Robert Semrau

Nuclear survivin expression is associated with HPV-independent carcinogenesis and is an indicator of poor prognosis in oropharyngeal cancer

The relationship between expression of the inhibitor of apoptosis protein survivin and the presence of high-risk human papillomavirus (HPV) in oropharyngeal squamous cell carcinoma (OSCC) remains unclear. This also accounts for its role as a predictor of survival. Therefore, we conducted a multicentre retrospective study on 106 consecutive oropharyngeal cancer patients. Human papillomavirus sequences were detected by nested PCR protocols. Survivin and p16 expression as a surrogate marker for HPV status were analysed by immunohistochemistry. Sequences of high-risk HPV were detected in 29% of cases. Prominent cytoplasmatic expression of survivin was found in 58% of cases and nuclear expression of survivin was found in 19% of the survivin-positive tumours. Nuclear expression of survivin was significantly correlated with HPV-negative tumours (P=0.023) and with a poor disease-free survival rate with an estimated 3-year disease-free survival probability of 35% for tumours with nuclear expression of survivin vs 78% for tumours with non-nuclear expression of survivin (hazard ratio=8.264; 95% confidence interval (95% CI)=2.510–27.210; P<0.001). In multivariate analysis, p16 expression status as well as nuclear expression of survivin were strong independent and opposing prognostic indicators of disease-free survival (hazard ratio=0.068; 95% CI=0.005–0.892; P=0.041 and hazard ratio=15.975; 95% CI=2.377–107.360; P=0.004, respectively). Our data show that nuclear accumulation of survivin correlates with HPV-independent carcinogenesis and is an independent predictor of poor survival in patients with OSCC.

Biomarkers for Cetuximab-Based Neoadjuvant Radiochemotherapy in Locally Advanced Rectal Cancer

Purpose: Phase II trials in locally advanced rectal cancer have shown that cetuximab-based neoadjuvant radiochemotherapy is feasible but without an improvement in complete pathologic response rates. Our goal was to identify patients who would benefit from cetuximab-based neoadjuvant chemoradiation measuring gene expression levels of proteins involved in tumor growth [endothelial growth factor receptor (EGFR)], angiogenesis [VEGF, VEGF receptors 1 and 2 (VEGFR1, VEGFR2)], DNA repair [excision repair cross-complementing 1 (ERCC1)], and drug metabolism [thymidylate synthetase (TS)]. We also determined mutation status of KRAS and BRAF. Experimental Design: This study was carried out on 130 patients with locally advanced rectal cancer who were enrolled in 4 different phase II clinical trials, using cetuximab-based chemoradiation. Tumor tissues were obtained before neoadjuvant and at surgical therapy. After microdissection, intratumoral gene expression levels and KRAS/BRAF mutation status were analyzed. Results: A significant decrease of TS, VEGFR1, and VEGFR2 gene expression was seen following neoadjuvant therapy (P < 0.03). High pretreatment VEGF gene expression levels were associated with nonresponse (P = 0.070). KRAS mutations were found in 42% and mutant KRAS (KRAS mt) was significantly associated with pathologic nonresponse (P = 0.037). In patients with wild-type KRAS (KRAS wt), low EGFR was significantly associated with higher nonresponse and VEGF mRNA expressions were associated with complete pathologic response (P = 0.012; P = 0.06). KRAS transversion (KRAS tv) was associated with tumor regression: nonresponse was more common in patients with KRAS tv than with KRAS wt (P = 0.007). BRAF V600E mutations were not detected in any of the patients. Conclusion: This study suggests that pretreatment intratumoral EGFR and VEGF mRNA expression levels as well as KRAS mutation status are predictive markers of pathologic response to neoadjuvant cetuximab-based chemoradiation in locally advanced rectal cancer. Clin Cancer Res; 17(10); 3469–77. ©2011 AACR.

