Hendrik A. Wolff

Oxaliplatin added to fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy of locally advanced rectal cancer (the German CAO/ARO/AIO-04 study): final results of the multicentre, open-label, randomised, phase 3 trial

BACKGROUND Preoperative chemoradiotherapy with infusional fluorouracil, total mesorectal excision surgery, and postoperative chemotherapy with fluorouracil was established by the German CAO/ARO/AIO-94 trial as a standard combined modality treatment for locally advanced rectal cancer. Here we compare the previously established regimen with an investigational regimen in which oxaliplatin was added to both preoperative chemoradiotherapy and postoperative chemotherapy. METHODS In this multicentre, open-label, randomised, phase 3 study we randomly assigned patients with rectal adenocarcinoma, clinically staged as cT3-4 or any node-positive disease, to two groups: a control group receiving standard fluorouracil-based combined modality treatment, consisting of preoperative radiotherapy of 50·4 Gy in 28 fractions plus infusional fluorouracil (1000 mg/m(2) on days 1-5 and 29-33), followed by surgery and four cycles of bolus fluorouracil (500 mg/m(2) on days 1-5 and 29); or to an investigational group receiving preoperative radiotherapy of 50·4 Gy in 28 fractions plus infusional fluorouracil (250 mg/m(2) on days 1-14 and 22-35) and oxaliplatin (50 mg/m(2) on days 1, 8, 22, and 29), followed by surgery and eight cycles of oxaliplatin (100 mg/m(2) on days 1 and 15), leucovorin (400 mg/m(2) on days 1 and 15), and infusional fluorouracil (2400 mg/m(2) on days 1-2 and 15-16). Randomisation was done with computer-generated block-randomisation codes stratified by centre, clinical T category (cT1-3 vs cT4), and clinical N category (cN0 vs cN1-2) without masking. The primary endpoint was disease-free survival, defined as the time between randomisation and non-radical surgery of the primary tumour (R2 resection), locoregional recurrence after R0/1 resection, metastatic disease or progression, or death from any cause, whichever occurred first. Survival and cumulative incidence of recurrence analyses followed the intention-to-treat principle; toxicity analyses included all patients treated. Enrolment of patients in this trial is completed and follow-up is ongoing. This study is registered with ClinicalTrials.gov, number NCT00349076. FINDINGS Of the 1265 patients initially enrolled, 1236 were assessable (613 in the investigational group and 623 in the control group). With a median follow-up of 50 months (IQR 38-61), disease-free survival at 3 years was 75·9% (95% CI 72·4-79·5) in the investigational group and 71·2% (95% CI 67·6-74·9) in the control group (hazard ratio [HR] 0·79, 95% CI 0·64-0·98; p=0·03). Preoperative grade 3-4 toxic effects occurred in 144 (24%) of 607 patients who actually received fluorouracil and oxaliplatin during chemoradiotherapy and in 128 (20%) of 625 patients who actually received fluorouracil chemoradiotherapy. Of 445 patients who actually received adjuvant fluorouracil and leucovorin and oxaliplatin, 158 (36%) had grade 3-4 toxic effects, as did 170 (36%) of 470 patients who actually received adjuvant fluorouracil. Late grade 3-4 adverse events in patients who received protocol-specified preoperative and postoperative treatment occurred in 112 (25%) of 445 patients in the investigational group, and in 100 (21%) of 470 patients in the control group. INTERPRETATION Adding oxaliplatin to fluorouracil-based neoadjuvant chemoradiotherapy and adjuvant chemotherapy (at the doses and intensities used in this trial) significantly improved disease-free survival of patients with clinically staged cT3-4 or cN1-2 rectal cancer compared with our former fluorouracil-based combined modality regimen (based on CAO/ARO/AIO-94). The regimen established by CAO/ARO/AIO-04 can be deemed a new treatment option for patients with locally advanced rectal cancer. FUNDING German Cancer Aid (Deutsche Krebshilfe).

Radiotherapy of malignant gliomas: Comparison of volumetric single arc technique (RapidArc), dynamic intensity-modulated technique and 3D conformal technique

PURPOSE The analysis was designed to identify the optimal radiation technique for patients with malignant glioma. METHODS A volumetric-modulated radiation treatment technique (RapidArc), an IMRT technique and a 3D conformal technique were calculated on computed tomograms of 14 consecutive patients with malignant glioma. The treatment plans were compared with each other using dose-volume histograms. RESULTS The 3D conformal technique showed a good PTV coverage, if PTV was distant to organs at risk (OAR). If PTV was nearby OAR, the 3D technique revealed a poor PTV coverage in contrast to both intensity-modulated techniques. The conventional IMRT technique showed a slightly better PTV coverage than RapidArc. The advantages of RapidArc were a shorter treatment time, less monitor units and a small V(107%). CONCLUSIONS If PTV is distant to OAR, the use of 3D conformal technique is sufficient. Otherwise an intensity-modulated technique should be used. RapidArc was faster than conventional IMRT and should be preferred if PTV coverage is adequate.

