Carmen Stromberger

Monitoring of Circulating Tumor Cells and Their Expression of EGFR/Phospho-EGFR During Combined Radiotherapy Regimens in Locally Advanced Squamous Cell Carcinoma of the Head and Neck

PURPOSE The numbers of circulating tumor cells (CTCs) and their expression/activation of epidermal growth factor receptor (EGFR) during the course of combined chemo- or bioradiotherapy regimens as potential biomarkers of treatment efficacy in squamous cell carcinoma of the head and neck (SCCHN) were determined. METHODS AND MATERIALS Peripheral blood samples from SCCHN patients with locally advanced stage IVA/B disease who were treated with concurrent radiochemotherapy or induction chemotherapy followed by bioradiation with cetuximab were included in this study. Using flow cytometry, the absolute number of CTCs per defined blood volume as well as their expression of EGFR and its phosphorylated form (pEGFR) during the course of treatment were assessed. RESULTS Before treatment, we detected ≥1 CTC per 3.75 mL blood in 9 of 31 patients (29%). Basal expression of EGFR was detected in 100% and pEGFR in 55% of the CTC+ cases. The frequency of CTC detection was not influenced by induction chemotherapy. However, the number of CTC+ samples significantly increased after radiotherapy. This radiation-induced increase in CTC numbers was less pronounced when radiotherapy was combined with cetuximab compared to its combination with cisplatin/5-fluorouracil. The former treatment regimen was also more effective in reducing pEGFR expression in CTCs. CONCLUSIONS Definitive radiotherapy regimens of locally advanced SCCHN can increase the number of CTCs and might thus contribute to a systemic spread of tumor cells. Further studies are needed to evaluate the predictive value of the radiation-induced increase in CTC numbers and the persistent activation of the EGFR signalling pathway in individual CTC+ cases.

Investigations on Parotid Gland Recovery after IMRT in Head and Neck Tumor Patients

Purpose:In recent years, the role of intensity-modulated radiotherapy (IMRT) for head and neck irradiation has increased. The main motivation is sparing the parotid gland and reduction of xerostomia. Generally, relative parotid volumes have been evaluated for treatment outcome and planning constraints, neglecting that absolute parotid volumes can vary significantly. The aim of the present study was to investigate changes in parotid gland function and set this in relation to absolute volumes.Material and Methods:: 46 head and neck patients were treated by sparing at least the contralateral parotid gland. The mean dose to the contralateral gland was limited to 26 Gy. Parotid function was measured with scintigraphy before and at 3, 6, 9, and 12 months after radiotherapy. Gland recovery was correlated with absolute parotid gland volumes and mean dose. Finally the dose–effect relationship was investigated.Results:The dose–volume histograms (DVHs) for the ipsi- and contralateral glands were significantly different. A correlation between absolute volumes receiving certain doses and the function loss after 3, 6, 9, and 12 months was found. The most significant correlation was found for the absolute volume that received at least 40 Gy (aV40). ED50 values of 23–38 Gy were observed for more than 50% function loss and and 52–68 Gy afor more than 75% function loss.Conclusion:The mean dose, aV40 or aV26, revealed similar correlations with the excretion rate and with recovery. Hence, also absolute volumes can be used for treatment planning. Longer recovery times show higher ED50 values indicating partial regeneration of gland functions.Ziel:In den letzten Jahren gewann die Intensitätsmodulierte Strahlentherapie (IMRT) bei der Behandlung von Kopf-Hals Tumoren immer mehr an Bedeutung. Hauptbeweggrund dafür ist die mögliche Schonung der Ohrspeicheldrüse und somit eine Reduktion von Xerostomie. Bisher wurden hauptsächlich relative Parotisvolumina für die Korrelation mit dem Behandlungserfolg und zur Schwellwertvorgabe in der Bestrahlungsplanung verwendet. Vernachlässigt wurde jedoch dabei eine signifikante Variabilität der absoluten Parotisvolumina. Ziel dieser Studie war es deshalb, Funktionsveränderungen zu quantifizieren und mit absoluten Volumina zu korrelieren.Material und Methoden:46 Kopf-Hals Patienten wurden mit IMRT behandelt und dabei wurde die kontralaterale Parotis geschont. Deren mittlere Dosis wurde dabei auf 26 Gy limitiert. Die Speicheldrüsenfunktion wurde mittels Szintigraphie vor sowie 3, 6, 9 und 12 Monate nach der Therapie erfasst. Das Erholungsverhalten wurde zu den absoluten Volumina und mittleren Dosen in Korrelation gesetzt. Abschließend wurde die Dosis-Wirkungs Beziehung untersucht.Ergebnisse:DVHs für ipsi- and contralaterale Parotis unterschieden sich signifikant. Korrelationen zeigten sich zwischen absoluten Volumina und Funktionsveränderungen nach 3, 6, 9 und 12 Monaten. Korrelation mit der höchsten Signifikanz erwies sich beim Volumen welches mehr als 40 Gy erhalten hatte (aV40). ED50 Werte von 23–38 Gy und 52–68 Gy wurden für mehr als 50 bzw. 75% Funktionsverlust beobachtet.Schlussfolgerung:Die mittlere Dosis wie auch aV40 oder aV26 führen zu denselben Korrelationen mit der Funktionsveränderung der Parotis. Somit können auch absolute Volumina bei der Planungsvorgabe verwendet werden. Längere Zeitabstände zur Therapie ergaben auch höhere ED50 Werte, was auf eine partielle Regeneration der Speicheldrüse schließen lässt.