Efficacy and Toxicity of Postoperative Temozolomide Radiochemotherapy in Malignant Glioma

Purpose:To evaluate the feasibility, safety and efficacy of daily temozolomide concurrent with postoperative radiotherapy in malignant glioma.Patients and Methods:From 11/1999 to 03/2003, n = 81 patients aged 15–72 years (median 52 years, Karnofsky score 80–100% in 83%) suffering from primary glioblastoma (n = 47), anaplastic astrocytoma (n = 6), anaplastic oligodendroglioma (n = 16), and recurrent glioma (n = 12) were treated. Patients with primary gliomas received a combination of postoperative radiotherapy (60 Gy/1.8- to 2.0-Gy fractions) and daily oral temozolomide (75 mg/m2) at all irradiation days (30–33 doses), while recurrent tumors were treated with 45–60 Gy and temozolomide. Initially, 6/81 patients had daily temozolomide doses of 50 mg/m2.Results:In total, 70/81 patients (86%) completed both radio- and chemotherapy. Grade 1 nausea/vomiting was seen in 28%, grade 2 in 11%, grade 3 in 1%. Antiemetics were applied in 41%. Hematologic toxicities were observed as follows: leukopenia grade 3/4 1%, lymphopenia grade 3/4 46%, thrombopenia grade 3/4 1%. Two patients under dexamethasone suffered herpes encephalitis after one and 16 doses of temozolomide (75 mg/m2). Median survival was 15 months for glioblastoma. In oligodendroglioma patients, a 4-year survival rate of 78% was observed.Conclusion:Postoperative radiochemotherapy with 30–33 daily doses of temozolomide (75 mg/m2) is safe in patients with malignant glioma. The combined schedule is effective in oligodendroglioma patients and may prolong survival in glioblastoma. Effort should be taken to minimize corticosteroid doses, since both steroids and temozolomide lead to immunosuppression.Ziel:Bestimmung der Durchführbarkeit, Toxizität und Effektivität einer kombinierten postoperativen Radiochemotherapie mit täglicher oraler Applikation von Temozolomid beim malignen Gliom.Patienten und Methodik:Von 11/1999 bis 03/2003 wurden n = 81 Patienten (Alter 15–72 Jahre, Median 52 Jahre, Karnofsky-Index 80–100% in 83%) mit primärem Glioblastom (n = 47), anaplastischem Astrozytom (n = 6), anaplastischem Oligodendrogliom (n = 16) oder Rezidivgliom (n = 12) behandelt. Patienten mit primären Gliomen erhielten simultan zur postoperativen Bestrahlung mit 60 Gy (1,8- bis 2,0-Gy-Fraktionen) an allen Bestrahlungstagen Temozolomid oral in einer Dosierung von 75 mg/m2 (30–33 Dosen), Rezidive wurden mit 45–60 Gy und Temozolomid behandelt. Initial wurde 6/81 Patienten Temozolomid in einer Dosierung von 50 mg/m2 verabreicht.Ergebnisse:Insgesamt konnte die Radiochemotherapie bei 70/81 Patienten (86%) komplett durchgeführt werden. Übelkeit und Erbrechen waren selten (Grad 1 28%, Grad 2 11%, Grad 3 1%); bei 41% der Patienten wurden Antiemetika eingesetzt. Höhergradige hämatologische Toxizitäten waren: Leukopenie Grad 3/4 1%, Lymphopenie Grad 3/4 46%, Thrombopenie Grad 3/4 1%. Zwei Patienten mit Dexamethason entwickelten nach einer bzw. 16 Temozolomid-Einzeldosen eine Herpesenzephalitis. Die mediane Überlebenszeit betrug für Glioblastome 15 Monate, die 4-Jahres-Überlebensrate für Oligodendrogliome 78%.Schlussfolgerung:Für Patienten mit malignen Gliomen ist die simultane postoperative Radiochemotherapie mit Temozolomid ein sicheres und wenig belastendes Verfahren. Wegen der immunsuppressiven Wirkung sollte die gleichzeitige Gabe von Dexamethason so weit wie möglich vermieden werden. Bei den chemosensiblen oligodendroglialen Tumoren ist die Radiochemotherapie effektiv; bei den Glioblastomen scheint eine Prognoseverbesserung möglich.