KRAS and BRAF mutations in patients with rectal cancer treated with preoperative chemoradiotherapy

BACKGROUND AND PURPOSE KRAS and BRAF are mutated in 35% and 10% of colorectal cancers, respectively. However, data specifically for locally advanced rectal cancers are scarce, and the frequency of KRAS mutations in codons 61 and 146 remains to be established. MATERIALS AND METHODS DNA was isolated from pre-therapeutic biopsies of 94 patients who were treated within two phase-III clinical trials receiving preoperative chemoradiotherapy. Mutation status of KRAS exons 1-3 and BRAF exon 15 was established using the ABI PRISM Big Dye Sequencing Kit and subsequently correlated with clinical parameters. RESULTS Overall, KRAS was mutated in 45 patients (48%). Twenty-nine mutations (64%) were located in codon 12, 10 mutations (22%) in codon 13, and 3 mutations (7%) in codons 61 and 146. No V600E BRAF mutation was detected. The presence of KRAS mutations was correlated neither with tumor response or lymph node status after preoperative chemoradiotherapy nor with overall survival or disease-free survival. When KRAS exon 1 mutations were separated based on the amino-acid exchange, we again failed to detect significant correlations (p=0.052). However, G12V mutations appeared to be associated with higher rates of tumor regression than G13D mutations (p=0.012). CONCLUSION We are the first to report the mutation status of KRAS and BRAF in pre-therapeutic biopsies from locally advanced rectal cancers. The high number of KRAS mutations in codons 61 and 146 emphasizes the importance to expand current mutation analyses, whereas BRAF mutations are not relevant for rectal carcinogenesis. Although the KRAS mutation status was not correlated with response, the subtle difference between G12V and G13D mutations warrants analysis of a larger patient population.

High-grade acute organ toxicity as positive prognostic factor in primary radio(chemo)therapy for locally advanced, inoperable head and neck cancer.

