Maarten Lambrecht

Value of Diffusion-Weighted Magnetic Resonance Imaging for Prediction and Early Assessment of Response to Neoadjuvant Radiochemotherapy in Rectal Cancer: Preliminary Results

PURPOSE To evaluate diffusion-weighted magnetic resonance imaging (DWI) for response prediction before and response assessment during and early after preoperative radiochemotherapy (RCT) for locally advanced rectal cancer (LARC). METHODS AND MATERIALS Twenty patients receiving RCT for LARC underwent MRI including DWI before RCT, after 10-15 fractions and 1 to 2 weeks before surgery. Tumor volume and apparent diffusion coefficient (ADC; b-values: 0-1000 s/mm(2)) were determined at all time points. Pretreatment tumor ADC and volume, tumor ADC change (∆ADC), and volume change (∆V) between pretreatment and follow-up examinations were compared with histopathologic findings after total mesorectal excision (pathologic complete response [pCR] vs. no pCR, ypT0-2 vs. ypT3-4, T-downstaging or not). The discriminatory capability of pretreatment tumor ADC and volume, ∆ADC, and ∆V for the detection of pCR was compared with receiver operating characteristics analysis. RESULTS Pretreatment ADC was significantly lower in patients with pCR compared with patients without (in mm(2)/s: 0.94 ± 0.12 × 10(-3) vs. 1.19 ± 0.22 × 10(-3), p = 0.003), yielding a sensitivity of 100% and specificity of 86% for detection of pCR. The volume reduction during and after RCT was significantly higher in patients with pCR compared with patients without (in %: ΔV(during): -62 ± 16 vs. -33 ± 16, respectively, p = 0.015; and ΔV(post): -86 ± 12 vs. -60 ± 21, p = 0.012), yielding a sensitivity of 83% and specificity of 71% for the ΔV(during) and, respectively, 83% and 86% for the ΔV(post). The ∆ADC during (ΔADC(during)) and after RCT (ΔADC(post)) showed a significantly higher value in patients with pCR compared with patients without (in %: ΔADC(during): 72 ± 14 vs. 16 ± 12, p = 0.0006; and ΔADC(post): 88 ± 35 vs. 26 ± 19, p = 0.0011), yielding a sensitivity and specificity of 100% for the ΔADC(during) and, respectively, 100% and 93% for the ΔADC(post). CONCLUSIONS These initial findings indicate that DWI, using pretreatment ADC, ΔADC(during), and ΔADC(post) may be useful for prediction and early assessment of pathologic response to preoperative RCT of LARC, with higher accuracy than volumetric measurements.

The use of FDG-PET/CT and diffusion-weighted magnetic resonance imaging for response prediction before, during and after preoperative chemoradiotherapy for rectal cancer

Abstract Purpose. To investigate the use of FDG-PET/CT before, during and after chemoradiotherapy (CRT) and diffusion-weighted magnetic resonance imaging (DW-MRI) before CRT for the prediction of pathological response (pCR) in rectal cancer patients. Material and methods. Twenty-two rectal cancer patients treated with long course CRT were included. An FDG-PET/CT was performed prior to the start of CRT, after 10 to 12 fractions of CRT and five weeks after the end of CRT. The tumor was delineated using a gradient based delineation method and the maximal standardized uptake values (SUVmax) were calculated. A DW-MRI was performed before start of CRT. Mean apparent diffusion coefficients (ADC) were determined. The ΔSUVmax during and after CRT and the initial ADC values were correlated to the histopathological findings after total mesorectal excision (TME). Results. ΔSUVmax during and after CRT significantly correlated with the pathological response to treatment (during CRT: ΔSUVmax = 59% ± 12% for pCR vs. 25% ± 27% if no pCR, p=0.0036; post-CRT: 90% ± 11 for pCR vs. 63% ± 22 if no pCR p=0.013). ROC curve analysis revealed an optimal threshold for ΔSUVmax of 40% during CRT and 76% after CRT. The initial ADC value was also significantly correlated with pCR (0.94 ± 0.12 × 10−3 mm2/s for pCR vs. 1.2 ± 0.24 × 10−3 mm2/s, p=0.002) and ROC curve analysis revealed an optimal threshold of 1.06 × 10−3 mm2/s. Combining the provided ΔSUVmax thresholds during and after CRT increased specificity of the prediction (sensitivity 100% and specificity 94%). The combination of the thresholds for the initial ADC value and the ΔSUVmax during CRT increased specificity of the prediction to a similar level (sensitivity of 100% and specificity of 94%). Conclusions. The combination of the different time points and the different imaging modalities increased the specificity of the response assessment both during and after CRT.

