Quantitative Analysis Of Normal Tissue Effects In The Clinic Research Articles

Cardiac protective techniques in left breast radiotherapy: rapid selection criteria for routine clinical decision making

ObjectiveIn left breast radiotherapy (RT) desired heart doses may be achieved without heart-sparing RT techniques in some patients. We aimed to examine the existence of predictive factors and cutoff points to determine which patients are the main candidates for heart-sparing RT techniques.Material and methodDosimetric data for left breast cancer was examined. RT plans were made at conventional doses to the breast and peripheral lymph nodes. Statistical analyses were performed using SPSS 22.0 (SPSS Inc., IBM Corp., Armonk, NY).Result114 cases were evaluated by ROC (Receiver operating characteristic) analysis in the breast-conserving surgery (BCS) and mastectomy groups. While only left lung volume (AUC: 0.74, 95% CI 0.61–0.87, p = 0.002) was significant in BCS cases, in cases with mastectomy, left lung volume (AUC: 0.81, 95% CI 0.69–0.94, p = 0.002) and lung/heart volume ratio (AUC: 0.83, 95% CI 0.70–0.96, p = 0.001) had a significant relationship with the relevance of heart doses. The cutoff point of 1.92 was selected for the lung/heart volume ratio for the mastectomized patients. Moreover, the cutoff point 1154 cc and 1208 cc was determined for the left lung volume for the BCS and mastectomized patients, respectively.ConclusionVarious cutoff points in left breast RT can be used to predict whether RT plans will meet QUANTEC (Quantitative Analysis of Normal Tissue Effects in the Clinic) heart dose limits. Evaluating only these few cutoff points before planning makes it possible to eliminate 70% of patients with BCS and 40% of patients with mastectomy from respiratory-controlled methods, which require time and effort. Patients with lung volume and lung/heart volume ratio smaller than the cutoff values can be considered primary candidates for heart-sparing techniques.

In Pursuit of Meaningfulness in the Biomedical Literature – Notes from a Scrap Booklet

"guestProfessor Søren M. Bentzen is the Director of the Division of Biostatistics and Bioinformatics, Department of Epidemiology and Public Health, University of Maryland School of Medicine, USA, and he is also an Adjunct Professor of Radiobiology and Medical Physics, University of Copenhagen, Denmark. Dr. Bentzen received a Master of Sciences in physics and mathematics, a PhD in medical image analysis, and he is a doctor of medical science in quantitative clinical radiobiology. He was one of the leaders of the Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC) initiative, and serves as a member of the Pediatric Normal Tissue Effects in the Clinic (PENTEC) steering committee. He was also a member of the American Society for Radiation Oncology (ASTRO) Task Forces to develop evidence-based guidelines on the appropriate fractionation for whole breast irradiation and for localized prostate cancer. He has served as chair or member of 17 (seven currently active) Independent Data and Safety Monitoring Committees or Trial Steering Committees and as co-chair for Translational Research for two Radiation Therapy Oncology Group (RTOG) phase III trials. He has published more than 500 original papers and book chapters, has presented >370 invited lectures, and he currently serves on 10 international cancer journal editorial boards. His main research interests include bioeffect modeling; biomathematics; applied biostatistics; clinical trial design; evidence-based medicine; late effects of radiotherapy; clinical radiobiology; integration of data from genomics, proteomics, and molecular imaging into novel therapeutic"

Why Do Both Mean Dose and V≥x Often Predict Normal Tissue Outcomes?

In the Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC), High Dose per Fraction, Hypofractionated Treatment Effects in the Clinic (HyTEC), and Pediatric Normal Tissue Effects in the Clinic (PENTEC) reviews, the mean dose was identified as a reasonable predictor for risk of toxic effects in some normal organs,1-5 particularly in organs classically considered to have a parallel-like architecture, such as the lung, liver, and parotid. The utility of the mean dose as a predictive metric is puzzling, because an underlying biological basis is challenging to define.

