Sabine Semrau

Safety and Efficacy of Stereotactic Body Radiotherapy for Stage I Non-Small-Cell Lung Cancer in Routine Clinical Practice A Patterns-of-Care and Outcome Analysis

Introduction: To evaluate safety and efficacy of stereotactic body radiotherapy (SBRT) for stage I non–small-cell lung cancer (NSCLC) in a patterns-of-care and patterns-of-outcome analysis. Methods: The working group “Extracranial Stereotactic Radiotherapy” of the German Society for Radiation Oncology performed a retrospective multicenter analysis of practice and outcome after SBRT for stage I NSCLC. Sixteen German and Austrian centers with experience in pulmonary SBRT were asked to participate. Results: Data of 582 patients treated at 13 institutions between 1998 and 2011 were collected; all institutions, except one, were academic hospitals. A time trend to more advanced radiotherapy technologies and escalated irradiation doses was observed, but patient characteristics (age, performance status, pulmonary function) remained stable over time. Interinstitutional variability was substantial in all treatment characteristics but not in patient characteristics. After an average follow-up of 21 months, 3-year freedom from local progression (FFLP) and overall survival (OS) were 79.6% and 47.1%, respectively. The biological effective dose was the most significant factor influencing FFLP and OS: after more than 106 Gy biological effective dose as planning target volume encompassing dose (N = 164), 3-year FFLP and OS were 92.5% and 62.2%, respectively. No evidence of a learning curve or improvement of results with larger SBRT experience and implementation of new radiotherapy technologies was observed. Conclusion: SBRT for stage I NSCLC was safe and effective in this multi-institutional, academic environment, despite considerable interinstitutional variability and time trends in SBRT practice. Radiotherapy dose was identified as a major treatment factor influencing local tumor control and OS.

Applicability of the linear-quadratic formalism for modeling local tumor control probability in high dose per fraction stereotactic body radiotherapy for early stage non-small cell lung cancer.

BACKGROUND AND PURPOSE To compare the linear-quadratic (LQ) and the LQ-L formalism (linear cell survival curve beyond a threshold dose dT) for modeling local tumor control probability (TCP) in stereotactic body radiotherapy (SBRT) for stage I non-small cell lung cancer (NSCLC). MATERIALS AND METHODS This study is based on 395 patients from 13 German and Austrian centers treated with SBRT for stage I NSCLC. The median number of SBRT fractions was 3 (range 1-8) and median single fraction dose was 12.5 Gy (2.9-33 Gy); dose was prescribed to the median 65% PTV encompassing isodose (60-100%). Assuming an α/β-value of 10 Gy, we modeled TCP as a sigmoid-shaped function of the biologically effective dose (BED). Models were compared using maximum likelihood ratio tests as well as Bayes factors (BFs). RESULTS There was strong evidence for a dose-response relationship in the total patient cohort (BFs>20), which was lacking in single-fraction SBRT (BFs<3). Using the PTV encompassing dose or maximum (isocentric) dose, our data indicated a LQ-L transition dose (dT) at 11 Gy (68% CI 8-14 Gy) or 22 Gy (14-42 Gy), respectively. However, the fit of the LQ-L models was not significantly better than a fit without the dT parameter (p=0.07, BF=2.1 and p=0.86, BF=0.8, respectively). Generally, isocentric doses resulted in much better dose-response relationships than PTV encompassing doses (BFs>20). CONCLUSION Our data suggest accurate modeling of local tumor control in fractionated SBRT for stage I NSCLC with the traditional LQ formalism.

