Clinical outcome in patients treated with simultaneous integrated boost - intensity modulated radiation therapy (SIB-IMRT) with and without concurrent chemotherapy for squamous cell carcinoma of the anal canal.

Background and purpose To retrospectively evaluate locoregional control (LRC), survival and toxicity in anal cancer patients treated with simultaneous integrated boost - intensity modulated radiation therapy (SIB-IMRT) ± concurrent chemotherapy. Methods and materials Patients with squamous cell anal carcinoma stage T1(≥1 cm)-4, N0-3, M0-1 were included. All patients were treated with SIB-IMRT to a total dose of 59.4 Gy delivered to the primary tumor and macroscopically involved lymph nodes and 49.5 Gy to elective lymph node areas. If macroscopic residual tumor was still present in the fifth week of irradiation, a sequential boost of 5.4 Gy was given. Concurrent chemotherapy was administered in locally advanced cases. Acute and late toxicity were scored. Results One hundred and six patients treated consecutively between April 2006 and December 2012 were included. Eighty-seven (82.1%) patients received concurrent chemotherapy. The median follow-up was 47 months (range 2-104 months). Ninety-eight patients reached a clinical complete response (92.5%). Four-year actuarial LRC rate, overall survival and colostomy-free survival were 79%, 77% and 77%, respectively. Acute grade ≥3 toxicity occurred in 67.9% of the patients. Late grade 3 toxicity was seen in 16 patients (15.1%). Conclusions SIB-IMRT ± concurrent chemotherapy for anal cancer was effective with acceptable toxicity.

A phase I study on the combination of neoadjuvant radiotherapy plus pazopanib in patients with locally advanced soft tissue sarcoma of the extremities.

UNLABELLED: Accumulating evidence suggests significant synergism combining radiotherapy (RT) with angiogenesis targeted therapies. This multicenter prospective phase I clinical trial established the safety profile and recommended dose for further studies of pazopanib concurrent with preoperative RT in patients with extremity soft tissue sarcomas (ESTS) in curative setting. METHODS: Patients with deep seated intermediate and high grade sarcomas, ≥ 5 cm, received once daily pazopanib (dose-escalation cohorts 400 mg, 600 mg and 800 mg) for 6 weeks and 50 Gy preoperative RT starting Day 8. Surgery was performed 5-7 weeks later. Toxicity was scored according to CTC criteria 4.0. Dose limiting toxicities (DLT) were divided into two separate sets; DLT-I being toxicities occurring during the 6-week chemoradiotherapy period within the radiation portals until day of surgery (designated as DLT-I) and those occurring perioperatively until Day 21 after surgery (DLT-II). RESULTS: A total of 12 patients were enrolled, 11 were evaluable (3 females and 8 males, median age 58 years, range 24-78 years, median tumor size 9 cm, range 5-15 cm). Ten underwent surgery. No increased toxicity inside the radiation fields was seen, but two of 10 patients (one each in the 400 mg and 600 mg cohorts) showed delayed wound healing after surgery. None of the patients showed significant volume reductions after RT. Evaluation of the resection specimen showed pathological (near) complete responses (≥ 95% necrosis rate) in four of 10 cases. Unexpectedly, grade 3 + hepatotoxicity led to premature pazopanib interruption in three of 11 (27%) of cases. CONCLUSION: Apart from hepatotoxicity, neoadjuvant pazopanib 800 mg daily in combination with 50 Gy seems tolerable; the regimen appears to demonstrate promising activity in ESTS and is the recommended dose for further studies.

Predicting and implications of target volume changes of brain metastases during fractionated stereotactic radiosurgery.

