A. Eisbruch

Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC): An Introduction to the Scientific Issues

Advances in dose-volume/outcome (or normal tissue complication probability, NTCP) modeling since the seminal Emami paper from 1991 are reviewed. There has been some progress with an increasing number of studies on large patient samples with three-dimensional dosimetry. Nevertheless, NTCP models are not ideal. Issues related to the grading of side effects, selection of appropriate statistical methods, testing of internal and external model validity, and quantification of predictive power and statistical uncertainty, all limit the usefulness of much of the published literature. Synthesis (meta-analysis) of data from multiple studies is often impossible because of suboptimal primary analysis, insufficient reporting and variations in the models and predictors analyzed. Clinical limitations to the current knowledge base include the need for more data on the effect of patient-related cofactors, interactions between dose distribution and cytotoxic or molecular targeted agents, and the effect of dose fractions and overall treatment time in relation to nonuniform dose distributions. Research priorities for the next 5-10 years are proposed.

Optimization and clinical use of multisegment intensity-modulated radiation therapy for high-dose conformal therapy

Intensity-modulated radiation therapy (IMRT) may be performed with many different treatment delivery techniques. This article summarizes the clinical use and optimization of multisegment IMRT plans that have been used to treat more than 350 patients with IMRT over the last 4.5 years. More than 475 separate clinical IMRT plans are reviewed, including treatments of brain, head and neck, thorax, breast and chest wall, abdomen, pelvis, prostate, and other sites. Clinical planning, plan optimization, and treatment delivery are summarized, including efforts to minimize the number of additional intensity-modulated segments needed for particular planning protocols. Interactive and automated optimization of segmental and full IMRT approaches are illustrated, and automation of the segmental IMRT planning process is discussed.

Is uniform target dose possible in IMRT plans in the head and neck

PURPOSE Various published reports involving intensity-modulated radiotherapy (IMRT) plans developed using automated optimization (inverse planning) have demonstrated highly conformal plans. These reported conformal IMRT plans involve significant target dose inhomogeneity, including both overdosage and underdosage within the target volume. In this study, we demonstrate the development of optimized beamlet IMRT plans that satisfy rigorous dose homogeneity requirements for all target volumes (e.g., +/-5%), while also sparing the parotids and other normal structures. METHODS AND MATERIALS The treatment plans of 15 patients with oropharyngeal cancer who were previously treated with forward-planned multisegmental IMRT were planned again using an automated optimization system developed in-house. The optimization system allows for variable sized beamlets computed using a three-dimensional convolution/superposition dose calculation and flexible cost functions derived from combinations of clinically relevant factors (costlets) that can include dose, dose-volume, and biologic model-based costlets. The current study compared optimized IMRT plans designed to treat the various planning target volumes to doses of 66, 60, and 54 Gy with varying target dose homogeneity while using a flexible optimization cost function to minimize the dose to the parotids, spinal cord, oral cavity, brainstem, submandibular nodes, and other structures. RESULTS In all cases, target dose uniformity was achieved through steeply varying dose-based costs. Differences in clinical plan evaluation metrics were evaluated for individual cases (eight different target homogeneity costlets), and for the entire cohort of plans. Highly conformal plans were achieved, with significant sparing of both the contralateral and ipsilateral parotid glands. As the homogeneity of the target dose distributions was allowed to decrease, increased sparing of the parotids (and other normal tissues) may be achieved. However, it was shown that relatively few patients would benefit from the use of increased target inhomogeneity, because the range of improvement in the parotid dose is relatively limited. Hot spots in the target volumes are shown to be unnecessary and do not assist in normal tissue sparing. CONCLUSION Sparing of both parotids in patients receiving bilateral neck radiation can be achieved without compromising strict target dose homogeneity criteria. The geometry of the normal tissue and target anatomy are shown to be the major factor necessary to predict the parotid sparing that will be possible for any particular case.