Local tumor control probability modeling of primary and secondary lung tumors in stereotactic body radiotherapy

BACKGROUND AND PURPOSE To evaluate whether local tumor control probability (TCP) in stereotactic body radiotherapy (SBRT) varies between lung metastases of different primary cancer sites and between primary non-small cell lung cancer (NSCLC) and secondary lung tumors. MATERIALS AND METHODS A retrospective multi-institutional (n=22) database of 399 patients with stage I NSCLC and 397 patients with 525 lung metastases was analyzed. Irradiation doses were converted to biologically effective doses (BED). Logistic regression was used for local tumor control probability (TCP) modeling and the second-order bias corrected Akaike Information Criterion was used for model comparison. RESULTS After median follow-up of 19 months and 16 months (n.s.), local tumor control was observed in 87.7% and 86.7% of the primary and secondary lung tumors (n.s.), respectively. A strong dose-response relationship was observed in the primary NSCLC and metastatic cohort but dose-response relationships were not significantly different: the TCD90 (dose to achieve 90% TCP; BED of maximum planning target volume dose) estimates were 176 Gy (151-223) and 160 Gy (123-237) (n.s.), respectively. The dose-response relationship was not influenced by the primary cancer site within the metastatic cohort. CONCLUSIONS Dose-response relationships for local tumor control in SBRT were not different between lung metastases of various primary cancer sites and between primary NSCLC and lung metastases.

SMARCB1(INI1)-deficient Sinonasal Basaloid Carcinoma A Novel Member of the Expanding Family of SMARCB1-deficient Neoplasms

Poorly differentiated sinonasal carcinomas are a heterogenous group of aggressive neoplasms that encompasses squamous cell carcinoma including basaloid variant, lymphoepithelial carcinoma, sinonasal undifferentiated carcinoma, and neuroendocrine-type small cell carcinoma. We herein describe 3 cases of a hitherto unreported variant combining features of basaloid carcinoma with variable intermingled rhabdoid cells. Patients were 2 women (aged 28 and 35) and a man (52 y) who presented with sinonasal masses. All had advanced local disease with bone involvement (pT4). None had a history of irradiation or a family history of rhabdoid tumors. Treatment was surgery and adjuvant chemoradiation. One patient developed liver, lung, pleural, and pericardial metastases (63 mo) and is currently (70 mo) alive under palliative treatment. Another developed recurrent cervical lymph node metastases and died of disease 8.5 years later. The youngest patient was disease-free at last follow-up 7 years later. Histologic features were very similar in all 3 cases and showed intimate admixture of compact basaloid cell nests with peripheral palisading, perivascular pseudorosettes, and a few scattered rhabdoid cells. Rhabdoid cells were more extensive in the metastasis in 1 case but formed a minor inconspicuous component in the primary tumors in all cases. Striking features common to all cases were (1) basaloid “blue” appearance at low power, (2) papilloma-like exophytic component, (3) extensive pagetoid surface growth with prominent denuding features, and (4) replacement of underlying mucous glands mimicking an inverted papilloma. Clear-cut origin from benign papilloma and overt squamous differentiation were lacking. Diffuse (2) or partial (1) p16 expression was noted, but all cases lacked human papillomavirus DNA by molecular tests. In situ hybridization was negative for Epstein-Barr virus. Immunohistochemistry showed diffuse expression of pancytokeratin. CK5 and vimentin showed intermingling of CK5+/vimentin− basaloid and CK5−/vimentin+ rhabdoid cells. Complete loss of nuclear SMARCB1 expression was seen in all cases including also the denuding carcinoma in situ–like surface lesions. To our knowledge, this variant of sinonasal carcinoma has not been reported before. The identical features in all 3 cases suggest a specific disease rather than a nonspecific dedifferentiated phenotype. Awareness of this rare variant and thus reporting of additional cases is necessary for defining its full morphologic and biological spectrum.