OBJECTIVE: To study the impact of target volume changes in brain metastases during fractionated stereotactic radiosurgery (fSRS) and identify patients that benefit from MRI guidance. MATERIAL AND METHODS: For 15 patients (18 lesions) receiving fSRS only (fSRSonly) and 19 patients (20 lesions) receiving fSRS postoperatively (fSRSpostop), a treatment planning MRI (MR0) and repeated MRI during treatment (MR1) were acquired. The impact of target volume changes on the target coverage was analyzed by evaluating the planned dose distribution (based on MR0) on the planning target volume (PTV) during treatment as defined on MR1. The predictive value of target volume changes before treatment (using the diagnostic MRI (MRD)) was studied to identify patients that experienced the largest changes during treatment. RESULTS: Target volume changes during fSRS did result in large declines of the PTV dose coverage up to -34.8% (median = 3.2%) for fSRSonly patients. For fSRSpostop the variation and declines were smaller (median PTV dose coverage change = -0.5% (-4.5% to 1.9%)). Target volumes changes did also impact the minimum dose in the PTV (fSRSonly; -2.7 Gy (-16.5 to 2.3 Gy), fSRSpostop; -0.4 Gy (-4.2 to 2.5 Gy)). Changes in target volume before treatment (i.e. seen between the MRD and MR0) predicted which patients experienced the largest dose coverage declines during treatment. CONCLUSION: Target volume changes in brain metastases during fSRS can result in worsening of the target dose coverage. Patients benefiting the most from a repeated MRI during treatment could be identified before treatment.

Gross tumour volume delineation in anal cancer on T2-weighted and diffusion-weighted MRI - Reproducibility between radiologists and radiation oncologists and impact of reader experience level and DWI image quality.

PURPOSE: To assess how gross tumour volume (GTV) delineation in anal cancer is affected by interobserver variations between radiologists and radiation oncologists, expertise level, and use of T2-weighted MRI (T2W-MRI) vs. diffusion-weighted imaging (DWI), and to explore effects of DWI quality. METHODS AND MATERIALS: We retrospectively analyzed the MRIs (T2W-MRI and b800-DWI) of 25 anal cancer patients. Four readers (Senior and Junior Radiologist; Senior and Junior Radiation Oncologist) independently delineated GTVs, first on T2W-MRI only and then on DWI (with reference to T2W-MRI). Maximum Tumour Diameter (MTD) was calculated from each GTV. Mean GTVs/MTDs were compared between readers and between T2W-MRI vs. DWI. Interobserver agreement was calculated as Intraclass Correlation Coefficient (ICC), Dice Similarity Coefficient (DSC) and Hausdorff Distance (HD). DWI image quality was assessed using a 5-point artefact scale. RESULTS: Interobserver agreement between radiologists vs. radiation oncologists and between junior vs. senior readers was good-excellent, with similar agreement for T2W-MRI and DWI (e.g. ICCs 0.72-0.94 for T2W-MRI and 0.68-0.89 for DWI). There was a trend towards smaller GTVs on DWI, but only for the radiologists (P = 0.03-0.07). Moderate-severe DWI-artefacts were observed in 11/25 (44%) cases. Agreement tended to be lower in these cases. CONCLUSION: Overall interobserver agreement for anal cancer GTV delineation on MRI is good for both radiologists and radiation oncologists, regardless of experience level. Use of DWI did not improve agreement. DWI artefacts affecting GTV delineation occurred in almost half of the patients, which may severely limit the use of DWI for radiotherapy planning if no steps are undertaken to avoid them.

Gross Tumor Delineation in Esophageal Cancer on MRI Compared With 18F-FDG-PET/CT.

PURPOSE: Current delineation of the gross tumor volume (GTV) in esophageal cancer relies on computed tomography (CT) and combination with 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET). There is increasing interest in integrating magnetic resonance imaging (MRI) in radiation treatment, which can potentially obviate CT- or FDG-PET/CT-based delineation. The aim of this study is to evaluate the feasibility of target delineation on T2-weighted (T2W) MRI and T2W including diffusion-weighted MRI (T2W + DW-MRI) compared with current-practice FDG-PET/CT. METHODS: Ten observers delineated primary esophageal tumor GTVs of 6 patients on FDG-PET/CT, T2W-MRI, and T2W + DW-MRI. GTVs, generalized conformity indices, in-slice delineation variation (root mean square), and standard deviations in the position of the most cranial and caudal delineated slice were calculated. RESULTS: Delineations on MRI showed smaller GTVs compared with FDG-PET/CT-based delineations. The main variation was seen at the cranial and caudal border. No differences were observed in conformity indices (FDG-PET/CT, 0.68; T2W-MRI, 0.66; T2W + DW-MRI, 0.68) and in-slice variation (root mean square, 0.13 cm on FDG-PET/CT; 0.10 cm on T2W-MRI; 0.14 cm on T2W + DW-MRI). In the 2 tumors involving the gastroesophageal junction, addition of DW-MRI to T2W-MRI significantly decreased caudal border variation. CONCLUSIONS: MRI-based target delineation of the esophageal tumor is feasible with interobserver variability comparable to that with FDG-PET/CT, despite limited experience with delineation on MRI. Most variation was seen at cranial-caudal borders, and addition of DW-MRI to T2W-MRI may reduce caudal delineation variation of gastroesophageal junction tumors.