Purpose:To test for a possible correlation between high-grade acute organ toxicity during primary radio(chemo)therapy and treatment outcome in patients with locally advanced head and neck squamous cell carcinoma (HNSCC).Patients and Methods:From 05/1994 to 01/2009, 216 HNSCC patients were treated with radio(chemo)therapy in primary approach. They received normofractionated (2 Gy/fraction) irradiation including associated nodal drainage sites to a cumulative dose of 70 Gy. 151 patients received additional concomitant chemotherapy (111 patients 5-fluorouracil/mitomycin C, 40 patients cisplatin-based). Toxicity during treatment was monitored weekly according to the Common Toxicity Criteria (CTC), and any toxicity grade CTC ≥ 3 of mucositis, dysphagia or skin reaction was assessed as high-grade acute organ toxicity for later analysis.Results:A statistically significant coherency between high-grade acute organ toxicity and overall survival as well as locoregional control was found: patients with CTC ≥ 3 acute organ toxicity had a 5-year overall survival rate of 44% compared to 8% in patients without (p < 0.01). Thereby, multivariate analyses revealed that the correlation was independent of other possible prognostic factors or factors that may influence treatment toxicity, especially concomitant chemotherapy and radiotherapy technique or treatment-planning procedure.Conclusion:These data indicate that normal tissue and tumor tissue may behave similarly with respect to treatment response, as high-grade acute organ toxicity during radio(chemo)therapy showed to be an independent prognostic marker in the own patient population. However, the authors are aware of the fact that a multivariate analysis in a retrospective study generally has statistical limitations. Therefore, their hypothesis should be further analyzed on biomolecular and clinical levels and other tumor entities in prospective trials.ZusammenfassungHintergrund und Ziel:Nach primärer Radio(chemo)therapie lokal fortgeschrittener Kopf-Hals-Tumoren kommt es bei einigen Patienten zu einer kompletten Remission, bei anderen lediglich zu einer partiellen Remission mit frühem Rezidiv. Unterschiedlich ist auch die Strahlenempfindlichkeit des Normalgewebes: Einige Patienten zeigen starke, andere hingegen weniger intensive Akutreaktionen. Im Rahmen dieser Arbeit wurde geprüft, ob Patienten, die höhergradige Akutreaktionen entwickeln, im Vergleich zu Patienten, bei denen diese nicht auftreten, eine bessere Prognose haben.Patienten und Methodik:Von 1994 bis 2009 wurden 216 Patienten mit lokal fortgeschrittenen Plattenepithelkarzinomen im Kopf-Hals-Bereich in der eigenen Klinik primär radiotherapiert (70 Gy). 151 Patienten erhielten begleitend eine Chemotherapie (111 Patienten 5-Fluorouracil/Mitomycin C, 40 Patienten Cisplatin-basiert). Jede Akuttoxizität ≥ Grad 3 in Form von Hautreaktion, Mukositis oder Dysphagie wurde als höhergradige akute Organtoxizität gewertet. Akuttoxizität ≥ Grad 3 wurde vor Beginn der Analyse als „cutoff value“ gewählt, da es ab dieser Toxizität zu einer signifikanten Einschränkung der Lebensqualität der Patienten kommt.Ergebnisse:Das Gesamtüberleben sowie die lokoregionäre Kontrolle nach 5 Jahren betrugen 18% bzw. 63%. Es fand sich dabei eine statistisch signifikante Korrelation zwischen höhergradiger akuter Organtoxizität und der Prognose: In der Gruppe der Patienten mit höhergradiger akuter Organtoxizität betrugen das Gesamtüberleben und die lokale Kontrolle nach 5 Jahren 44% und 74% im Vergleich zu 8% und 56% bei den Patienten ohne akute höhergradige Nebenwirkungen (p < 0,01, p = 0,04). Diese Korrelation war in multivariater Analyse statistisch unabhängig von anderen Faktoren, die möglicherweise die Toxizität beeinflussen, wie begleitende Chemotherapie oder Strahlentherapieplanung (konventionell/dreidimensional).Schlussfolgerung:Höhergradige akute Organtoxizität ist im untersuchten Kollektiv ein unabhängiger positiver prognostischer Faktor. Der Zusammenhang zwischen höhergradiger akuter Organtoxizität unter Radio(chemo)therapie und der Prognose sollte in prospektiven Studien weiter evaluiert werden.

Silencing of the Wnt transcription factor TCF4 sensitizes colorectal cancer cells to (chemo-) radiotherapy.

A considerable percentage of rectal cancers are resistant to standard preoperative chemoradiotherapy. Because patients with a priori-resistant tumors do not benefit from multimodal treatment, understanding and overcoming this resistance remains of utmost clinical importance. We recently reported overexpression of the Wnt transcription factor TCF4, also known as TCF7L2, in rectal cancers that were resistant to 5-fluorouracil-based chemoradiotherapy. Because Wnt signaling has not been associated with treatment response, we aimed to investigate whether TCF4 mediates chemoradioresistance. RNA interference-mediated silencing of TCF4 was employed in three colorectal cancer (CRC) cell lines, and sensitivity to (chemo-) radiotherapy was assessed using a standard colony formation assay. Silencing of TCF4 caused a significant sensitization of CRC cells to clinically relevant doses of X-rays. This effect was restricted to tumor cells with high T cell factor (TCF) reporter activity, presumably in a β-catenin-independent manner. Radiosensitization was the consequence of (i) a transcriptional deregulation of Wnt/TCF4 target genes, (ii) a silencing-induced G(2)/M phase arrest, (iii) an impaired ability to adequately halt cell cycle progression after radiation and (iv) a compromised DNA double strand break repair as assessed by γH2AX staining. Taken together, our results indicate a novel mechanism through which the Wnt transcription factor TCF4 mediates chemoradioresistance. Moreover, they suggest that TCF4 is a promising molecular target to sensitize resistant tumor cells to (chemo-) radiotherapy.

Organ function and quality of life after transoral laser microsurgery and adjuvant radiotherapy for locally advanced laryngeal cancer.