Feasibility, Toxicity, and Efficacy of Short Induction Chemotherapy of Docetaxel Plus Cisplatin or Carboplatin (TP) Followed by Concurrent Chemoradio ­ therapy for Organ Preservation in Advanced Cancer of the Hypopharynx, Larynx, and Base of Tongue

AbstractPurpose:Concurrent chemoradiotherapy (CRT) is standard treatment for advanced head and neck cancer. Whether short induction chemotherapy (ICT) provides additional benefit or, in particular, predictive benefit for the response to chemoradiotherapy is an open question. The present study aimed to assess the feasibility, toxicity, and efficacy of induction with docetaxel and platinum salt (TP) and subsequent CRT.Patients and Methods:A total of 25 patients with functionally inoperable cancer of the base of the tongue, hypopharynx, or larynx received 1 cycle of docetaxel (75 mg/m², day 1) combined with either cisplatin (30 mg/m², days 1–3; n = 23) or carboplatin (AUC 1.5 days 1–3; n = 2). Responders (n = 22, >30% tumor reduction, graded by endoscopy) and 1 non-responder received CRT (target dose: 69–72 Gy) with cisplatin/paclitaxel, carboplatin/paclitaxel, or cisplatin/docetaxel.Results:All patients completed ICT with acceptable toxicity (leukocytopenia grade 4: 8%). The remission rate of the primary tumor was 88% (22/25 patients). There was no need to delay CRT due to toxicity in any case. Each patient received the full radiation dose. Of the patients, 56% received >80% of the chemotherapy. The acute toxicity of CRT was moderate, no grade 4 toxicities occurred, while grade 3 toxicities included the following: infection (39%), dermatitis (13%), leukocytopenia (30%), and thrombocytopenia (4%). The local control rate was 84.6% ± 8.5% and the survival rate was 89.6% ± 7.2% at 12 months. Organ preservation was possible in 22/23 (95%) cases.Conclusion:Short induction with a TP regimen and subsequent CRT with a taxan is feasible and associated with an encouraging local control rate.ZusammenfassungZiel:Die simultane Radiochemotherapie (CRT) ist Standard bei fortgeschrittenen Kopf-Hals-Tumoren. Offen ist der Stellenwert einer Kurzzeitinduktionschemotherapie (ICT), insbesondere deren prädiktive Bedeutung für das Ansprechen der Radiochemotherapie. In der Studie werden Durchführbarkeit, Toxizität und Effektivität einer Induktionschemotherapie mit Docetaxel und einem Platinsalz einschließlich der folgenden RCT berichtet.Patienten und Methode:25 Patienten mit einem nicht funktionserhaltend operablen Zungengrund-, Hypopharynx- und Larynxkarzinom erhielten einen Zyklus Docetaxel (75 mg/m2, d1) und Cisplatin (30 mg/m2 d-1–3) (n = 23) oder Carboplatin (AUC 1,5 d1-3) (n = 2). Responder (n = 22, mehr als 30% Rückbildung endoskopisch) und ein Non-Responder erhielten nachfolgend eine RCT (Zieldosis: 69–72 Gy) mit Cisplatin/Paclitaxel rsp. Carboplatin/Paclitaxel oder Cisplatin/Docetaxel.Ergebnisse:Die Induktionstherapie konnte bei allen Patienten mit akzeptabler Toxizität (Leukozytopenie Grad 4: 8%) durchgeführt werden. Die Remissionsrate des Primärtumors betrug 88% (22/25 Pat). Die Radiochemotherapie wurde in keinem Fall toxizitätsbedingt verzögert. Die Radiotherapiedosis wurde vollständig gegeben. 56% der Patienten erhielten >80% der geplanten Chemotherapie. Die Akuttoxizität der RCT war moderat, keine Grad-4-Toxizität; Grad-3-Toxizitäten: Infektion (39%), Dermatitis (13%), Leukozytopenie (30%), Thrombozytopenie (4%). Nach 12 Monaten lag die Lokalkontrolle bei 84,6% ± 8,5%, das Gesamtüberleben 89,6% ± 7,2%. Die Organerhaltquote lag bei 95% (22/23).Schlussfolgerung:Die Kurzinduktion mit TP und die nachfolgende CRT mit einem Taxan sind durchführbar und führten zu einer ermutigenden Tumorkontrolle.