INITIATION OF A TELERADIOTHERAPEUTIC NETWORK FOR PATIENTS IN GERMAN LYMPHOMA STUDIES

PURPOSE Deviations of radiation treatment portals and dose from prospective treatment plans are unfavorable prognostic factors for lymphoma patients. Therefore, an extensive radiotherapy quality assurance program is used in the ongoing German lymphoma studies. The introduction of teleradiotherapy offered the opportunity to optimize and simplify the workflow of these quality assurance programs. The purpose of this report was to evaluate the feasibility of teleradiotherapy and to describe our experiences with these innovative tools. METHODS AND MATERIALS During this pilot phase, five radiotherapy centers were equipped with the hardware and software that guarantees a rapid and high-quality transfer of imaging data, as well as real-time teleconferences. The workstation consists of standard PCs with Windows NT as the operating system and the commercial telemedicine software Hipax. RESULTS As a first step, imaging communication between the radiotherapy reference centers in Cologne and Homburg/Saar was established. Subsequently, three additional radiotherapy departments (Universities of Berlin, Münster, and Munich) with large numbers of lymphoma patients were connected. Other study centers delivered digital imaging on mobile data carriers or via an Integrated Services Digital Network point-to-point connection. Communication units were completed for interactive teleconferences. A facility for central online documentation was installed. Telemedical functions were integrated into the ongoing radiotherapy quality assurance program. Since the introduction of a teleradiotherapeutic workstation in the radiotherapy reference center in Cologne in January 2001, the images of 10% (n = 228 patients) of all reviewed cases of the ongoing Hodgkins disease 10-12 trials were delivered digitally. The amount of digitally available imaging is continuously increasing. CONCLUSION The introduction of teleradiotherapy improved the dialog between the radiotherapy reference centers and study centers and thus contributed toward high radiotherapy quality for lymphoma patients in Germany.

Diagnostic work-up and outcome of cervical metastases from an unknown primary.

Conclusions. An intensive diagnostic work-up including 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) detects many unknown primary tumours, leads to a low emergence rate of primary tumours, and selects carcinoma of unknown primary with much more favourable results after neck dissection and postoperative radiotherapy. Objective. To investigate the optimal diagnostic approach and best treatment modality for rare head and neck cancer of unknown primary. Patients and methods. In a retrospective study, 69 patients admitted from 1987 to 2002 with cervical lymph node metastases without apparent primary were reviewed. Test characteristics of all diagnostic procedures were calculated. Disease-free and overall survival rates were calculated. Major prognostic factors were analysed univariately. Results. At the primary site FDG-PET showed the best sensitivity with 69% and the highest negative predictive value with 87%. Computed tomography and magnetic resonance imaging had a better specificity with 87% and 95%, respectively. The primary tumour was detected in 23 cases (33%). Frequent primary tumour origin was the palatine tonsil (n=8, 35%), base of the tongue (n=6, 26%) and lung (n=4, 17%). All patients with unknown primary were treated by neck dissection. Adjuvant radiotherapy was performed in 26 patients (57%), concurrent radiochemotherapy was performed in 12 patients (26%). The primary emergence rate was 7%. The 5-year overall survival rate was inferior in patients with detected primary in comparison with patients with unknown primary (22% versus 52%). Significant prognostic factors in case of unknown primary were M stage, smoking, alcohol consumption and tonsillectomy. Radiotherapy but not chemotherapy with carboplatin influenced the overall survival.

p16 Expression in carcinoma of unknown primary: Diagnostic indicator and prognostic marker

Carcinoma of unknown primary (CUP) of the neck are heterogeneous tumors in their clinical and biological characteristics, and a preoperative prognostic marker is desirable to optimize staging and therapy and to improve outcome and survival. For CUP syndrome, no optimized diagnostic and treatment strategy or biomarker have yet been determined.

EGF61 polymorphism predicts complete pathologic response to cetuximab-based chemoradiation independent of KRAS status in locally advanced rectal cancer patients

