Stability of metabolic tumor volume may enable radiotherapy dose painting in anal cancer.

PURPOSE: To evaluate the variability of the 18F-FDG-PET/CT-based metabolic tumor volume (MTV) in anal cancers during fractionated chemoradiotherapy (CRT), and assess the impact of this variability on dosimetric accuracy in MTV-targeted dose painting. METHODS: Eleven patients with anal squamous cell carcinoma who received fractionated chemoradiotherapy with curative intent were included. 18F-FDG PET/CT images were acquired at pre- and mid-treatment. Target volumes and organs at risk (OARs) were contoured manually on both image series. The MTV was generated from the PET images by thresholding. Treatment plans were retrospectively optimized for both image series using volumetric modulated arc therapy (VMAT). Standard plans prescribed 48.6 Gy, 54 Gy and 57.5 Gy in 27 fractions to elective regions, lymph node metastases and primary tumor, respectively. Dose painting plans included an extra dose level of 65 Gy to the MTV. Pre-treatment plans were transferred and re-calculated at mid-treatment basis. RESULTS: MTV decreased from pre- to mid-treatment in 10 of the 11 patients. On average, 71 % of MTVmid overlapped with MTVpre. The median and mean doses to the MTV were robust against anatomical changes, but the transferred dose painting plans had lower D98% values than the original and re-optimized plans. No major differences were found between standard and dose painting plans for OARs. CONCLUSIONS: Despite volumetric changes in the MTV, adequate dose coverage was observed in most dose painting plans. The findings indicate little or no need for adaptive dose painting at mid-treatment. Dose painting appears to be a safe treatment alternative with similar dose sparing of OARs.

Re-irradiation for recurrent rectal cancer - a single-center experience.

Background: There is no clear consensus on the use of re-irradiation (reRT) in the management of locally recurrent rectal cancer (LRRC). The aim of the present study was to investigate all reRT administered for rectal cancer at a large referral institution and to evaluate patient outcomes and toxicity.Material and methods: All patients with rectal cancer were identified who had received previous pelvic radiotherapy (RT) and underwent reRT during 2006-2016. Medical records and RT details of the primary tumor treatments and rectal cancer recurrence treatments were registered, including details on reRT, chemotherapy, surgery, adverse events, and long-term outcomes.Results: Of 77 patients who received ReRT, 67 had previously received pelvic RT for rectal cancer and were administered reRT for LRRC. Re-irradiation doses were 30.0-45.0 Gy, most often given as hyperfractionated RT in 1.2-1.5 Gy fractions twice daily with concomitant capecitabine. The median time since initial RT was 29 months (range, 13-174 months). Of 36 patients considered as potentially resectable, 20 underwent surgery for LRRC within 3 months after reRT. Operated patients had better 3-year overall survival (OS) (62%) compared to those who were not operated (16%; HR 0.32, p = .001). The median gross tumor volume (GTV) was 107 cm3, and 3-year OS was significantly better in patients with GTV <107 cm3 (44%) compared to patients with GTV ≥107 cm3 (21%; HR 0.52, p = .03).Conclusion: Three-year survival was significantly better for patients who underwent surgery after reRT or who had small tumor volume. Prospective clinical trials are recommended for further improvements in patient selection, outcomes, and toxicity assessment.

Anal cancer chemoradiotherapy outcome prediction using 18F-fluorodeoxyglucose positron emission tomography and clinicopathological factors.

OBJECTIVE: To assess the role of [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET), obtained before and during chemoradiotherapy, in predicting locoregional failure relative to clinicopathological factors for patients with anal cancer. METHODS: 93 patients with anal squamous cell carcinoma treated with chemoradiotherapy were included in a prospective observational study (NCT01937780). FDG-PET/CT was performed for all patients before treatment, and for a subgroup (n = 39) also 2 weeks into treatment. FDG-PET was evaluated with standardized uptake values (SUVmax/peak/mean), metabolic tumor volume (MTV), total lesion glycolysis (TLG), and a proposed Z-normalized combination of MTV and SUVpeak (ZMP). The objective was to predict locoregional failure using FDG-PET, tumor and lymph node stage, gross tumor volume (GTV) and human papilloma virus (HPV) status in univariate and bivariate Cox regression analysis. RESULTS: N3 lymph node stage, HPV negative tumor, GTV, MTV, TLG and ZMP were in univariate analysis significant predictors of locoregional failure (p < 0.01), while SUVmax/peak/mean were not (p > 0.2). In bivariate analysis HPV status was the most independent predictor in combinations with N3 stage, ZMP, TLG, and MTV (p < 0.02). The FDG-PET parameters at 2 weeks into radiotherapy decreased by 30-40 % of the initial values, but neither absolute nor relative decrease improved the prediction models. CONCLUSION: Pre-treatment PET parameters are predictive of chemoradiotherapy outcome in anal cancer, although HPV negativity and N3 stage are the strongest single predictors. Predictions can be improved by combining HPV with PET parameters such as MTV, TLG or ZMP. PET 2 weeks into treatment does not provide added predictive value. ADVANCES IN KNOWLEDGE: Pre-treatment PET parameters of anal cancer showed a predictive role independent of clinicopathological factors. Although the PET parameters show substantial reduction from pre- to mid-treatment, the changes were not predictive of chemoradiotherapy outcome.