Reducing xerostomia through advanced technology

Radiation-related xerostomia has been the most signifi cant and disabling side-eff ect of radiotherapy for head and neck cancer for more than 50 years. With the PARSPORT trial, reported in The Lancet Oncology, the largest and best designed of several randomised trials focusing on xerostomia, radiation oncologists and their partners in physics and dosimetry should take pride that signifi cant progress has been made. Before the introduction of intensity-modulated radiotherapy (IMRT), more than 80% of survivors experienced substantial dry mouth syndrome and associated eff ects on dental health, swallowing, taste, and quality of life. By contrast, Nutting and colleagues report about 25% of 2-year survivors had signifi cant clinician-rated xerostomia. Taken together with two randomised trials of IMRT for nasopharyngeal cancer, there is now compelling evidence of the power of advanced technology in reducing toxicity from head and neck radiotherapy. Can even better use of technology help us to further reduce xerostomia? The parotid glands provide watery saliva during eating, which is largely replaceable by consuming more water or lubricants. The submandibular, sublingual, and minor salivary glands provide mucinous saliva, associated with the resting sense of moisture and dry mouth symptoms. Future work should systematically explore the prioritisation of diff erent components of the salivary gland system. A clinical benefi t from sparing the submandibular glands may be seen, beyond that seen by sparing the parotid glands. The mean dose delivered to the minor salivary glands within the oral cavity has also been reported to be a signifi cant factor in patient-reported xerostomia. Further possibilities include gland repair or regenerative strategies with stem cells, acupuncture, or acupuncture-like stimulation. The promise of intensity-modulated protons provides even more optimism for reducing xerostomia and other acute and late eff ects. Another important aspect of PARSPORT is the evolution of quantitative methods to assess xerostomia—eg, pre and post stimulation salivary fl ow, quality of life, clinical grading, and diet tolerance scales. While there is no agreement on which is the gold standard, we should use multiple measures which refl ect diff erent aspects and perspectives (patient vs clinician) on the issue. One must recognise an inherent weakness in technology-based xerostomia trials: neither patients nor clinicians are blinded. However, for those practicing radiotherapy for head and neck cancer, and for our patients, the improved outcomes are empirically obvious every day. Xerostomia is now an uncommon fi rst complaint among survivors more than 3 months from treatment. This concern has been replaced by the next most bothersome issues: swallowing, taste, and fatigue. Reduction in the burden of treatment-related side-eff ects is especially important given the increasing number of patients presenting with oropharyngeal cancer (85% of patients in PARSPORT had disease at this site), related to the surge in cases of HPV infection. Considering the excellent prognosis of patients with oropharyngeal cancer with no or minimal smoking history (>80% 3-year survival), the potential for striking reductions in duration and magnitude of symptom burden is clear. Several ongoing studies are examining strategies to reduce treatment intensity for these patients, including radiation dose reduction, and substitution of cytotoxic drugs with targeted agents (eg, the recently approved RTOG-1016 for HPV-positive cancers). Lastly, a recent report suggests that surgical relocation of a submandibular gland might be an eff ective way to reduce the sense of dry mouth at rest. This intervention can be applied anywhere surgeons are trained for this procedure, in collaboration with two-dimensional radiotherapy, and demands further investigation. Some of us may under-appreciate that IMRT technology is available to less than 10% of the global population. Salivary gland transfer thus may have a more immediate and long-term eff ect on the global burden of radiationrelated xerostomia than all the beam modulation done for many decades.

TH‐E‐M100J‐03: Early Tumor Response Assessment of Advanced Head and Neck Cancer Using DCE MRI

Purpose: This study investigates whether changes in dynamic contrast enhanced (DCE) MR imaging during the early course of radiation therapy (RT) are correlated with local tumorcontrol in patients with advanced head and neck (H/N) cancer. We hypothesize that an early decrease in tumor perfusion or vascular permeability would be an indicator of early tumor response to RT. Methods: Patients who had newly diagnosed extracranial head and neck cancer and underwent a 7‐week course of definitive chemo‐RT participated in an IRB approved pilot study. Patients had three DCE MRI scans prior to RT, after 2 weeks of RT, and 3 months after the completion of RT. Perfusion parameters of the Gd‐DTPA transfer constant (K represents a combination of blood flow and vascular permeability) and the fractional blood volume (Vp) were estimated using the modified Toft model. Local tumor response was assessed clinically. The association between the changes in perfusion parameters of the tumor during the early course of RT and local tumor responses was analyzed. Results: For the patients in whom complete response was achieved, K in the tumor had the largest reduction, approximately 30%, after 2 weeks of RT compared to prior to RT. However, for the patients whose tumors failed to respond to or partially responded to RT, K in the tumor either increased by ∼80%, or decreased slightly. In contrast, changes in tumor Vp after 2 weeks of radiation were less specific for non‐responders compared to the changes in the tumor K. Conclusion: Preliminary data of this on‐going study suggest that DCE might have potential for early assessment of tumor response to radiation and chemo therapy in advance head and neck cancers.