Background: Cetuximab has shown significant clinical activity in metastatic colon cancer. However, cetuximab-containing neoadjuvant chemoradiation has not been shown to improve tumor response in locally advanced rectal cancer patients in recent phase I/II trials. We evaluated functional germline polymorphisms of genes involved in epidermal growth factor receptor pathway, angiogenesis, antibody-dependent cell-mediated cytotoxicity, DNA repair, and drug metabolism, for their potential role as molecular predictors for clinical outcome in locally advanced rectal cancer patients treated with preoperative cetuximab-based chemoradiation. Methods: 130 patients (74 men and 56 women) with locally advanced rectal cancer (4 with stage II, 109 with stage III, and 15 with stage IV, 2 unknown) who were enrolled in phase I/II clinical trials treated with cetuximab-based chemoradiation in European cancer centers were included. Genomic DNA was extracted from formalin-fixed paraffin-embedded tumor samples and genotyping was done by using PCR-RFLP assays. Fishers exact test was used to examine associations between polymorphisms and complete pathologic response (pCR) that was determined by a modified Dworak classification system (grade III vs. grade IV: complete response). Results: Patients with the epidermal growth factor (EGF) 61 G/G genotype had pCR of 45% (5/11), compared with 21% (11/53) in patients heterozygous, and 2% (1/54) in patients homozygous for the A/A allele (P < 0.001). In addition, this association between EGF 61 G allele and pCR remained significant (P = 0.019) in the 59 patients with wild-type KRAS. Conclusion: This study suggested EGF A+61G polymorphism to be a predictive marker for pCR, independent of KRAS mutation status, to cetuximab-based neoadjuvant chemoradiation of patients with locally advanced rectal cancer. Clin Cancer Res; 17(15); 5161–9. ©2011 AACR.

Phase I/II trial of simultaneous whole-brain irradiation and dose-escalating topotecan for brain metastases.

Background and Purpose:Topotecan penetrates the blood-brain barrier and sensitizes tumor cells against radiation. A phase I/II dose-escalating trial of repetitive daily i. v. topotecan application simultaneously with whole-brain irradiation (WBRT) was conducted to estimate toxicity, maximum tolerated dose and survival in patients with inoperable brain metastases.Patients and Methods:In 47 patients suffering from previously untreated brain metastases, topotecan was applied on a daily i. v. schedule simultaneously with WBRT (36 Gy/3-Gy fractions). The infusion schedule started at the beginning of WBRT and was discontinued during weekends. Each infusion was completed within 1–2 h before irradiation. In a dose-finding study, topotecan was escalated from 5 × 0.5 mg/m2, 8 × 0.5 mg/m2, 12 × 0.5 mg/m2 to 12 × 0.6 mg/m2.Results:Altogether, 38/47 patients (81%) completed the prescribed schedule. Leukopenia and thrombocytopenia were dose-limiting. Grade 3/4 hematologic toxicity occurred in 5/32 chemonaive patients (16%) and 7/15 patients (47%) with previous chemotherapy. At 12 × 0.6 mg/m2, 2/4 patients experienced grade 4 leukopenia/thrombopenia. Nonhematologic toxicities were generally mild to moderate and unrelated to topotecan. Response evaluation was possible in 26/47 patients, overall response rate was 58% (CR [complete remission] 5/26, PR [partial remission] 10/26, NC [no change] 8/26). Median survival amounted to 5.1 months. In 15/42 patients (36%), brain metastases were the dominant cause of death.Conclusion:For a daily topotecan schedule simultaneous to WBRT, the maximum tolerated dose is 12 × 0.5 mg/m2 in chemonaive patients. For chemo-pretreated patients, daily doses should be reduced to 0.4 mg/m2. A phase III trial has now been started to find out whether WBRT + topotecan increases survival compared to WBRT alone.Hintergrund und Ziel:Topotecan, ein Topoisomeraseinhibitor, gehört zu den wenigen Substanzen, die die Blut-Hirn-Schranke durchdringen und Tumorzellen gegenüber ionisierender Strahlung sensibilisieren. Daher wurde eine Phase-I/II-Studie zur kombinierten Radiochemotherapie bei Patienten mit inoperablen Hirnmetastasen durchgeführt. Untersucht wurden Toxizität, maximal tolerable Dosis, Ansprechen der Hirnmetastasen und Überlebenszeit.Patienten und Methodik:Bei 47 Patienten mit unvorbehandelten Hirnmetastasen wurde eine palliative Ganzhirnbestrahlung mit 36 Gy/3 Gy mit einer täglichen Kurzinfusion von Topotecan 1–2 h vor der Bestrahlung kombiniert. Die erste Topotecaninfusion erfolgte am 1. Bestrahlungstag; an den Wochenenden wurden Bestrahlung und Topotecan ausgesetzt. Die Topotecandosis wurde wie folgt eskaliert: 5 × 0,5 mg/m2, 8 × 0,5 mg/m2, 12 × 0,5 mg/m2, 12 × 0,6 mg/m2.Ergebnisse:Insgesamt konnte bei 38/47 Patienten (81%) die Therapie wie vorgesehen durchgeführt werden. Dosislimitierend für die Topotecan-Chemotherapie waren Leukopenie und Thrombopenie. Eine Hämatotoxizität Grad 3/4 trat bei 5/32 chemotherapeutisch unvorbehandelten Patienten (16%) und bei 7/15 Patienten (47%) auf, die bereits zuvor eine Chemotherapie erhalten hatten. Unter einer Dosis von 12 × 0,6 mg/m2 kam es bei 2/4 Patienten zu einer Leukopenie/Thrombopenie Grad 4. Nichthämatologische Toxizitäten waren gering bis mäßig ausgeprägt und meist nicht durch Topotecan bedingt. Bei 26/47 Patienten konnte das Ansprechen beurteilt werden; die Ansprechrate lag bei 58% (CR [komplette Remission] 5/26, PR [partielle Remission] 10/26, NC [stabile Erkrankung] 8/26). Die mediane Überlebenszeit betrug 5,1 Monate. Bei 15/42 Patienten (36%) waren zerebrale Metastasen die Todesursache.Schlussfolgerung:Bei simultaner, täglicher Applikation von Topotecan beträgt die maximal tolerable Dosis für nicht chemotherapeutisch vorbehandelte Patienten 12 × 0,5 mg/m2. Für chemotherapeutisch vorbehandelte Patienten sollte die tägliche Dosis auf 0,4 mg/m2 reduziert werden. Ob sich durch die Kombination mit Topotecan im Vergleich zu einer alleinigen Ganzhirnbestrahlung das Überleben verbessern lässt, wird jetzt in einer Phase-III-Studie untersucht.