Target volume delineation of anal cancer based on magnetic resonance imaging or positron emission tomography.

PURPOSE: To compare target volume delineation of anal cancer using positron emission tomography (PET) and magnetic resonance imaging (MRI) with respect to inter-observer and inter-modality variability. METHODS: Nineteen patients with anal cancer undergoing chemoradiotherapy were prospectively included. Planning computed tomography (CT) images were co-registered with 18F-fluorodexocyglucose (FDG) PET/CT images and T2 and diffusion weighted (DW) MR images. Three oncologists delineated the Gross Tumor Volume (GTV) according to national guidelines and the visible tumor tissue (GTVT). MRI and PET based delineations were evaluated by absolute volumes and Dice similarity coefficients. RESULTS: The median volume of the GTVs was 27 and 31 cm3 for PET and MRI, respectively, while it was 6 and 11 cm3 for GTVT. Both GTV and GTVT volumes were highly correlated between delineators (r = 0.90 and r = 0.96, respectively). The median Dice similarity coefficient was 0.75 when comparing the GTVs based on PET/CT (GTVPET) with the GTVs based on MRI and CT (GTVMRI). The median Dice coefficient was 0.56 when comparing the visible tumor volume evaluated by PET (GTVT_PET) with the same volume evaluated by MRI (GTVT_MRI). Margins of 1-2 mm in the axial plane and 7-8 mm in superoinferior direction were required for coverage of the individual observer's GTVs. CONCLUSIONS: The rather good agreement between PET- and MRI-based GTVs indicates that either modality may be used for standard target delineation of anal cancer. However, larger deviations were found for GTVT, which may impact future tumor boost strategies.

Short-course PET based simultaneous integrated boost for locally advanced cervical cancer.

BACKGROUND: Patients with large, locally advanced cervical cancers (LACC) are challenging to treat. The purpose of this work is to use 18F-FDG PET as planning basis for a short-course simultaneous integrated boost (SIB) in external beam radiotherapy of LACC in order to increase tumour shrinkage and likelihood of local control. METHODS: Ten previously treated patients with LACC were included, all with pre-treatment FDG PET/CT images available. The FDG avid tumour volume, MTV50, was dose escalated in silico by intensity modulated radiotherapy from the standard 1.8 Gy to 2.8 Gy per fraction for the 10 first fractions; a short-course SIB. For the 18 remaining external fractions, standard pelvic treatment followed to total PTV and MTV50 doses of 50.4 Gy and 60.4 Gy, respectively. Photon and proton treatment were considered using volumetric modulated arc treatment (VMAT) and intensity-modulated proton therapy (IMPT), respectively. All treatment plans were generated using the Eclipse Treatment Planning System (TPS). The impact of tumour shrinkage on doses to organs at risk (OARs) was simulated in the TPS for the SIB plans. RESULTS: Dose escalation could be implemented using both VMAT and IMPT, with a D98 ≥ 95 % for MTV50 being achieved in all cases. The sum of the 10 fraction short-course SIB and subsequent 18 standard fractions was compared to the standard non-SIB approach by dose volume histogram (DVH) analysis. Only marginal increase of dose to OARs was found for both modalities and a small further increase estimated from tumour shrinkage. Most DVH parameters showed a mean difference below 2 %. IMPT had, compared to VMAT, reduced OAR doses in the low to intermediate dose range, but showed no additional advantage in dose escalation. CONCLUSIONS: Planning of dose escalation based on a FDG avid boost volume was here demonstrated feasible. The concept may allow time for enhanced tumour shrinkage before brachytherapy. Thus, this strategy may prove clinically valuable, in particular for patients with large tumours.

Validation of dose painting of lung tumours using alanine/EPR dosimetry.