Diffusion-weighted magnetic resonance imaging early after chemoradiotherapy to monitor treatment response in head-and-neck squamous cell carcinoma.

PURPOSE To evaluate diffusion-weighted imaging (DWI) for assessment of treatment response in head and neck squamous cell carcinoma (HNSCC) three weeks after the end of chemoradiotherapy (CRT). METHODS AND MATERIALS Twenty-nine patients with HNSCC underwent magnetic resonance imaging (MRI) prior to and 3 weeks after CRT, including T(2)-weighted and pre- and postcontrast T(1)-weighted sequences and an echo-planar DWI sequence with six b values (0 to 1,000 s/mm(2)), from which the apparent diffusion coefficient (ADC) was calculated. ADC changes 3 weeks posttreatment compared to baseline (∆ADC) between responding and nonresponding primary lesions and adenopathies were correlated with 2 years locoregional control and compared with a Mann-Whitney test. In a blinded manner, the ∆ADC was compared to conventional MRI 3 weeks post-CRT and the routinely implemented CT, on average 3 months post-CRT, which used size-related and morphological criteria. Positive and negative predictive values (PPV and NPV, respectively) were compared between the ∆ADC and anatomical imaging. RESULTS The ∆ADC of lesions with later tumor recurrence was significantly lower than lesions with complete remission for both primary lesions (-2.3% ± 0.3% vs. 80% ± 41%; p < 0.0001) and adenopathies (19.9% ± 32% vs. 63% ± 36%; p = 0.003). The ∆ADC showed a PPV of 89% and an NPV of 100% for primary lesions and a PPV of 70% and an NPV of 96% for adenopathies per neck side. DWI improved PPV and NPV compared to anatomical imaging. CONCLUSION DWI with the ∆ADC 3 weeks after concluding CRT for HNSCC allows for early assessment of treatment response.

Development and external validation of a predictive model for pathological complete response of rectal cancer patients including sequential PET-CT imaging

PURPOSE To develop and validate an accurate predictive model and a nomogram for pathologic complete response (pCR) after chemoradiotherapy (CRT) for rectal cancer based on clinical and sequential PET-CT data. Accurate prediction could enable more individualised surgical approaches, including less extensive resection or even a wait-and-see policy. METHODS AND MATERIALS Population based databases from 953 patients were collected from four different institutes and divided into three groups: clinical factors (training: 677 patients, validation: 85 patients), pre-CRT PET-CT (training: 114 patients, validation: 37 patients) and post-CRT PET-CT (training: 107 patients, validation: 55 patients). A pCR was defined as ypT0N0 reported by pathology after surgery. The data were analysed using a linear multivariate classification model (support vector machine), and the models performance was evaluated using the area under the curve (AUC) of the receiver operating characteristic (ROC) curve. RESULTS The occurrence rate of pCR in the datasets was between 15% and 31%. The model based on clinical variables (AUC(train)=0.61±0.03, AUC(validation)=0.69±0.08) resulted in the following predictors: cT- and cN-stage and tumour length. Addition of pre-CRT PET data did not result in a significantly higher performance (AUC(train)=0.68±0.08, AUC(validation)=0.68±0.10) and revealed maximal radioactive isotope uptake (SUV(max)) and tumour location as extra predictors. The best model achieved was based on the addition of post-CRT PET-data (AUC(train)=0.83±0.05, AUC(validation)=0.86±0.05) and included the following predictors: tumour length, post-CRT SUV(max) and relative change of SUV(max). This model performed significantly better than the clinical model (p(train)<0.001, p(validation)=0.056). CONCLUSIONS The model and the nomogram developed based on clinical and sequential PET-CT data can accurately predict pCR, and can be used as a decision support tool for surgery after prospective validation.

