gy in 44 days). The full cisplatin dose was applied in 93% and 71% of patients during the first and second treatment cycles, respectively. Acute toxicity was similar in both arms. Median time to any treatment failure was not significantly different between treatment arms (19 months for combined treatment and 16 months for radiotherapy only, respectively) and the failure-free rate at 2.5 years was 45% and 33%, respectively. Locoregional control and distant disease-free survival were significantly improved with cisplatin (log-rank test, P = .039 and .011, respectively). The difference in overall survival did not reach significance (log-rank test, P = .147). Late toxicity was comparable in both treatment groups. CONCLUSION: The therapeutic index of hyperfractionated radiotherapy is improved by concomitant cisplatin.