Background and Purpose:Transoral laser microsurgery (TLM) and adjuvant radiotherapy are an established therapy regimen for locally advanced laryngeal cancer at our institution. Aim of the present study was to assess value of quality of life (QoL) data with special regard to organ function under consideration of treatment efficacy in patients with locally advanced laryngeal cancer treated with larynx-preserving TLM and adjuvant radiotherapy.Patients and Methods:From 1994 to 2006, 39 patients (ten UICC stage III, 29 UICC stage IVA/B) with locally advanced laryngeal carcinomas were treated with TLM and adjuvant radiotherapy. Data concerning treatment efficacy, QoL (using the VHI [Voice Handicap Index], the EORTC QLQ-C30 and QLQ-H&N35 questionnaires) and organ function (respiration, deglutition, voice quality) were obtained for ten patients still alive after long-term follow-up. Correlations were determined using the Spearman rank test.Results:After a median follow-up of 80.8 months, the 5-year overall survival rate was 46.8% and the locoregional control rate 76.5%, respectively. The larynx preservation rate was 89.7% for all patients and 100% for patients still alive after follow-up. Despite some verifiable problems in respiration, speech and swallowing, patients showed a subjectively good QoL.Conclusion:TLM and adjuvant radiotherapy is a curative option for patients with locally advanced laryngeal cancer and an alternative to radical surgery. Even if functional deficits are unavoidable in the treatment of locally advanced laryngeal carcinomas, larynx preservation is associated with a subjectively good QoL.Hintergrund und Ziel:Lasermikrochirurgie und adjuvante Strahlentherapie sind in der Klinik der Autoren etablierte Behandlungsmethoden lokal fortgeschrittener Larynxkarzinome mit guten onkologischen Ergebnissen und einer hohe Rate an Organerhalt. Bei organerhaltender Therapie sind funktionelle Einschränkungen oft unvermeidbar. Neben den onkologischen Ergebnissen sollten in dieser Studie das objektive Ausmaß solcher Einschränkungen und deren subjektive Wertung durch die Patienten untersucht werden.Patienten und Methodik:Von 1994 bis 2006 wurden 39 Patienten (zehn UICC-Stadium III, 29 UICC-Stadium IVA/B) mit lokal fortgeschrittenen Larynxkarzinomen mittels Lasermikrochirurgie und adjuvanter Strahlentherapie behandelt. Bei zehn Patienten erfolgte im Rahmen der Nachsorge in den Jahren 2006/2007 eine Erhebung von Lebensqualitätsdaten. Die Schluckfunktion wurde flexibel endoskopisch überprüft, die Atmung durch eine Bodyplethysmographie. Die Objektivierung der Stimmqualität erfolgte durch das Göttinger Heiserkeitsdiagramm.Ergebnisse:Nach einer medianen Beobachtungsdauer von 80,8 Monaten betrugen die 5-Jahres-Überlebensrate 46,8% und die lokoregionale Kontrollrate 76,5%. Eine Salvage-Laryngektomie bei Lokalrezidiv erhielten vier Patienten, so dass im Verlauf eine 89,7%ige Rate an Larynxerhalt erreicht werden konnte. Bei der objektiven Untersuchung der Funktionseinschränkungen zeigte sich bei fünf Patienten eine gelegentliche Aspiration bei kräftigem Hustenreflex. Die übrigen fünf Patienten wiesen keine Schluckstörung auf. Eine Normalstimme lag bei keinem Patienten vor. Es bestand jedoch keine signifikante Korrelation der objektivierten Funktionsstörungen mit den Lebensqualitätsfunktionsskalen: Subjektiv schätzen die Patienten ihre Lebensqualität als gut ein.Schlussfolgerung:Lasermikrochirurgie und adjuvante Strahlentherapie sind eine Therapieoption für lokal fortgeschrittene Larynxkarzinome, die neben guten onkologischen Ergebnissen eine hohe Rate an Organerhalt ermöglicht. Die Patienten schätzen ihre Lebensqualität im weiteren Verlauf subjektiv als gut ein. Die tatsächlichen funktionellen Einschränkungen werden durch die Lebensqualitätsdaten allerdings nicht sicher abgebildet. Daher ist zur objektiven Beurteilung posttherapeutischer Funktionsergebnisse die klinische Erhebung funktioneller Befunde erforderlich.

Transoral laser microsurgery in treatment of pT2 and pT3 glottic laryngeal squamous cell carcinoma - results of 391 patients.

The purpose of this study was to evaluate oncological and functional results of transoral laser microsurgery (TLM) in patients with T2 and T3 glottic laryngeal squamous cell carcinoma (SCC).