Applications of diffusion-weighted magnetic resonance imaging in head and neck squamous cell carcinoma

In the head and neck, squamous cell carcinoma is one of the most common tumour types. Currently, the primary imaging modalities for initial locoregional staging are computed tomography and—to a lesser extent—magnetic resonance imaging, whilst [18F]fluorodeoxyglucose (FDG) positron emission tomography has additional value in the detection of subcentimetric metastatic lymph nodes and of tumour recurrence after chemoradiotherapy (CRT). However, dependency on the morphological and size-related criteria of anatomical imaging and the limited spatial resolution and FDG avidity of inflammation in metabolic imaging may reduce diagnostic accuracy in the head and neck. Diffusion-weighted magnetic resonance imaging (DWI) is a noninvasive imaging technique that measures the differences in water mobility in different tissue microstructures. Water mobility is likely influenced by cell size, density, and cellular membrane integrity and is quantified by means of the apparent diffusion coefficient. As such, the technique is able to differentiate tumoural tissue from normal tissue, inflammatory tissue and necrosis. In this article, we examine the use of DWI in head and neck cancer, focussing on technique optimization and image interpretation. Afterwards, the value of DWI will be outlined for clinical questions regarding nodal staging, lesion characterization, differentiation of post-CRT tumour recurrence from necrosis and inflammation, and predictive imaging towards treatment outcome. The possible consequences of adding DWI towards therapeutic management are outlined.

LungTech, an EORTC Phase II trial of stereotactic body radiotherapy for centrally located lung tumours: a clinical perspective

Evidence supports stereotactic body radiotherapy (SBRT) as a curative treatment option for inoperable early stage non-small-cell lung cancer (NSCLC) resulting in high rates of tumour control and low risk of toxicity. However, promising results are mainly derived from SBRT of peripheral pulmonary lesions, whereas SBRT for the central tumours can lead to severe radiation sequelae owing to the spatial proximity to the serial organs at risk. Robust data on the tolerance of mediastinal structures to high-dose hypofractionated radiation are limited; furthermore, there are many open questions regarding the efficiency, safety and response assessment of SBRT in inoperable, centrally located early stage NSCLC, which are addressed in a prospective multicentre study [sponsored by the European Organization for Research and Treatment of Cancer (EORTC 22113-08113-LungTech)]. In this review, we summarize the current status regarding SBRT for centrally located early stage NSCLC that leads to the rationale of the LungTech trial. Outline and some essential features of the study with focus on a summary of current experiences in dose/fraction-toxicity coherences after SBRT to the mediastinal structures that lead to LungTech normal tissue constraints are provided.

Advances in the management of squamous cell carcinoma of the head and neck

Squamous cell carcinoma of the head and neck (SCCHN) is the sixth most common cancer worldwide. The main risk factors for cancers of the oral cavity, larynx, oropharynx, and hypopharynx are alcohol and tobacco use. In addition, the human papillomavirus (HPV) is an established cause of oropharyngeal cancer. An experienced multidisciplinary team is necessary for adequate management and optimal outcome. The treatment of locally advanced disease generally requires various combinations of radiotherapy, surgery, and systemic therapy, but despite this aggressive multimodal treatment, 40% to 60% of the patients will relapse. In this report, we will discuss recent advances in the management of SCCHN, including new developments in molecular biology, imaging, and treatment.

Integrating pretreatment diffusion weighted MRI into a multivariable prognostic model for head and neck squamous cell carcinoma