Support Vector Machine-Based Prediction of Local Tumor Control After Stereotactic Body Radiation Therapy for Early-Stage Non-Small Cell Lung Cancer

BACKGROUND Several prognostic factors for local tumor control probability (TCP) after stereotactic body radiation therapy (SBRT) for early stage non-small cell lung cancer (NSCLC) have been described, but no attempts have been undertaken to explore whether a nonlinear combination of potential factors might synergistically improve the prediction of local control. METHODS AND MATERIALS We investigated a support vector machine (SVM) for predicting TCP in a cohort of 399 patients treated at 13 German and Austrian institutions. Among 7 potential input features for the SVM we selected those most important on the basis of forward feature selection, thereby evaluating classifier performance by using 10-fold cross-validation and computing the area under the ROC curve (AUC). The final SVM classifier was built by repeating the feature selection 10 times with different splitting of the data for cross-validation and finally choosing only those features that were selected at least 5 out of 10 times. It was compared with a multivariate logistic model that was built by forward feature selection. RESULTS Local failure occurred in 12% of patients. Biologically effective dose (BED) at the isocenter (BED(ISO)) was the strongest predictor of TCP in the logistic model and also the most frequently selected input feature for the SVM. A bivariate logistic function of BED(ISO) and the pulmonary function indicator forced expiratory volume in 1 second (FEV1) yielded the best description of the data but resulted in a significantly smaller AUC than the final SVM classifier with the input features BED(ISO), age, baseline Karnofsky index, and FEV1 (0.696 ± 0.040 vs 0.789 ± 0.001, P<.03). The final SVM resulted in sensitivity and specificity of 67.0% ± 0.5% and 78.7% ± 0.3%, respectively. CONCLUSIONS These results confirm that machine learning techniques like SVMs can be successfully applied to predict treatment outcome after SBRT. Improvements over traditional TCP modeling are expected through a nonlinear combination of multiple features, eventually helping in the task of personalized treatment planning.

SMARCB1 (INI-1)-deficient Sinonasal Carcinoma: A Series of 39 Cases Expanding the Morphologic and Clinicopathologic Spectrum of a Recently Described Entity

To more fully characterize the clinical and pathologic spectrum of a recently described tumor entity of the sinonasal tract characterized by loss of nuclear expression of SMARCB1 (INI1), we analyzed 39 SMARCB1-deficient sinonasal carcinomas collected from multiple medical centers. The tumors affected 23 males and 16 females with an age range of 19 to 89 years (median, 52). All patients presented with locally advanced disease (T3, n=5; T4, n=27) involving the sinuses (mainly ethmoid) with variable involvement of the nasal cavity. Thirty patients received surgery and/or radiochemotherapy with curative intent. At last follow-up, 56% of patients died of disease 0 to 102 months after diagnosis (median, 15), 2 were alive with disease, and 1 died of an unrelated cause. Only 9 patients (30%) were alive without disease at last follow-up (range, 11 to 115 mo; median, 26). The original diagnosis of retrospectively identified cases was most often sinonasal undifferentiated carcinoma (n=14) and nonkeratinizing/basaloid squamous cell carcinoma (n=5). Histologically, most tumors displayed either a predominantly basaloid (61%) or plasmacytoid/rhabdoid morphology (36%). The plasmacytoid/rhabdoid form consisted of sheets of tumor cells with abundant, eccentrically placed eosinophilic cytoplasm, whereas similar cells were typically rare and singly distributed in the basaloid variant. Glandular differentiation was seen in a few tumors. None of the cases showed squamous differentiation or surface dysplasia. By immunohistochemistry, the tumors were positive for pancytokeratin (97%), CK5 (64%), p63 (55%), and CK7 (48%); and they were negative for NUT (0%). Epstein-Barr virus and high-risk human papillomavirus was not detected by in situ hybridization. Immunohistochemical loss of SMARCB1 (INI1) expression was confirmed for all 39 tumors. Investigation of other proteins in the SWI/SNF complex revealed co-loss of SMARCA2 in 4 cases, but none were SMARCA4 deficient or ARID1A deficient. Of 27 tumors with SMARCB1 fluorescence in situ hybridization analysis, 14 showed homozygous (biallelic) deletions and 7 showed heterozygous (monoallelic) deletions. SMARCB1-deficient sinonasal carcinoma represents an emerging poorly differentiated/undifferentiated sinonasal carcinoma that (1) cannot be better classified as another specific tumor type, (2) has consistent histopathologic findings (albeit with some variability) with varying proportions of plasmacytoid/rhabdoid cells, and (3) demonstrates an aggressive clinical course. This entity should be considered in any difficult-to-classify sinonasal carcinoma, as correct diagnosis will be mandatory for optimizing therapy and for further delineation of this likely underdiagnosed disease.