Significant tumor shift in patients treated with stereotactic radiosurgery for brain metastasis.

INTRODUCTION: Linac-based stereotactic radiosurgery (SRS) for brain metastases may be influenced by the time interval between treatment preparation and delivery, related to risk of anatomical changes. We studied tumor position shifts and its relations to peritumoral volume edema changes over time, as seen on MRI. METHODS: Twenty-six patients who underwent SRS for brain metastases in our institution were included. We evaluated the occurrence of a tumor shift between the diagnostic MRI and radiotherapy planning MRI. For 42 brain metastases the tumor and peritumoral edema were delineated on the contrast enhanced T1weighted and FLAIR images of both the diagnostic MRI and planning MRI examinations. Centre of Mass (CoM) shifts and tumor borders were evaluated. We evaluated the influence of steroids on peritumoral edema and tumor volume and the correlation with CoM and tumor border changes. RESULTS: The median values of the CoM shifts and of the maximum distances between the tumor borders obtained from the diagnostic MRI and radiotherapy planning MRI were 1.3 mm (maximum shift of 5.0 mm) and 1.9 mm (maximum distance of 7.4 mm), respectively. We found significant correlations between the absolute change in edema volume and the tumor shift of the CoM (p < 0.001) and tumor border (p = 0.040). Patients who received steroids did not only had a decrease in peritumoral edema, but also had a median decrease in tumor volume of 0.02 cc while patients who did not receive steroids had a median increase of 0.06 cc in tumor volume (p = 0.035). CONCLUSION: Our results show that large tumor shifts of brain metastases can occur over time. Because shifts may have a significant impact on the local dose coverage, we recommend minimizing the time between treatment preparation and delivery for Linac based SRS.

Reproducibility of the MRI-defined spinal cord position in stereotactic radiotherapy for spinal oligometastases.

PURPOSE: To establish the reproducibility of the MRI-defined spinal cord position within the spinal canal. MATERIALS AND METHODS: We acquired T1- and T2-weighted MRI scans of 15 volunteers on spine levels C7, T8 or L2. The scan protocol was repeated several times for different postures and time intervals. We determined the spinal cord shift (LR, AP, CC) using a rigid, grey value, vertebral body registration, followed by a spinal cord registration. We tested the sensitivity of our method, introducing artificial spinal cord shifts by varying the size and direction of the water-fat-shift (WFS) of the MR sequences. RESULTS: The spinal cord position on MRI is reproducible within approximately 0.2mm SD (LR, AP) and 0.7mm SD (CC) when reproducing the posture on the same day, as well as several weeks later. However, when comparing different postures, shifts of ∼1.5mm were found. Varying the WFS difference between scans (0.6-3.0mm) induced equivalent virtual spinal cord shifts (0.5-2.5mm). CONCLUSIONS: Displacement of the spinal cord inside the spinal canal may occur as a result of posture change. Considering the total geometric accuracy of spine SBRT, MRI-defined spinal cord position is sufficiently reproducible and requires no addition to the typical setup-and-intrafraction motion PRV margin if posture is identical throughout the RT process.

Tumour regression grading after chemoradiotherapy for locally advanced rectal cancer: a near pathologic complete response does not translate into good clinical outcome.

