Jehad Abu Jawad

Intensified High-Dose Chemoradiotherapy With Induction Chemotherapy in Patients With Locally Advanced Non–Small-Cell Lung Cancer—Safety and Toxicity Results Within a Prospective Trial

PURPOSE To analyze the toxicity profile of an intensified definitive chemoradiotherapy (CRT) schedule in patients with locally advanced non-small-cell lung cancer (Stage IIIA N2/selected IIIB) treated within a prospective multicenter trial. PATIENTS AND METHODS After mediastinoscopy and routine staging procedures, three cycles of induction chemotherapy (cisplatin 50 mg/m(2), Days 1 and 8; paclitaxel 175 mg/m(2) Day 1, every 21 days) were planned, followed by concurrent CRT (accelerated-hyperfractionated regimen, 45 Gy, 2 x 1.5 Gy/d, cisplatin 50 mg/m(2), Days 64 and 71, vinorelbine 20 mg/m(2), Days 64 and 71). At 45 Gy, a multidisciplinary panel decision was made regarding operability. Inoperable patients received definitive radiotherapy (total dose 65 or 71 Gy, depending on the mean lung dose) with additional concurrent chemotherapy (cisplatin 40 mg/m(2), Day 85; vinorelbine 15 mg/m(2), Days 85 and 92). RESULTS A total of 28 patients (23 men and 5 women; median age, 58 years; range 41-73; Stage IIIA in 3 and Stage IIIB in 25) were judged ineligible for surgery by the multidisciplinary panel and underwent definitive CRT (75% of the patients received 71 Gy). The maximum toxicity (Grade 3 or greater) during induction chemotherapy included leukopenia (11%) and anemia (4%). During concurrent CRT, leukopenia (Grade 3 or greater) was observed in 39% of the patients. The maximal nonhematologic toxicity during concurrent CRT included esophagitis (Grade 3 or greater) in 18% and pneumonitis (Grade 3 or greater) in 4% of the patients. At 3 years, the locoregional control rate was 52% (95% confidence interval, 29-75%) and the overall survival rate was 31% (95% confidence interval, 12-50%). CONCLUSION This intensified treatment protocol with induction chemotherapy and concurrent CRT, including hyperfractionated-accelerated RT, showed only moderate toxicity and proved feasible. This treatment represents the definitive CRT arm of our ongoing multicenter randomized trial comparing definitive CRT and trimodality treatment.

Impact of human papilloma virus infection on the response of head and neck cancers to anti-epidermal growth factor receptor antibody therapy

Infection with human papillomaviruses (HPVs) characterizes a distinct subset of head and neck squamous cell cancers (HNSCCs). HPV-positive HNSCC preferentially affect the oropharynx and tonsils. Localized HPV-positive HNSCCs have a favorable prognosis and treatment outcome. However, the impact of HPV in advanced or metastatic HNSCC remains to be defined. In particular, it is unclear whether HPV modulates the response to cetuximab, an antibody targeting the epidermal growth factor receptor (EGFR), which is a mainstay of treatment of advanced HNSCC. To this end, we have examined the sensitivity of HPV-positive and -negative HNSCC models to cetuximab and cytotoxic drugs in vitro and in vivo. In addition, we have stably expressed the HPV oncogenes E6 and E7 in cetuximab-sensitive cancer cell lines to specifically investigate their role in the antibody response. The endogenous HPV status or the expression of HPV oncogenes had no significant impact on cetuximab-mediated suppression of EGFR signaling and proliferation in vitro. Cetuximab effectively inhibited the growth of E6- and E7-expressing tumors grafted in NOD/SCID mice. In support, formalin-fixed, paraffin-embedded tumor samples from cetuximab-treated patients with recurrent or metastatic HNSCC were probed for p16INK4a expression, an established biomarker of HPV infection. Response rates (45.5% versus 45.5%) and median progression-free survival (97 versus 92 days) following cetuximab-based therapy were similar in patients with p16INK4A-positive and p16INK4A-negative tumors. In conclusion, HPV oncogenes do not modulate the anti-EGFR antibody response in HSNCC. Cetuximab treatment should be administered independently of HPV status.