COMPARISON OF TWO RADIOTHERAPY TECHNIQUES IN TREATMENT OF PATIENTS WITH DIAGNOSED INOPERABLE CERVICAL CANCER

Advanced cervical cancer is treated with radiotherapy, target therapy, chemotherapy or a combination of those. Standardized accepted treatment of inoperable cervical cancer is concurrent chemo-radiotherapy (CCRT) followed by brachytherapy. Radiotherapy techniques used are three-dimensional conformal radiotherapy (3D-CRT) and intensity modulated radiation therapy (IMRT). In this study participated 30 female patients, average age of 52 at the time of irradiation.3D-CRT plans were made, patients were treated on linear accelerator (LINAC) with 3D-CRT. IMRT plans were made additionally. Planning target volume (PTV) dose coverage was 105.36% for 3D-CRT and 105.64% for IMRT. Homogeneity index (HI) was 0.062 for 3D-CRT and 0.048 for IMRT. Conformity index (CI) for 3D-CRT was 1.93 for PTV of 2990.77 ccm. CI for IMRT  was 1.305 for PTV of 2019.83 ccm. Bladder V40 (%) for 3D-CRT averaged 96.61%, while IMRT averaged 73.11%. Rectal V50 (%) for 3D-CRT was 72.55% and for IMRT was 17.80%. Rectal V40 (%) for 3D-CRT and IMRT averaged 92.12% and 73.49% respectively. Quantitative Analysis of normal Tissue Effects in the Clinic (QUANTEC) – V45 for 3D-CRT was 228.80ccm and for IMRT was 104.55ccm. Femoral heads dose for 3D-CRT was 51.50Gy for left and 51.29Gy for right. Absorbed doses for IMRT were 47.28Gy for left and 47.32Gy for right femoral head, respectively. 13 patients had grade 1 cystitis and urethritis, 2 with grade 2. 7 patients developed grade 1 diarrhea, 1 with grade 2. It can be concluded that dosimetrically IMRT is superior to 3D-CRT in patients treating cervical cancer. Keywords: cervical cancer, 3D-CRT, IMRT.  

Pulmonary dose tolerance in hemithorax radiotherapy for Ewing sarcoma of the chest wall: Are we overestimating the risk of radiation pneumonitis?

Children with chest wall Ewing sarcoma with malignant pulmonary effusion or pleural stranding require hemithorax radiation, often with plans that exceed lung constraints. We investigated disease control and pneumonitis in children requiring hemithorax radiation. Eleven children (median age 13years) received hemithorax radiotherapy. Symptomatic radiation pneumonitis was considered National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) grade 1+ with respiratory symptoms. Mean lung dose (MLD), volume of lung exposed to a dose ≥5Gy (V5), ≥20Gy (V20), and ≥35Gy (V35) were recorded. Adult and pediatric lung constraints were obtained from Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) guidelines and Children's Oncology Group (COG) protocols, respectively. Median hemithorax dose was 15Gy (1.5Gy/fraction). Median total dose was 51Gy (1.8Gy/fraction). Most plans delivered both protons and photons. The ipsilateral MLD, V5, and V20 were 27.2Gy, 100%, and 48.3%; the bilateral MLD, V20, and V35 were 14.1Gy, 22.8%, and 14.3%, respectively. One hundred percent, 36%, and 91% of treatments exceeded recommended adult ipsilateral lung constraints of V5 <65%, V20 <52%, and MLD of 22Gy; 64%, 45%, and 82% exceeded COG bilateral lung constraints of V20 <20%, MLD <15Gy, and MLD <12Gy, respectively; 82% of treatments exceeded the COG ipsilateral lung constraint of V20 <30%. At a median 36months (range 12-129), the symptomatic radiation pneumonitis incidence was 0%. Two patients progressed with nonpulmonary metastatic disease and died at a median 12months following radiotherapy. Existing guidelines may overestimate pneumonitis risk, even among young children receiving multiagent chemotherapy. For children with chest wall Ewing sarcoma and other thoracic malignancies, more data are needed to refine pediatric dose-effect models for pulmonary toxicity.