TU-AB-303-05: Clinical Guidelines for Determining When An Adaptive Replan May Be Warranted for Head and Neck Patients

Purpose: Tools are now available to perform daily dose assessment in radiotherapy, however, guidance is lacking as to when to replan to limit increase in normal tissue dose. This work performs statistical analysis to provide guidance for when adaptive replanning may be necessary for head/neck (HN) patients. Methods: Planning CT and daily kVCBCT images for 50 HN patients treated with VMAT were retrospectively evaluated. Twelve of 50 patients were replanned due to anatomical changes noted over their RT course. Daily dose assessment was performed to calculate the variation between the planned and delivered dose for the 38 patients not replanned and the patients replanned using their delivered plan. In addition, for the replanned patients, the dose that would have been delivered if the plan was not modified was also quantified. Deviations in dose were analyzed before and after replanning, the daily variations in patients who were not replanned assessed, and the predictive power of the deviation after 1, 5, and 15 fractions determined. Results: Dose deviations were significantly reduced following replanning, compared to if the original plan would have been delivered for the entire course. Early deviations were significantly correlated with total deviations (p<0.01). Using the criteria that a 10% increase in the final delivered dose indicates a replan may be needed earlier in the treatment course, the following guidelines can be made with a 90% specificity after the first 5 fractions: deviations of 7% in the mean dose to the inferior constrictors and 5% in the mean dose to the parotid glands and submandibular glands. No significant dose deviations were observed in any patients for the CTV _70Gy (max deviation 4%). Conclusions: A 5–7% increase in mean dose to normal tissues within the first 5 fractions strongly correlate to an overall deviatios in the delivered dose for HN patients. This work is funded in part by NIH 2P01CA059827-16

SU‐FF‐T‐499: Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC): Limits and Recommendations for Use in Treatment Planning

Purpose: Via a workshop and the concerted efforts of many investigators (and with support from the AAPM and ASTRO) the dose‐volume relationships for many normal tissues sites have been examined and pulled together within the QUANTEC initiative. Here the summary recommendations of those studies are critiqued by members of the QUANTEC steering committee from a “physicist/treatment planner” perspective. Method and Materials: Sixteen site‐specific articles (written by knowledgeable physicians and physicists) have been submitted for simultaneous publication. Part of each report was a review of (where available) published dose volume histogram (DVH) point metrics and normal tissue complication model (NTCP) parameters associated with complications. Each report also provided information related to the quality of the data/results and their applicability for clinical use. The QUANTEC steering committee has summarized the site‐specific results together with a critical assessment of their strengths and shortcomings. Results: All reported values are apropos to the circumstances under which they were measured (primarily 3DCRT with conventional fractionation) and should be used with caution for other treatment schemes. The reported metrics generally fall into the categories of DVH points (e.g., Vxx, the volume of the normal tissue in excess of dose level xx associated with a complication threshold) and Lyman NTCP model parameters. The quality of the data/results ranges from combined analyses among several institutions (or combined analysis of literature values) to single institution experiences. In general, the recommended parameters and limits are more differential (separating safe from unsafe domains) rather than universal (spanning a continuous range of complications). However, clinically useful summaries can be made. Conclusion: The QUANTEC effort has been largely successful in updating the available dose/volume data. However, the resulting recommendations for clinical use need to be carefully assessed and cautiously applied as the quality of these data varies. Future QUANTEC initiatives are in progress.

SU‐DD‐A3‐02: Quantification of Heterogeneous Tumor Blood Volume as Early Predictors for Treatment Outcome in Advanced Head‐And‐Neck Cancer

Purpose: To evaluate the predicting values of metrics that quantify poorly perfused tumor volumes in patients with advanced head‐and‐neck cancer (HNC) treated with chemo‐radiation therapy (chemo‐RT) for outcomes. Materials and Method: Dynamic contrast‐enhanced (DCE) MRI scans were acquired for thirteen patients treated with concomitant chemo‐RT for advanced HNC, before therapy and 2 weeks after start of therapy. Blood volume (BV) maps were computed from the DCE MRI. Fuzzy C‐means clusteringanalysis (FCM), a segmentation method for partitioning a dataset into multiple clusters by minimizing the intracluster distance among members, was utilized to analyze heterogeneous BV in primary tumor volumes. The pre‐treatment tumor BV (TBV) values from all patients were used as training data and partitioned into 2, 3, or 4 clusters using FCM; and the resulting prototype vectors were adopted to partition each individual TBV before and during therapy. The volumes of the clusters with the lowest BV values were tested for their associations with treatment outcome. In addition, the cut‐off BV values for the lowest 1 cc, 2 cc, or 5 cc primary tumor sub‐volumes were calculated at both time points; and their predicting values for treatment outcome were evaluated. Results: Four of the 13 patients had local failure. Eight metrics differentiate local failure vs. local control significantly: pre‐treatment cut‐off TBV for the lowest 5 cc (p=0.03); average cut‐off TBVs of the lowest 2 cc (p=0.01) or 5 cc (p=0.04) over pre‐ and during‐ treatment; the volumes of the lowest TBV cluster at pre‐treatment (p=0.02), during‐treatment (p⩽0.03), as well as the average value over pre‐ and during‐ treatment (p⩽0.03). Conclusion: Our results suggest that poorly perfused sub‐volumes of the tumor before and/or early after start of treatment differentiate local failure vs. local control. The metrics discovered here will be candidates for future larger studies. Supported by NIHP01CA59827.