Results of chemoselection with short induction chemotherapy followed by chemoradiation or surgery in the treatment of functionally inoperable carcinomas of the pharynx and larynx

OBJECTIVES Chemoradiation is the treatment of choice for carcinomas of the pharynx and larynx with imminent loss of organ or function. However, the prognosis after CRT decreases when salvage surgery becomes necessary. Single-cycle induction chemotherapy is therefore performed to identify patients who would benefit more from S than from CRT. The present study aims to evaluate the feasibility and effectiveness of this approach. MATERIALS AND METHODS Forty-seven patients received Induction Chemotherapy (IC) with docetaxel plus cisplatin or carboplatin and were subsequently assessed for tumor response. Responders achieving a ≥30% decrease in endoscopic tumor size and a ≥20% decrease in 18F-fluorodeoxyglucose uptake proceeded to primary Chemoradiation (CRT) and non-responders received surgery (S). Six weeks after CRT patients with residual tumors underwent secondary surgery (S). RESULTS Thirty eight patients were elected for CRT and 9 received S. A local control rate of 86.1% and disease-free survival of 80.4% was achieved at 2 years. Overall treatment time in CRT-patients >80 days was associated with inferior disease-free survival (p = 0.05), cause-specific survival (p = 0.02), overall survival (p = 0.01) and a trend to inferior local control (p = 0.07) at 2 years. CONCLUSION The strategy of selecting patients for CRT vs. S based on the response to IC achieves encouraging rates of disease control by surgery and CRT.

Increased skin and mucosal toxicity in the combination of vemurafenib with radiation therapy