Irradiation with protons for the individualized treatment of patients with locally advanced rectal cancer: A planning study with clinical implications

BACKGROUND AND PURPOSE Ongoing clinical trials aim to improve local control and overall survival rates by intensification of therapy regimen for patients with locally advanced rectal cancer. It is well known that whenever treatment is intensified, risk of therapy-related toxicity rises. An irradiation with protons could possibly present an approach to solve this dilemma by lowering the exposure to the organs-at-risk (OAR) without compromising tumor response. MATERIAL AND METHODS Twenty five consecutive patients were treated from 04/2009 to 5/2010. For all patients, four different treatment plans including protons, RapidArc, IMRT and 3D-conformal-technique were retrospectively calculated and analyzed according to dosimetric aspects. RESULTS Detailed DVH-analyses revealed that protons clearly reduced the dose to the OAR and entire normal tissue when compared to other techniques. Furthermore, the conformity index was significantly better and target volumes were covered consistent with the ICRU guidelines. CONCLUSIONS Planning results suggest that treatment with protons can improve the therapeutic tolerance for the irradiation of rectal cancer, particularly for patients scheduled for an irradiation with an intensified chemotherapy regimen and identified to be at high risk for acute therapy-related toxicity. However, clinical experiences and long-term observation are needed to assess tumor response and related toxicity rates.

STAT3 inhibition sensitizes colorectal cancer to chemoradiotherapy in vitro and in vivo.

Increased activity of signal transducer and activator of transcription 3 (STAT3) is common in human malignancies, including colorectal cancers (CRCs). We have recently reported that STAT3 gene expression correlates with resistance of CRC cell lines to 5‐fluorouracil (5‐FU)‐based chemoradiotherapy (CT/RT). This is of considerable clinical importance, because a large proportion of rectal cancers are resistant to preoperative multimodal treatment. To test whether STAT3 contributes to CT/RT‐resistance, we first confirmed that STAT3 protein expression correlated positively with increasing resistance. While STAT3 was not constitutively active, stimulation with interleukin‐6 (IL‐6) resulted in remarkably higher expression levels of phosphorylated STAT3 in CT/RT‐resistant cell lines. A similar result was observed when we determined IL‐6‐induced expression levels of phosphorylated STAT3 following irradiation. Next, STAT3 was inhibited in SW480 and SW837 using siRNA, shRNA and the small‐molecule inhibitor STATTIC. Successful silencing and inhibition of phosphorylation was confirmed using Western blot analysis and a luciferase reporter assay. RNAi‐mediated silencing as well as STATTIC treatment resulted in significantly decreased clonogenic survival following exposure to 3 µM of 5‐FU and irradiation in a dose‐dependent manner, with dose‐modifying factors of 1.3–2.5 at a surviving fraction of 0.37. Finally, STAT3 inhibition led to a profound CT/RT‐sensitization in a subcutaneous xenograft model, with a significantly delayed tumor regrowth in STATTIC‐treated mice compared with control animals. These results highlight a potential role of STAT3 in mediating treatment resistance and provide first proof of concept that STAT3 represents a promising novel molecular target for sensitizing resistant rectal cancers to CT/RT.

Human papillomavirus DNA load and p16INK4a expression predict for local control in patients with anal squamous cell carcinoma treated with chemoradiotherapy.

As the detection rate of HPV‐DNA in anal carcinoma commonly exceeds 90%, a comparison between sole HPV‐positive and HPV‐negative cancers with respect to treatment response following chemoradiotherapy (CRT) and long‐term oncological outcome is challenging. Against this background, we aimed to assess HPV types and HPV DNA load in formalin‐fixed paraffin‐embedded tissue (FFPE) of 95 patients treated with standard CRT for anal cancer to correlate viral load (≤/> median) with local failure, distant metastases, cancer‐specific (CSS) and overall survival (OS) rates. Various clinicopathologic parameters and the immunohistochemical marker p16INK4a were evaluated for any correlation with HPV16 DNA load and were included in uni‐ and multivariate analyses. The overall prevalence of HPV DNA was 95.8% with HPV16 monoinfection being the most commonly encountered HPV type (78.9%), followed by HPV16 and 31, 35, 39, 44, 58, 66 and 81 dual infection in 9 patients (9.5%). HPV16 DNA load was significantly associated with p16INK4a expression (p = 0.001). Patients with HPV16 DNA load ≤ median and low p16INK4a expression showed significantly worse local control (HPV16 DNA load: univariate p = 0.023, multivariate p = 0.042; p16INK4a: univariate p = 0.021), and OS (HPV16 DNA load: univariate p = 0.02, multivariate p = 0.03). Moreover, a combined HPV16 DNA load and p16INK4a variable revealed a significant correlation to decreased local failure, and increased CSS and OS (p = 0.019, p = 0.04 and p = 0.031). In conclusion, these data indicate that HPV16 DNA load and p16INK4a expression are significant prognostic factors for local tumor control and overall survival of patients with anal SCC following CRT.