Detection of circulating tumor cells for prediction of recurrence after adjuvant chemoradiation in locally advanced squamous cell carcinoma of the head and neck

BACKGROUND The prognostic role of persistence of circulating tumor cells (CTC) after upfront tumor surgery for outcome of adjuvant (chemo)radiation in locally advanced squamous cell carcinoma of the head and neck (LASCCHN) was evaluated. PATIENTS AND METHODS In this prospective study, peripheral blood samples from 144 patients with LASCCHN presenting after tumor resection for adjuvant treatment were analyzed for CTC. Their detection was correlated with tumor site, clinical risk factors, disease-free (DFS) and overall survival (OS). RESULTS CTC were detected in 42 of 144 patients (29%). CTC detection was higher in cases with nodal involvement and in carcinomas located at the tonsil or base of tongue but was not influenced by age, smoking history, T stage, extracapsular lymph node extension, surgical margins or the human papillomavirus status. Overall, the presence of CTC was not predictive for OS or DFS. However, while in oropharyngeal carcinomas (OPC, n = 63), the detection of CTC was associated per trend with improved DFS [CTC+ versus CTC- (% of patients without evidence of disease at 2 years): 100% versus 79%; log rank: P = 0.059]; the reverse was observed for carcinomas from other sites (non-OPC, n = 81; CTC+ versus CTC-: 29% versus 75%; P = 0.001). In multivariate analysis, CTC remained an independent prognostic marker for DFS [hazard ratio (HR) 4.3, 95% confidence interval (CI) 1.7-10.9, P = 0.002] and OS (HR 2.7, 95% CI 1.2-6.3, P = 0.016) in non-OPC. CONCLUSIONS Assessment of CTC in non-OPC should prove useful for identification of patients who benefit from treatment intensification. The basis for the good prognostic value of CTC in OPC has to be elucidated in future studies.

Helical Tomotherapy With Simultaneous Integrated Boost After Laparoscopic Staging in Patients With Cervical Cancer: Analysis of Feasibility and Early Toxicity