Survivin and epidermal growth factor receptor expression in surgically treated oropharyngeal squamous cell carcinoma

The epidermal growth factor receptor (EGFR) and the inhibitor of apoptosis protein survivin play important roles in the regulation of cellular proliferation and survival in squamous cell carcinomas. Their correlation in oropharyngeal squamous cell carcinoma (OSCC) has not been evaluated yet.

Prognostic impact of neoadjuvant chemoradiation in cT3 oesophageal cancer – A propensity score matched analysis

BACKGROUND The prognostic effect of neoadjuvant treatment in advanced oesophageal cancer is still debated because most studies included undefined T-stages, different radio/chemotherapies or different types of surgery. OBJECTIVES To analyse the prognostic impact of neoadjuvant chemoradiation in patients with clinical T3 oesophageal cancer and oesophagectomy. METHODS In a retrospective study 768 patients from two centres with cT3/Nx/M0 oesophageal cancer and transthoracic en-bloc oesophagectomy were selected. Clinical staging was based on endoscopy, endosonography and spiral-CT scan. Propensity score matching using histology, location of tumour, age, gender and ASA-classification identified 648 patients (n=302 adenocarcinoma (AC), n=346 squamous cell carcinoma (SCC)) for the intention-to-treat analysis comparing group-I (n=324) patients with planned oesophagectomy and group-II (n=324) patients with planned neoadjuvant chemoradiation (40Gy, 5-FU, cisplatin) followed by oesophagectomy. The prognosis was analysed by univariate and multivariate analyses. RESULTS In the intention-to-treat analysis group-I had a 17% and group-II a 28% 5-year survival rate (5-YSR) (p<0.001). After excluding patients without oesophagectomy the 5-YSR of group-II increased to 30%. The results were more favourable for patients with AC (5y-SR of 38%) compared to SCC (22%) (p=0.060). In group-II patients with major response (n=128) had a 41% 5-YSR compared to 20% for those with minor response (n=155, p<0,001). In multivariate analysis neoadjuvant chemoradiation was a favourable independent prognostic factor. CONCLUSION Neoadjuvant chemoradiation followed by oesophagectomy results in 11% higher 5-YSR than surgery alone for patients with cT3/Nx/M0 oesophageal cancer. This effect is due to the substantial prognostic benefit of the major responders.