Helical Tomotherapy for Whole-Brain Irradiation With Integrated Boost to Multiple Brain Metastases: Evaluation of Dose Distribution Characteristics and Comparison With Alternative Techniques

PURPOSE To quantitatively evaluate dose distribution characteristics achieved with helical tomotherapy (HT) for whole-brain irradiation (WBRT) with integrated boost (IB) to multiple brain metastases in comparison with alternative techniques. METHODS AND MATERIALS Dose distributions for 23 patients with 81 metastases treated with WBRT (30 Gy/10 fractions) and IB (50 Gy) were analyzed. The median number of metastases per patient (N(mets)) was 3 (range, 2-8). Mean values of the composite planning target volume of all metastases per patient (PTV(mets)) and of the individual metastasis planning target volume (PTV(ind met)) were 8.7 ± 8.9 cm(3) (range, 1.3-35.5 cm(3)) and 2.5 ± 4.5 cm(3) (range, 0.19-24.7 cm(3)), respectively. Dose distributions in PTV(mets) and PTV(ind met) were evaluated with respect to dose conformity (conformation number [CN], RTOG conformity index [PITV]), target coverage (TC), and homogeneity (homogeneity index [HI], ratio of maximum dose to prescription dose [MDPD]). The dependence of dose conformity on target size and N(mets) was investigated. The dose distribution characteristics were benchmarked against alternative irradiation techniques identified in a systematic literature review. RESULTS Mean ± standard deviation of dose distribution characteristics derived for PTV(mets) amounted to CN = 0.790 ± 0.101, PITV = 1.161 ± 0.154, TC = 0.95 ± 0.01, HI = 0.142 ± 0.022, and MDPD = 1.147 ± 0.029, respectively, demonstrating high dose conformity with acceptable homogeneity. Corresponding numbers for PTV(ind met) were CN = 0.708 ± 0.128, PITV = 1.174 ± 0.237, TC = 0.90 ± 0.10, HI = 0.140 ± 0.027, and MDPD = 1.129 ± 0.030, respectively. The target size had a statistically significant influence on dose conformity to PTV(mets) (CN = 0.737 for PTV(mets) ≤4.32 cm(3) vs CN = 0.848 for PTV(mets) >4.32 cm(3), P=.006), in contrast to N(mets). The achieved dose conformity to PTV(mets), assessed by both CN and PITV, was in all investigated volume strata well within the best quartile of the values reported for alternative irradiation techniques. CONCLUSIONS HT is a well-suited technique to deliver WBRT with IB to multiple brain metastases, yielding high-quality dose distributions. A multi-institutional prospective randomized phase 2 clinical trial to exploit efficacy and safety of the treatment concept is currently under way.

Hyperfractionated Accelerated Radiotherapy versus Conventional Fractionation Both Combined with Chemotherapy in Patients with Locally Advanced Head and Neck Carcinomas

Objective: Hyperfractionated accelerated radiotherapy (HART) has been combined with chemotherapy (CC) for locally advanced head and neck cancer, but no data from randomized trials are available for a comparison with conventionally fractionated radiotherapy (CFRT) and CC. Methods: This monoinstitutional retrospective study compares the results of both treatment schedules: 315 patients with locally advanced carcinoma (UICC stage III and IV) of the oral cavity and the orohypopharynx were treated from January 1990 to March 2006 with a radiochemotherapy combination based on mitomycin C and fluorouracil (HART-CC: 203 patients, CFRT-CC: 112 patients, total dose: 70–72 Gy) with curative intent. Results: Two- and 4-year survival was 60 and 42 (HART-CC) and 59 and 42% (CFRT-CC; p = 0.82, log-rank test), respectively. Using multivariate Cox regression, pretreatment hemoglobin level, N stage, tumor site but not the year of treatment, gender and T stage were significant prognosticators for survival. For locoregional control, only N stage was significant. The prognostic value of these pretreatment factors did not variate with the fractionation schedule used. Conclusions: In combination with CC, there was no trend towards an improved efficacy of HART in comparison with CFRT.

SDF-1/CXCR4 expression in head and neck cancer and outcome after postoperative radiochemotherapy

Highlights • Outcome after postoperative radiochemotherapy in head and neck cancer is unsatisfactory.• We propose the chemokine axis SDF-1/CXCR4 as biomarker for patients stratification.• SDF-1 overexpression is an negative prognostic marker for locoregional control.• Prospective validation is warranted.