PURPOSE To demonstrate the feasibility and safety of the simultaneous integrated boost technique for dose escalation in combination with helical tomotherapy in patients with cervical cancer. METHODS AND MATERIALS Forty patients (International Federation of Gynecology and Obstetrics Stage IB1 pN1-IVA) underwent primary chemoradiation with helical tomotherapy. Before therapy, 29/40 patients underwent laparoscopic pelvic and para-aortic lymphadenectomy. In 21%, 31%, and 3% of the patients, pelvic, pelvic and para-aortic, and skip metastases in the para-aortic region could be confirmed. All patients underwent radiation with 1.8-50.4 Gy to the tumor region and the pelvic (para-aortic) lymph node region (planning target volume-A), and a simultaneous boost with 2.12-59.36 Gy to the boost region (planning target volume-B). The boost region was defined using titan clips during laparoscopic staging. In all other patients, standardized borders for the planning target volume-B were defined. High-dose-rate brachytherapy was performed in 39/40 patients. The mean biologic effective dose to the macroscopic tumor ranged from 87.5 to 97.5 Gy. Chemotherapy consisted of weekly cisplatin 40 mg/m(2). Dose-volume histograms and acute gastrointestinal, genitourinary, and hematologic toxicity were evaluated. RESULTS The mean treatment time was 45 days. The mean doses to the small bowel, rectum, and bladder were 28.5 ± 6.1 Gy, 47.9 ± 3.8 Gy, and 48 ± 3 Gy, respectively. Hematologic toxicity Grade 3 occurred in 20% of patients, diarrhea Grade 2 in 5%, and diarrhea Grade 3 in 2.5%. There was no Grade 3 genitourinary toxicity. All patients underwent curettage 3 months after chemoradiation, which confirmed complete pathologic response in 38/40 patients. CONCLUSIONS The concept of simultaneous integrated boost for dose escalation in patients with cervical cancer is feasible, with a low rate of acute gastrointestinal and genitourinary toxicity. Whether dose escalation can be translated into improved outcome will be assessed after a longer follow-up time.

Helical tomotherapy versus conventional intensity-modulated radiation therapy for primary chemoradiation in cervical cancer patients: an intraindividual comparison.

PURPOSE To compare intensity-modulated radiotherapy (IMRT) delivered by helical tomotherapy (HT) with conventional IMRT for primary chemoradiation in cervical cancer patients. METHODS AND MATERIALS Twenty cervical cancer patients undergoing primary chemoradiation received radiation with HT; 10 patients underwent pelvic irradiation (PEL) and 10 extended-field irradiation (EXT). For treatment planning, the simultaneously integrated boost (SIB) concept was applied. Tumor, pelvic, with or without para-aortic lymph nodes were defined as planning target volume A (PTV-A) with a prescribed dose of 1.8/50.4 Gy (28 fractions). The SIB dose for the parametrium (PTV-B), was 2.12/59.36 Gy. The lower target constraints were 95% of the prescribed dose in 95% of the target volume, and the upper dose constraint was 107%. The irradiated small-bowel volumes were kept as low as possible. For every HT plan, a conventional IMRT plan was calculated and compared with regard to dose-volume histogram, conformity index and conformity number, and homogeneity index. RESULTS Both techniques allowed excellent target volume coverage and sufficient SB sparing. Conformity index and conformity number results for both PTV-A and PTV-B, homogeneity index for PTV-B, and SB sparing for V45, V50, Dmax, and D1% were significantly better with HT. SB sparing was significantly better for conventional IMRT at low doses (V10). CONCLUSIONS Both HT and conventional IMRT provide optimal treatment of cervical cancer patients. The HT technique was significantly favored with regard to target conformity, homogeneity, and SB sparing. Randomized trials are needed to assess the oncological outcome, toxicity, and clinical relevance of these differences.

Helical tomotherapy in cervical cancer patients: simultaneous integrated boost concept: technique and acute toxicity.