BackgroundPalliative radiotherapy is often required for patients with metastatic malignant melanoma in the case of bone or brain metastases. Since BRAF inhibitor therapy is highly efficient in V600-mutated melanomas, there is hesitation to stop it during radiotherapy. Consequently, radiotherapy under simultaneous vemurafenib treatment is frequently needed.Case reportWe report the case of a patient receiving palliative radiotherapy of spinal bone metastases before and during vemurafenib therapy. The skin reactions were quantitatively scored using computer-assisted digital image evaluation.ResultsRadiotherapy without vemurafenib was tolerated very well, whereas radiotherapy under simultaneous vemurafenib treatment resulted in accentuated skin reactions. Furthermore, the patient developed dysphagia and had to be hospitalized for parenteral nutrition. In the quantitative analysis, there was a twofold increase in pigmentation and erythema of the irradiated skin area of the thoracic spine when vemurafenib was combined with radiotherapy compared with radiotherapy treatment alone. This is the first reported case of a patient showing no complications during radiotherapy without vemurafenib but remarkable skin and mucosal toxicity under concurrent vemurafenib therapy. Thus, a genetically conditioned individually elevated radiosensitivity can definitely be excluded. Compared with other reported cases, radiosensitization was not limited to the skin, but also affected the esophageal mucosa.ConclusionVemurafenib is a strong radiosensitizer. Patients receiving radiotherapy under simultaneous vemurafenib treatment should be monitored very closely.ZusammenfassungHintergrundBei Patienten mit metastasiertem Melanom ist die palliative Bestrahlung von Knochen- oder Hirnmetastasen häufig erforderlich. Da eine Therapie mit BRAF-Inhibitoren bei Patienten mit V600-mutierten Melanomen hoch effektiv ist, sollte man sie während einer Strahlentherapie nicht unterbrechen. Daher ist eine Strahlentherapie unter laufender Behandlung mit Vemurafenib häufig erforderlich.MethodenHier wird der Fall eines Patienten dargestellt, der palliative Bestrahlungen von Wirbelkörpermetastasen vor und während einer Behandlung mit Vemurafenib erhalten hat. Bei diesem Fallbericht wurde die Stärke der Hautreaktionen mit computerassistierter digitaler Bildanalyse quantitativ ausgewertet.ErgebnisDie Strahlentherapie ohne Vemurafenib wurde gut vertragen, wogegen es bei der Bestrahlung unter simultaner Vemurafenib-Therapie zu verstärkten Hautreaktionen kam. Darüber hinaus entwickelte der Patient eine Mukositis mit ausgeprägten Schluckbeschwerden, so dass er zur parenteralen Ernährung stationär aufgenommen werden musste. Verglichen zur alleinigen Bestrahlung waren Pigmentierung und Rötung in der quantitativen Auswertung bei der Kombination von Bestrahlung mit Vemurafenib auf das Doppelte erhöht. Dies ist der erste berichtete Fall eines Patienten, bei dem ohne Vemurafenib eine Strahlentherapie komplikationslos durchführbar war und in Kombination mit Vemurafenib Haut- und Schleimhauttoxizität auftraten. Daher kann eine genetisch bedingte individuell erhöhte Strahlenempfindlichkeit definitiv ausgeschlossen werden. Verglichen mit anderen berichteten Fällenbetraf die erhöhte Strahlenempfindlichkeit nicht nur die Haut, sondern auch die Schleimhaut des Ösophagus.SchlussfolgerungVemurafenib wirkt stark strahlensensibilisierend. Patienten, die unter simultaner Behandlung mit Vemurafenib bestrahlt werden, sollten engmaschig überwacht werden.

Combined treatment of human colorectal tumor cell lines with chemotherapeutic agents and ionizing irradiation can in vitro induce tumor cell death forms with immunogenic potential.

Chemotherapeutic agents (CT) and ionizing radiation (X-ray) induce DNA damage and primarily aim to stop the proliferation of tumor cells. However, multimodal anti-cancer therapies should finally result in tumor cell death and, best, in the induction of systemic anti-tumor immunity. Since distinct therapy-induced tumor cell death forms may create an immune activating tumor microenvironment, this study examined whether sole treatment with CT that are used in the therapy for colorectal cancer or in combination with X-ray result in colorectal tumor cell death with immunogenic potential. 5-Fluorouracil (5-FU), Oxaliplatin (Oxp), or Irinotecan (Irino) in combination with X-ray were all potent inhibitors of colorectal tumor cell colony formation. This study then examined the forms of cell death with AnnexinA5-FITC/Propidium Iodide staining. Necrosis was the prominent form of cell death induced by CT and/or X-ray. While only a combination of Irino with X-ray leads to death induction already 1 day after treatment, also the combinations of Oxp or 5-FU with X-ray and X-ray alone resulted in high necrosis rates at later time points after treatment. Inhibition of apoptosis increased the amount of necrotic tumor cells, suggesting that a programmed form of necrosis can be induced by CT + X-ray. 5-FU and Oxp alone or in combination with X-ray and Irino plus X-ray were most effective in increasing the expression of RIP, IRF-5, and p53, proteins involved in necrotic and apoptotic cell death pathways. All treatments further resulted in the release of the immune activating danger signals high-mobility group box 1 (HMGB1) and heat shock protein 70 (HSP70). The supernatants of the treated tumor cells induced maturation of dendritic cells. It is, therefore, concluded that combination of CT with X-ray is capable of inducing in vitro cell death forms of colorectal tumors with immunogenic potential.