Assessing the Need for Adjusted Organ-at-Risk Planning Goals for Patients Undergoing Adjuvant Radiation Therapy for Locally Advanced Breast Cancer with Proton Radiation

PurposeLocally advanced breast cancer requires surgical management via lumpectomy or mastectomy with or without systemic therapy followed by chest wall or breast (CW) and comprehensive nodal irradiation (CNI). Radiation (RT) dose constraints for the heart and ipsilateral lung have been developed based on photon RT. Proton therapy (PBT) can deliver significantly lower doses of RT to these organs-at-risk (OARs) and may warrant adjustments to OAR planning goals. Methods and MaterialsThe RT plans of consecutive patients undergoing adjuvant CW-CNI RT with PBT within a single center were reviewed. A inital treatment volume, comprised of CW/intact breast + CNI (CTV_init) structure, including the CW and CNI but excluding any boost plans was analyzed. Frequency distributions were generated based on doses received by the heart, lungs, and esophagus for validated dosimetric parameters. Frequency distributions were generated and then stratified by laterality and compared using the Kruskal-Wallis H test. The 75th, 85th, and 95th percentiles for each dosimetric parameter were calculated, overall and by laterality. The 75th percentile (Q3), was used as a suggested primary goal, and the 95th percentile was used as a suggested secondary goal. ResultsOne hundred and seventy-two plans were analyzed. Forty-nine plans were right-sided, 107 were left-sided, and 16 were bilateral. The overall Q3 of the mean and V25 of the heart were 1.5 Gy and 1.7%, respectively. The mean and V25 to the heart differed significantly by laterality. Pulmonary values were similar to current recommendations. For all lateralites, the median volume of the esophagus receiving 70% prescription dose was ≤1 cm3. ConclusionsWe present the first dosimetric study providing complete OAR dose-volume histograms data for patients undergoing adjuvant pencil-beam scanning-PBT for locally advanced breast cancer, with detailed information on central tendencies, ranges and distributions of data. We have provided suggested planning goals and metrics for the lungs, heart, and esophagus; the latter 2 differing significantly from current Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) constraints and classical photon goals.

Application of Radiomics for the Prediction of Radiation-Induced Toxicity in the IMRT Era: Current State-of-the-Art.

Normal tissue complication probability (NTCP) models that were formulated in the Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC) are one of the pillars in support of everyday’s clinical radiation oncology. Because of steady therapeutic refinements and the availability of cutting-edge technical solutions, the ceiling of organs-at-risk-sparing has been reached for photon-based intensity modulated radiotherapy (IMRT). The possibility to capture heterogeneity of patients and tissues in the prediction of toxicity is still an unmet need in modern radiation therapy. Potentially, a major step towards a wider therapeutic index could be obtained from refined assessment of radiation-induced morbidity at an individual level. The rising integration of quantitative imaging and machine learning applications into radiation oncology workflow offers an unprecedented opportunity to further explore the biologic interplay underlying the normal tissue response to radiation. Based on these premises, in this review we focused on the current-state-of-the-art on the use of radiomics for the prediction of toxicity in the field of head and neck, lung, breast and prostate radiotherapy.

Impact of radiation techniques on lung toxicity in patients with mediastinal Hodgkin\u2019s lymphoma