AbstractPurpose:To evaluate the acute toxicity of simultaneous integrated boost (SIB) technique for dose escalation with helical tomotherapy (HT) in patients with locally advanced cervical cancer.Patients and Methods:20 patients (FIGO IB1 pN1-IIIB) underwent primary chemoradiation. Prior to chemoradiation, a laparoscopic pelvic and para-aortic lymphadenectomy was performed. A boost region was defined using titanium clips during staging for planning target volume (PTV-B). Patients were treated with five weekly fractions of 1.8 Gy to a total dose of 50.4 Gy to the tumor region and the pelvic (para-aortic) lymph node region (PTV-A), and five weekly fractions of 2.12 Gy to a total dose of 59.36 Gy to the PTV-B. Chemotherapy consisted of weekly cisplatin 40 mg/m2. 19 patients underwent brachytherapy. Dose-volume histograms were evaluated and acute gastrointestinal (GI), genitourinary (GU), and hematologic toxicity were documented (CTCAE v3.0).Results:Pelvic and para-aortic lymph node metastases were confirmed in nine and four patients, respectively. Five patients refused laparoscopic staging. The mean volume of PTV-A and PTV-B was 1,570 ± 404 cm3and 341 ± 125 cm3, respectively. The mean dose to the bladder, rectum, and small bowel was 47.85 Gy, 45.76 Gy, and 29.71 Gy, respectively. No grade 4/5 toxicity was observed. Grade 2/3 hematologic toxicity occurred in 50% of patients and 5% experienced grade 3 diarrhea. There was no grade 3 GU toxicity. 19 patients underwent curettage 6–9 weeks after chemoradiation without any evidence of tumor.Conclusion:The concept of SIB for dose escalation in patients with locally advanced cervical cancer is feasible with a low rate of acute toxicity. Whether dose escalation can translate into improved outcome will be assessed after a longer follow-up.ZusammenfassungZiel:Die Akuttoxizität der simultanen integrierten Boost-(SBI-)Technik der helikalen Tomotherapie (HT) in der primären Radiochemotherapie bei Patientinnen mit lokal fortgeschrittenen Zervixkarzinomen wurde untersucht.Patienten und Methodik:20 Patientinnen mit Zervixkarzinomen (FIGO IB1 pN1-IIIB) erhielten nach laparoskopischer transperitonealer pelviner und paraaortaler Lymphonodektomie eine primäre Radiochemotherapie. Unter Einschluss der pelvinen/paraaortalen Lymphknoten und der Tumorregion (PTV-A [Planungszielvolumen]) wurden die Patientinnen mit fünf wöchentlichen Einzeldosen von 1,8 Gy bis 50,4 Gy bestrahlt. Eine standardisierte Boostregion wurde mit Hilfe von Titanclips (PTV-B) markiert. Simultan betrug hier die Einzeldosis im PTV-B 2,12 Gy, die Gesamtdosis 59,36 Gy. Eine simultane Chemotherapie (40 mg/m2 Cisplatin wöchentlich) wurde appliziert. 19 Patientinnen erhielten zusätzlich eine intrazervikale Brachytherapie. Die Dosis-Volumen- Histogramme wurden ausgewertet und akute gastrointestinale (GI), urogenitale (GU) und hämatologische Toxizitäten dokumentiert (CTCAE v3.0). Ergebnisse:Pelvine und paraaortale Lymphknotenmetastasen wurden bei neun und vier Patientinnen gesichert. Fünf Patientinnen hatten das laparoskopische Staging abgelehnt. Das mittlere Volumen von PTV-A bzw. PTV-B betrug 1 570 ± 404 ml bzw. 341 ± 125 ml. Die mittlere Dosis von Blase, Rektum und Dünndarm lag bei 47,85 Gy, 45,76 Gy und 29,71 Gy. Es trat keine Grad- 4/5-Toxizität auf. Hämatologische Toxizität Grad 2/3 entwickelten 50 % der Patientinnen, 5 % wiesen eine Grad-3-Diarrhö auf. GU-Toxizität Grad 3 trat nicht auf. Die Abrasio 6–9 Wochen nach Therapieende zeigte bei 19 Patientinnen keinen vitalen Resttumor.Schlussfolgerung:Das SIB-Konzept ist mittels HT in der primären Radiochemotherapie durchführbar. Insgesamt sind niedrige Raten höhergradiger Toxizität beobachtet worden. Ob die Dosiserhöhung zu einer verbesserten lokalen Kontrolle führt, muss evaluiert werden.

Oligometastases: the new paradigm and options for radiotherapy. A critical review