BACKGROUND: After preoperative chemoradiotherapy (CRT) for rectal cancer, clinically undetectable residual tumour deposits or pathologic lymph nodes may remain in the mesorectum. AIM: The aim of this study was to report histopathological effects of CRT and factors affecting outcome in a uniformly treated series of locally advanced rectal cancer (LARC) patients. METHODS: Between 2004 and 2008, 107 patients with cT3 (threatening the mesorectal fascia or <5 cm from the anal verge), cT4 or cN2 rectal cancer were treated with preoperative CRT (25 × 2 Gy with capecitabine) and TME 6-8 weeks later. Central histopathological review followed. Tumour regression grade (TRG) was scored in pCR, near-pCR, response and no response. Cox regression was performed to identify prognosticators. RESULTS: The 3-year distant metastasis-free interval, disease-free rate and overall survival rate were 82%, 73% and 87% (median 44 months follow-up). TRG consisted of 20% pCR, 11% near-pCR, 55% response and 14% no response. 6/21 pCR patients harboured nodal metastases. 5/12 near-pCR had ypT3 disease, while 6 harboured node metastases. 5/12 near-PCR patients developed distant metastases. ypN and TRG were powerful outcome discriminators. CONCLUSION: The high number of near-pCR with ypT3 or ypN1/2 and their poor outcome demonstrates that "watch-and-wait" in LARC patients should be applied with care.

Simultaneous integrated boost-intensity modulated radiation therapy with concomitant capecitabine and mitomycin C for locally advanced anal carcinoma: a phase 1 study.

PURPOSE: Newer radiation techniques, and the application of continuous 5-FU exposure during radiation therapy using oral capecitabine may improve the treatment of anal cancer. This phase 1, dose-finding study assessed the feasibility and efficacy of simultaneous integrated boost-intensity modulated radiation therapy (SIB-IMRT) with concomitant capecitabine and mitomycin C in locally advanced anal cancer, including pharmacokinetic and pharmacogenetic analyses. METHODS AND MATERIALS: Patients with locally advanced anal carcinoma were treated with SIB-IMRT in 33 daily fractions of 1.8 Gy to the primary tumor and macroscopically involved lymph nodes and 33 fractions of 1.5 Gy electively to the bilateral iliac and inguinal lymph node areas. Patients received a sequential radiation boost dose of 3 × 1.8 Gy on macroscopic residual tumor if this was still present in week 5 of treatment. Mitomycin C 10 mg/m(2) (maximum 15 mg) was administered intravenously on day 1, and capecitabine was given orally in a dose-escalated fashion (500-825 mg/m(2) b.i.d.) on irradiation days, until dose-limiting toxicity emerged in ≥2 of maximally 6 patients. An additional 8 patients were treated at the maximum tolerated dose (MTD). RESULTS: A total of 18 patients were included. The MTD of capecitabine was determined to be 825 mg/m(2) b.i.d. The predominant acute grade ≥3 toxicities included radiation dermatitis (50%), fatigue (22%), and pain (6%). Fifteen patients (83% [95%-CI: 66%-101%]) achieved a complete response, and 3 (17%) patients a partial response. With a median follow-up of 28 months, none of the complete responders, and 2 partial responders had relapsed. CONCLUSIONS: SIB-IMRT with concomitant single dose mitomycin C and capecitabine 825 mg/m(2) b.i.d. on irradiation days resulted in an acceptable safety profile, and proved to be a tolerable and effective treatment regimen for locally advanced anal cancer.

High risk of colostomy with primary radiotherapy for anal cancer.

BACKGROUND: Radiotherapy (RT) has become the primary treatment of choice for anal cancer in an effort to avoid colostomy. The current role of surgery appears generally to be underestimated, since diverting colostomy or abdominoperineal resection still often seems to be necessary for complications and local treatment failure after RT. METHODS: The data of 83 patients primarily treated by RT with curative intent throughout a 20-year period in our institute were analyzed regarding the need for colostomy. RESULTS: Totally, 28 patients (34%) required creation of a colostomy after primary RT for local failure or treatment-related complications during a mean follow-up period of 39 months. The 3-year actuarial colostomy-free rate was 59% (mean 85 +/- 9 months). Early stage disease, low T-score and absence of infiltration in adjacent organs were associated with a reduced need for colostomy in univariate analysis. In multivariate analysis only T-score was an independent variable in predicting prolonged colostomy-free interval. In this study, no statistically significant differences were noted for gender, age, nodal status, total radiation dose, radiation boost and concurrent chemotherapy. CONCLUSIONS: In approximately one-third of the patients treated by anal sphincter saving management with curative aimed primary RT, the creation of a colostomy appeared to be necessary for RT complications and local treatment failure. Therefore, patients should be well informed regarding the considerable risk of need for colostomy after RT for anal cancer.