PurposeMediastinal radiotherapy (RT), especially when combined with bleomycin, may result in substantial pulmonary morbidity and mortality. The use of modern RT techniques like intensity-modulated radiotherapy (IMRT) is gaining interest to spare organs at risk.MethodsWe evaluated 27 patients who underwent RT for Hodgkin’s lymphoma between 2009 and 2013 at our institution. For each patient, three different treatment plans for a 30-Gy involved-field RT (IFRT) were created (anterior-posterior-posterior-anterior setup [APPA], 5‑field IMRT, and 7‑field IMRT) and analyzed concerning their inherent “normal tissue complication probability” (NTCP) for pneumonitis and secondary pulmonary malignancy.ResultsThe comparison of different radiation techniques showed a significant difference in favor of standard APPA (p < 0.01). The risk of lung toxicity was significantly higher in plans using 7‑field IMRT than in plans using 5‑field IMRT. The absolute juxtaposition showed an increase in risk for radiation pneumonitis of 1% for plans using 5‑field IMRT over APPA according to QUANTEC (Quantitative Analyses of Normal Tissue Effects in the Clinic) parameters (Burman: 0.15%) and 2.6% when using 7‑field IMRT over APPA (Burman: 0.7%) as well as 1.6% when using 7‑field IMRT over 5‑field IMRT (Burman: 0.6%). Further analysis showed an increase in risk for secondary pulmonary malignancies to be statistically significant (p < 0.01); mean induction probability for pulmonary malignoma was 0.1% higher in plans using 5‑field IMRT than APPA and 0.19% higher in plans using 7‑field IMRT than APPA as well as 0.09% higher in plans using 7‑field IMRT than 5‑field IMRT. During a median follow-up period of 65 months (95% confidence interval: 53.8–76.2 months), only one patient developed radiation-induced pneumonitis. No secondary pulmonary malignancies have been detected to date.ConclusionRadiation-induced lung toxicity is rare after treatment for Hodgkin lymphoma but may be influenced significantly by the RT technique used. In this study, APPA RT plans demonstrated a decrease in potential radiation pneumonitis and pulmonary malignancies. Biological planning using NTCP may have the potential to define personalized RT strategies

Updating Photon-Based Normal Tissue Complication Probability Models for Pneumonitis in Patients With Lung Cancer Treated With Proton Beam Therapy

PurposeNo validated models for predicting the risk of radiation pneumonitis (RP) with proton beam therapy (PBT) currently exist. Our goal was to externally validate and recalibrate multiple established photon-based normal tissue complication probability models for RP in a cohort with locally advanced nonsmall cell lung cancer treated with contemporary doses of chemoradiation using PBT. Methods and MaterialsThe external validation cohort consisted of 99 consecutive patients with locally advanced nonsmall cell lung cancer treated with chemoradiation using PBT. RP was retrospectively scored at 3 and 6 months posttreatment. We evaluated the performance of the photon Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC) pneumonitis model, the QUANTEC model adjusted for clinical risk factors, and the newer Netherlands updated QUANTEC model. A closed testing procedure was performed to test the need for model updating, either by recalibration-in-the-large (re-estimation of intercept), recalibration (re-estimation of intercept/slope), or model revision (re-estimation of all coefficients). ResultsThere were 21 events (21%) of ≥grade 2 RP. The closed testing procedure on the PBT data set did not detect major deviations between the models and the data and recommended adjustment of the intercept only for the photon-based Netherlands updated QUANTEC model (intercept update: –1.2). However, an update of the slope and revision of the model coefficients were not recommended by the closed testing procedure, as the deviations were not significant within the power of the data. ConclusionsThe similarity between the dose-response relationship for PBT and photons for normal tissue complications has been an assumption until now. We demonstrate that the preexisting, widely used photon based models fit our PBT data well with minor modifications. These now-validated and updated normal tissue complication probability models can aid in individualizing selection of the most optimal treatment technique for a particular patient.

Bony-based and prostate-based image guidance for lo-calized prostate cancer radiotherapy