Traditional oncology distinguishes between two separate and incommensurable states in the evolution of solid malignancies: the localized disease, which is curable; and the disseminated status, which is per se palliative. Recently, a huge body of evidence suggests a fundamental change in the understanding of cancer, indicating an intermediate state in the trajectory of solid malignancies: the oligometastatic state. The following review will critically analyse existing hypotheses and facts from the basic sciences and try to contextualize it in regard to the clinical evidence available to date. Consecutively, it will try to draw possible clinical consequences for application of radiotherapy in this specific clinical scenario.ZusammenfassungDie traditionelle Onkologie trennt hinsichtlich therapeutischer Optionen zwei grundlegend unterschiedliche klinische Situationen: die lokalisierte Erkrankung mit kurativen Therapiechancen und die disseminierte Situation mit nur noch palliativen Lösungen. Die aktuelle Datenlage suggeriert die Notwendigkeit der Adaptation unseres klinischen Verständnisses onkologischer Erkrankungen im Sinne des Vorliegens einer intermediären, nämlich oligometastasierten Situation. Diese Arbeit setzt sich kritisch mit den Hypothesen und dem Wissen der Grundlagenforschung auseinander und kontextualisiert die vorliegende klinische Evidenz. Ziel ist die Auslotung der Radiotherapieoptionen für oligometastasierte Patienten.

Patient and treatment-related risk factors for osteoradionecrosis of the jaw in patients with head and neck cancer

OBJECTIVE The purpose of this study was to evaluate risk factors for and the incidence of osteoradionecrosis (ORN) of the jaw in patients with head and neck cancer. STUDY DESIGN This study was a retrospective analysis of the risk for ORN and outcome for 149 of 540 patients with head and neck cancer of the oral cavity (65%), oropharynx (26%), or other head and neck sites (9%) treated with radiotherapy between 2004 and 2009. ORN was graded according to Late Effects of Normal Tissues/Somatic Objective Management Analytic Scale (LENT/SOMA) criteria. RESULTS Within a median follow-up of 41 months (95% confidence interval: 27.4-54.6), 38 patients (25.5%) had developed ORN, 37 patients (25%) had a local recurrence, and 53 patients (36%) had died. The median time to diagnosis of ORN was 14.5 months (range: 3-80), and 79% were diagnosed within 2 years of RT. Eleven of these patients had undergone previous mandibular surgery. Univariate significant risk factors for ORN were any comorbidity, poor oral hygiene, pre-radiotherapy osteotomy, close tumor-to-bone proximity, post-radiotherapy dentoalveolar surgery (DAS), DAS without sufficient wound closure, alcohol consumption, and denture pressure sores. In multivariate analysis, comorbidities, pre-radiotherapy mandibular surgery, poor oral hygiene, and insufficient DAS remained significant. CONCLUSIONS Reducing the risk of ORN calls for maintaining optimal oral hygiene, ensuring good denture fit, receiving proper training in DAS, and helping patients to stop drinking and smoking.

Oligometastases: the new paradigm and options for radiotherapy

Traditional oncology distinguishes between two separate and incommensurable states in the evolution of solid malignancies: the localized disease, which is curable; and the disseminated status, which is per se palliative. Recently, a huge body of evidence suggests a fundamental change in the understanding of cancer, indicating an intermediate state in the trajectory of solid malignancies: the oligometastatic state. The following review will critically analyse existing hypotheses and facts from the basic sciences and try to contextualize it in regard to the clinical evidence available to date. Consecutively, it will try to draw possible clinical consequences for application of radiotherapy in this specific clinical scenario.ZusammenfassungDie traditionelle Onkologie trennt hinsichtlich therapeutischer Optionen zwei grundlegend unterschiedliche klinische Situationen: die lokalisierte Erkrankung mit kurativen Therapiechancen und die disseminierte Situation mit nur noch palliativen Lösungen. Die aktuelle Datenlage suggeriert die Notwendigkeit der Adaptation unseres klinischen Verständnisses onkologischer Erkrankungen im Sinne des Vorliegens einer intermediären, nämlich oligometastasierten Situation. Diese Arbeit setzt sich kritisch mit den Hypothesen und dem Wissen der Grundlagenforschung auseinander und kontextualisiert die vorliegende klinische Evidenz. Ziel ist die Auslotung der Radiotherapieoptionen für oligometastasierte Patienten.