SDF-1/CXCR4 expression is an independent negative prognostic biomarker in patients with head and neck cancer after primary radiochemotherapy

INTRODUCTION Preclinical and clinical data suggest that the chemokine pathway governed by SDF-1 and CXCR4 contributes to a resistant phenotype. This retrospective biomarker study aims to explore the specific prognostic value of SDF-1 and CXCR4 expression in locally advanced head and neck squamous cell carcinomas (HNSCC) treated with primary radiochemotherapy (RT-CT). MATERIAL AND METHODS Biopsies from 141 HNSCC tumours of the oral cavity, oropharynx and hypopharynx were evaluated for SDF-1 and CXCR4 expression by immunofluorescence. SDF-1 and CXCR4 expression was correlated with clinico-pathological characteristics and outcome after RT-CT. RESULTS Patients with tumours exhibiting overexpression of intracellular SDF-1 and CXCR4 have a higher risk for loco-regional relapse and a worse overall survival after RT-CT (multivariate analysis, hazard ratio 2.33, CI [1.18-4.62], p = 0.02 and hazard ratio 2.02, CI [1.13-3.59], p = 0.02, respectively). Similar results were observed when only the subgroup of HPV DNA negative patients were analysed (hazard ratio 2.23 and 2.16, p = 0.02 and p = 0.01, respectively). CONCLUSIONS Our data support the importance of SDF-1 and CXCR4 expression for loco-regional control and overall survival in HNSCC after primary radiochemotherapy. Prospective multivariate validation and further studies into CXCR4 inhibition to overcome radiation resistance are warranted.

Strahlentherapie in der geriatrische Urologie

Ist die Indikation zur Strahlentherapie bei alteren Menschen gegeben, dann kann diese in vielen klinischen Situationen wie bei jungeren Patienten durchgefuhrt werden. Hypofraktionierte Strahlentherapieschemata konnen insbesondere in der palliativen Situation die Gesamtbehandlungszeit verkurzen. Mit der bildgefuhrten hochkonformalen Strahlentherapie, insbesondere mit der intensitatsmodulierten Radiotherapie (IMRT), kann auch bei grosen Zielvolumina die Vertraglichkeit durch enge Anpassung des Hochdosisbereichs an das Zielvolumen verbessert werden.

Accelerated radiotherapy and concurrent chemotherapy for patients with contralateral central or mediastinal lung cancer relapse after pneumonectomy

BACKGROUND Treatment options are very limited for patients with lung cancer who experience contralateral central or mediastinal relapse following pneumonectomy. We present results of an accelerated salvage chemoradiotherapy regimen. METHODS Patients with localized contralateral central intrapulmonary or mediastinal relapse after pneumonectomy were offered combined chemoradiotherapy including concurrent weekly cisplatin (25 mg/m(2)) and accelerated radiotherapy [accelerated fractionated (AF), 60 Gy, 8×2 Gy per week] to reduce time for repopulation. Based on 4D-CT-planning, patients were irradiated using multifield intensity-modulated radiotherapy (IMRT) or helical tomotherapy. RESULTS Between 10/2011 and 12/2012, seven patients were treated. Initial stages were IIB/IIIA/IIIB: 3/1/3; histopathological subtypes scc/adeno/large cell: 4/1/2. Tumour relapses were located in mediastinal nodal stations in five patients with endobronchial tumour in three patients. The remaining patients had contralateral central tumour relapses. All patients received 60 Gy (AF), six patients received concurrent chemotherapy. Median dose to the remaining contralateral lung, esophagus, and spinal cord was 6.8 (3.3-11.4), 8.0 (5.1-15.5), and 7.6 (2.8-31.2) Gy, respectively. With a median follow-up of 29 [17-32] months, no esophageal or pulmonary toxicity exceeding grade 2 [Common terminology criteria for adverse events (CTC-AE) v. 3] was observed. Median survival was 17.2 months, local in-field control at 12 months 80%. Only two local recurrences were observed, both in combination with out-field metastases. CONCLUSIONS This intensified accelerated chemoradiotherapy schedule was safely applicable and offers a curative chance in these pretreated frail lung cancer patients.