INTRODUCTION In head and neck squamous cell carcinoma (HNSCC) the ability to anticipate an individual patients outcome is very valuable. With this study we wanted to assess the prognostic value of pretreatment apparent diffusion coefficient (ADC) in a large patient population and integrate it into a multivariable prognostic model. METHODS From 2004 to 2010 175 patients with pathology proven HNSCC were included in this study. All patients underwent a pretreatment MRI with diffusion weighted imaging (DWI) using six b-values. For each tumor, three ADC values were calculated using different b-value combinations: ADC(low) (b 0-50-100 s/mm(2)), ADChigh (b 500-750-1000 s/mm(2)) and ADC(avg) (all b-values). The clinical and radiological variables included: tumor and nodal volume, tumor location and age. Disease recurrence was analyzed using competing risk regression. A prognostic model for disease recurrence was developed, and internal validation was performed using bootstrapping and by dividing patients in three equal sized groups based on prognosis. RESULTS One hundred and sixty-one patients were eligible for analysis. Median follow-up was 50 months (range 4-86). A total of 67 patients experienced disease recurrence during follow-up (42%). ADC(high) was a prognostic factor for disease recurrence (adjusted hazard ratio: 1.14 per 10(-4) mm(2)/s, 95% CI 1.04-1.25). Harrells c-index of the multivariable prognostic model was 0.62 (95% CI 0.56-0.70) after internal validation. The validated 3-year disease recurrence rates for the groups with worst, intermediate, and best prognosis were 56%, 33% and 31% respectively. CONCLUSION Pretreatment ADC value derived from high b-values is an independent prognostic factor in HNSCC and increases the performance of a multivariable prognostic model in addition to known clinical and radiological variables. Integration of other biomarkers and external validation is necessary to ensure its clinical applicability.

Reduction of the dose to the elective neck in head and neck squamous cell carcinoma, a randomized clinical trial using intensity modulated radiotherapy (IMRT). Dosimetrical analysis and effect on acute toxicity

BACKGROUND AND PURPOSE A randomized trial was initiated to investigate whether a reduction of the dose to the elective nodal sites and the swallowing apparatus delivered by IMRT would result in a reduction of acute and late side effects without compromising tumor control. The aim of this paper is to report on dosimetrical analysis and acute toxicity. MATERIALS & METHODS Two-hundred patients were randomized. In the standard arm, elective nodal volumes (PTVelect) were irradiated up to an equivalent dose of 50Gy. In the experimental arm an equivalent dose of 40Gy was prescribed to the PTVelect. The dose to the swallowing apparatus was kept as low as possible without compromising therapeutic PTV (PTVther) coverage. RESULTS No significant difference was seen between both arms concerning PTVther coverage. The median D95 of the PTVelect was significantly lower in the experimental arm (39.5 vs 49.8Gy; p<0.001). Concerning the organs at risk, the dose to swallowing structures and spinal cord was significantly reduced. There was no significant difference in acute toxicity. Three months after radiotherapy there was significantly less grade ⩾3 dysphagia in the experimental arm (2% vs 11%; p=0.03). With a median follow-up of 6months no significant differences were observed in locoregional control, disease free survival or overall survival. CONCLUSIONS Using IMRT we were able to significantly reduce the dose to the PTVelect and several organs at risk without compromising PTVther coverage. This resulted in a significant reduction of severe dysphagia 3months after radiotherapy. Further follow-up is necessary to investigate whether these observations translate into a benefit on late treatment related dysphagia without affecting treatment outcome.

Incidence of isolated regional recurrence after definitive (chemo-) radiotherapy for head and neck squamous cell carcinoma

OBJECTIVE To evaluate the incidence and localization of regional recurrences after definitive (chemo-) radiotherapy for head and neck squamous cell carcinoma (HNSCC). METHODS From May 1987 to March 2008, 368 patients with advanced HNSCC were irradiated to 66-80.5 Gray in 6-7 weeks, with (37%) or without (63%) concomitant chemotherapy (Cisplatinum 100mg/m(2)) every 3 weeks. No planned neck dissections were performed. Data on clinical outcome were retrospectively reviewed, location of the original nodal disease and the regional recurrence was indicated on imaging and correlated with radiation dose. RESULTS Mean follow-up was 34 months (range: 50 days-216 months). Three-year overall survival and disease-specific survival were 55% and 62%, respectively. Loco-regional, local and regional controls were 58%, 65%, and 80%, respectively. Forty-one patients (11.1%) relapsed in the neck, but only 11 patients (2.99%) developed a true isolated regional recurrence, 6 of whom could be successfully salvaged by surgery. Only 2 patients (0.54%) developed an isolated recurrence in the electively treated nodal levels. CONCLUSION Isolated nodal recurrences are uncommon and recurrences in the electively treated neck are extremely uncommon.