Helical Tomotherapy in Cervical Cancer Patients

AbstractPurpose:To evaluate the acute toxicity of simultaneous integrated boost (SIB) technique for dose escalation with helical tomotherapy (HT) in patients with locally advanced cervical cancer.Patients and Methods:20 patients (FIGO IB1 pN1-IIIB) underwent primary chemoradiation. Prior to chemoradiation, a laparoscopic pelvic and para-aortic lymphadenectomy was performed. A boost region was defined using titanium clips during staging for planning target volume (PTV-B). Patients were treated with five weekly fractions of 1.8 Gy to a total dose of 50.4 Gy to the tumor region and the pelvic (para-aortic) lymph node region (PTV-A), and five weekly fractions of 2.12 Gy to a total dose of 59.36 Gy to the PTV-B. Chemotherapy consisted of weekly cisplatin 40 mg/m2. 19 patients underwent brachytherapy. Dose-volume histograms were evaluated and acute gastrointestinal (GI), genitourinary (GU), and hematologic toxicity were documented (CTCAE v3.0).Results:Pelvic and para-aortic lymph node metastases were confirmed in nine and four patients, respectively. Five patients refused laparoscopic staging. The mean volume of PTV-A and PTV-B was 1,570 ± 404 cm3and 341 ± 125 cm3, respectively. The mean dose to the bladder, rectum, and small bowel was 47.85 Gy, 45.76 Gy, and 29.71 Gy, respectively. No grade 4/5 toxicity was observed. Grade 2/3 hematologic toxicity occurred in 50% of patients and 5% experienced grade 3 diarrhea. There was no grade 3 GU toxicity. 19 patients underwent curettage 6–9 weeks after chemoradiation without any evidence of tumor.Conclusion:The concept of SIB for dose escalation in patients with locally advanced cervical cancer is feasible with a low rate of acute toxicity. Whether dose escalation can translate into improved outcome will be assessed after a longer follow-up.ZusammenfassungZiel:Die Akuttoxizität der simultanen integrierten Boost-(SBI-)Technik der helikalen Tomotherapie (HT) in der primären Radiochemotherapie bei Patientinnen mit lokal fortgeschrittenen Zervixkarzinomen wurde untersucht.Patienten und Methodik:20 Patientinnen mit Zervixkarzinomen (FIGO IB1 pN1-IIIB) erhielten nach laparoskopischer transperitonealer pelviner und paraaortaler Lymphonodektomie eine primäre Radiochemotherapie. Unter Einschluss der pelvinen/paraaortalen Lymphknoten und der Tumorregion (PTV-A [Planungszielvolumen]) wurden die Patientinnen mit fünf wöchentlichen Einzeldosen von 1,8 Gy bis 50,4 Gy bestrahlt. Eine standardisierte Boostregion wurde mit Hilfe von Titanclips (PTV-B) markiert. Simultan betrug hier die Einzeldosis im PTV-B 2,12 Gy, die Gesamtdosis 59,36 Gy. Eine simultane Chemotherapie (40 mg/m2 Cisplatin wöchentlich) wurde appliziert. 19 Patientinnen erhielten zusätzlich eine intrazervikale Brachytherapie. Die Dosis-Volumen- Histogramme wurden ausgewertet und akute gastrointestinale (GI), urogenitale (GU) und hämatologische Toxizitäten dokumentiert (CTCAE v3.0). Ergebnisse:Pelvine und paraaortale Lymphknotenmetastasen wurden bei neun und vier Patientinnen gesichert. Fünf Patientinnen hatten das laparoskopische Staging abgelehnt. Das mittlere Volumen von PTV-A bzw. PTV-B betrug 1 570 ± 404 ml bzw. 341 ± 125 ml. Die mittlere Dosis von Blase, Rektum und Dünndarm lag bei 47,85 Gy, 45,76 Gy und 29,71 Gy. Es trat keine Grad- 4/5-Toxizität auf. Hämatologische Toxizität Grad 2/3 entwickelten 50 % der Patientinnen, 5 % wiesen eine Grad-3-Diarrhö auf. GU-Toxizität Grad 3 trat nicht auf. Die Abrasio 6–9 Wochen nach Therapieende zeigte bei 19 Patientinnen keinen vitalen Resttumor.Schlussfolgerung:Das SIB-Konzept ist mittels HT in der primären Radiochemotherapie durchführbar. Insgesamt sind niedrige Raten höhergradiger Toxizität beobachtet worden. Ob die Dosiserhöhung zu einer verbesserten lokalen Kontrolle führt, muss evaluiert werden.