Biologic image guided radiotherapy (RT) with escalated doses to tumour sub volumes challenges today's RT dose planning and delivery systems. In this phantom study, we verify the capability of a clinical dose planning and delivery system to deliver an 18F-FDG-PET based dose painted treatment plan to a lung tumour. Furthermore, we estimate the uncertainties of the dose painted treatment compared to conventional RT plans. An anthropomorphic thorax phantom of polystyrene and polyurethane was constructed based on CT images of a lung cancer patient. 101 EPR/alanine dosimeters were placed in separate cavities within the phantom. IMRT and VMAT plans were generated in Eclipse (version 10.0, Analytical Anisotropic Algorithm version 10.2.28, Varian Medical Systems, Inc.) for 6 and 15 MV photons, based on 18F-FDG-PET/CT images of the patient. A boost dose of 3.8 Gy/fraction was given to the 18F-FDG-avid region (biological planning volume; BTV), whereas 3.1 Gy/fraction was planned to the planning target volume (PTV, excluding the BTV). For the homogenous plans, 3.2 Gy/fraction was given to the PTV. Irradiation of the phantom was carried out at a Varian Trilogy linear accelerator (Varian Medical Systems, Inc.). Uncertainties involved in treatment planning and delivery were estimated from portal dosimetry gamma evaluation. Measured and calculated doses were compared by Bland-Altmann analysis. For all treatment plans, all dose-volume objectives could be achieved in the treatment planning system. The mean absolute differences between calculated and measured doses were small (<0.1 Gy) for BTV, PTV-BTV, lung and soft tissue. The estimated uncertainty of the planned doses was less than 3% for all plans, whereas the estimated uncertainty in the measured doses was less 2.3%. Our results show that planning and delivery of dose escalated lung cancer treatment on a clinical dose planning and delivery system has high dosimetric accuracy. The uncertainties associated with the dose escalated treatment plans are comparable to the conventional plans.

Dose painting by numbers in a standard treatment planning system using inverted dose prescription maps.

BACKGROUND: Dose painting by numbers (DPBN) is a method to deliver an inhomogeneous tumor dose voxel-by-voxel with a prescription based on biological medical images. However, planning of DPBN is not supported by commercial treatment planning systems (TPS) today. Here, a straightforward method for DPBN with a standard TPS is presented. MATERIAL AND METHODS: DPBN tumor dose prescription maps were generated from (18)F-FDG-PET images applying a linear relationship between image voxel value and dose. An inverted DPBN prescription map was created and imported into a standard TPS where it was defined as a mock pre-treated dose. Using inverse optimization for the summed dose, a planned DPBN dose distribution was created. The procedure was tested in standard TPS for three different tumor cases; cervix, lung and head and neck. The treatment plans were compared to the prescribed DPBN dose distribution by three-dimensional (3D) gamma analysis and quality factors (QFs). Delivery of the DPBN plans was assessed with portal dosimetry (PD). RESULTS: Maximum tumor doses of 149%, 140% and 151% relative to the minimum tumor dose were prescribed for the cervix, lung and head and neck case, respectively. DPBN distributions were well achieved within the tumor whilst normal tissue doses were within constraints. Generally, high gamma pass rates (> 89% at 2%/2 mm) and low QFs (< 2.6%) were found. PD showed that all DPBN plans could be successfully delivered. CONCLUSIONS: The presented methodology enables the use of currently available TPSs for DPBN planning and delivery and may therefore pave the way for clinical implementation.

Reirradiation of locally recurrent rectal cancer: a systematic review.

BACKGROUND: Many patients with rectal cancer receive radiotherapy as a component of primary multimodality treatment. Although local recurrence is infrequent, reirradiation may be needed to improve resectability and outcomes. This systematic review investigated the effects of reirradiation in terms of feasibility, toxicity, and long-term outcomes. METHODS: A Medline, Embase and Cochrane search resulted in 353 titles/abstracts. Ten publications describing seven prospective or retrospective studies were included, presenting results of 375 patients reirradiated for rectal cancer. RESULTS: Median initial radiation dose was 50.4Gy, median 8-30months before reirradiation. Reirradiation was mostly administered using hyperfractionated (1.2-1.5Gy twice-daily) or 1.8Gy once-daily chemoradiotherapy. Median total dose was 30-40Gy to the gross tumour volume with 2-4cm margins. Median survival was 39-60months in resected patients and 12-16months in palliative patients. Good symptomatic relief was reported in 82-100%. Acute toxicity with diarrhoea was reported in 9-20%, late toxicity was insufficiently reported. CONCLUSIONS: Reirradiation of rectal cancer to limited volumes is feasible. When curative resection is possible, the goal is radical resection and long-term survival, and hyperfractionated chemoradiotherapy should be preferred to limit late toxicity. Reirradiation yielded good symptomatic relief in palliative treatment.