TH-EF-BRD-11: Clinical Skin Toxicity Comparison and Phantom Dose Measurements for Head and Neck Patients Treated with IMRT Vs. VMAT

Purpose: Observations in our clinic have suggested a trend towards increased skin-toxicity for head and neck (HN) patients treated with Volumetric Modulated Arc Therapy (VMAT) compared with Intensity Modulated Radiation Therapy (IMRT). Here, we report on these observations and quantify surface dose differences between VMAT and IMRT treatment plans for HN cancer patients. Methods: We retrospectively compared skin-toxicity scores gathered by the treating physician according to the Common Terminology Criteria for Adverse Events (CTCAE v4.0) for head and neck squamous cell carcinoma (HNSCC) patients treated with IMRT (102) and VMAT (88) . A Cochran-Armitage test evaluated the relationship between treatment modality, chemotherapy and toxicity. Six patients with grade 3 skin-toxicities were selected from this cohort and the target/organ at risk volumes were transferred onto an anthropomorphic phantom using a deformable image registration based atlas (SmartSegmentation, Varian Medical). Two-arc VMAT and 9-field IMRT plans were optimized and delivered to the anthropomorphic phantom to produce similar, clinically-acceptable, dose distributions. Surface dose was measured using optically-stimulated luminescent dosimeters placed at 2 positions on the phantom’s neck which were identical between VMAT and IMRT deliveries. N-factor ANOVA was performed to identify statistically significant differences in surface dose. Results: Our retrospective study showed a marginally significant higher skin-toxicity (Grade≥ 2) for VMAT compared with IMRT (35%vs.20%, p=0.06) for patients treated with radiation alone. Phantom measurements showed a significant effect of treatment modality on surface dose (F=42.5,p<0.001) with VMAT delivering 8% higher surface doses on average. No interaction was found between use of a thermoplastic mask and treatment with VMAT (F=0.02,p=0.884). Conclusion: This work indicates that marginal increases in skin dose and subsequent toxicity may be expected from HN patients treated with VMAT compared with IMRT. Our results motivate the need for techniques to spare the skin during VMAT treatment planning and for the early assessment of skin-toxicity.

SU‐E‐J‐241: Wavelet‐Based Temporal Feature Extraction From DCE‐MRI to Identify Sub‐Volumes of Low Blood Volume in Head‐And‐Neck Cancer

Purpose: A previous study showed that large sub-volumes of tumor with low blood volume (BV) (poorly perfused) in head-and-neck (HN) cancers are significantly associated with local-regional failure (LRF) after chemoradiation therapy, and could be targeted with intensified radiation doses. This study aimed to develop an automated and scalable model to extract voxel-wise contrast-enhanced temporal features of dynamic contrastenhanced (DCE) MRI in HN cancers for predicting LRF. Methods: Our model development consists of training and testing stages. The training stage includes preprocessing of individual-voxel DCE curves from tumors for intensity normalization and temporal alignment, temporal feature extraction from the curves, feature selection, and training classifiers. For feature extraction, multiresolution Haar discrete wavelet transformation is applied to each DCE curve to capture temporal contrast-enhanced features. The wavelet coefficients as feature vectors are selected. Support vector machine classifiers are trained to classify tumor voxels having either low or high BV, for which a BV threshold of 7.6% is previously established and used as ground truth. The model is tested by a new dataset. The voxel-wise DCE curves for training and testing were from 14 and 8 patients, respectively. A posterior probability map of the low BV class was created to examine the tumor sub-volume classification. Voxel-wise classification accuracy was computed to evaluate performance of the model. Results: Average classification accuracies were 87.2% for training (10-fold crossvalidation) and 82.5% for testing. The lowest and highest accuracies (patient-wise) were 68.7% and 96.4%, respectively. Posterior probability maps of the low BV class showed the sub-volumes extracted by our model similar to ones defined by the BV maps with most misclassifications occurred near the sub-volume boundaries. Conclusion: This model could be valuable to support adaptive clinical trials with further validation. The framework could be extendable and scalable to extract temporal contrastenhanced features of DCE-MRI in other tumors. We would like to acknowledge NIH for funding support: UO1 CA183848