An important modality for the treatment of prostate cancer is teletherapy. The use of image-guided radiotherapy (IGRT) is a valuable tool in this treatment. This study retrospectively compared how repositioning the patient based on bone structure (B-ISO) and the prostate itself (P-ISO) affected the volumetric dose in the rectum, bladder, and clinical treatment volume (CTV). Additionally, the probability of normal tissue complication (NTCP) for the rectum was computed. We evaluated 155 cone-beam computed tomography (CBCT) from 8 patients. The treatment plans used beam modulation techniques. The planning target volume (PTV) margin adopted in both scenarios was 1 cm. The organs of interest were outlined over each CBCT and then treatment plans were applied so that the absorbed dose could be computed. NTCP values were calculated for the rectum. Analyzing dose-volume metrics published by the Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC), there was no significant difference between the two repositioning strategies for the rectum and bladder. There was a slight degradation in CTV coverage for the B-ISO strategy, but still with adequate coverage. Analysis of the uniform equivalent dose (EUD) and NTCP for the rectum showed little sensitivity to the strategy used. The present study showed that the use of CBCT in radiotherapy for prostate cancer treatment did not significantly improve volumetric doses for the rectum, bladder, and CTV, as well as NTCP for the rectum.

Effect of lung volume on helical radiotherapy in esophageal cancer: are there predictive factors to achieve acceptable lung doses?

The dose received by the lungs in radiotherapy (RT) is affected by the patient's current lung volume. The presence of predictive factors and cut-off points were investigated to achieve acceptable lung doses in esophageal cancer (EC) treatment. Virtual RT volumes of supracarinal EC were delineated. RT plans were designed with standard criteria in the TomoTherapy planning system (TomoTherapy Inc., Madison, WI, USA). The total dose was 50.4 Gy (1.8 Gy/fraction). ROC (Receiver operating characteristic) analysis and Mann-WhitneyU tests were performed. There was atotal of 65patient plans included. ROC analysis showed that lung/PTV (Planning target volume) volume ratio (AUC [Area under curve]: 0.91, 95% CI: 0.83-0.99, p = 0.000) and bilateral lung volume (AUC: 0.81, 95% CI: 0.70-0.92, p = 0.000) have diagnostic power to predict the suitability of RT plans according to QUANTEC (Quantitative Analyses of Normal Tissue Effects in the Clinic) for lung dose constraints. The cut-off points of 7 and 3500 cc were selected for lung/PTV ratio and bilateral lung volume, respectively. The effect of the cut-off points on the dose data was assessed with the Mann-WhitneyU test. The mean lung and heart doses, lung V5, V15, and V20, as well as heart V5, V20, V30, and V45 values were found to be lower in both groups separated by cut-off points (p < 0.05). The lung/PTV ratio ≥7 and bilateral lung volume ≥3500 cc cut-off points are predictive of whether TomoTherapy plans may meet QUANTEC lung dose limits in patients with supracarinal esophageal cancer. The patients with lung/PTV ratio and lung volume above these cut-off points may be candidates for treatment with TomoTherapy.

Who Benefits From a Prostate Rectal Spacer? Secondary Analysis of a Phase III Trial

PurposePreviously a phase III trial of a hydrogel rectal spacer during prostate radiation therapy found decreased toxicity and a clinically significant improvement in bowel quality of life (QOL) at 3 years by the Expanded Prostate Cancer Index. We performed a secondary analysis to identify men less likely to benefit. Methods and MaterialsClinical and dosimetric data for the 222 patients enrolled on the SpaceOAR phase III trial were analyzed. The volume of rectum treated to 70 Gy (V70) and the quantitative analysis of normal tissue effects in the clinic (QUANTEC) rectal dose goals were used as surrogates for clinical benefit and plan quality. Mean bowel QOL was assessed at 15 and 36 months posttreatment and the likelihood of 1× (5 points) or 2× (10 points) minimally important difference changes were assessed. ResultsRectal V70 was correlated with physician scored toxicity (P = .033) and was used as a surrogate for plan quality. There was no correlation between prostate volume and rectal V70 (r = 0.077). Rectal V70 pre- and post-hydrogel was 13% and 3% for the smallest prostates (<40 mL) and 12% and 2% for the largest (>80 mL). The relative reduction in rectal V70 of 78% did not vary by prespacer V70, but the absolute reduction was greater for a higher V70. All spacer plans met the 5 QUANTEC rectal dose constraints, although 92% of control plans met all constraints. At 3 years, those not meeting all QUANTEC goals had a 15.0-point (standard deviation 15.1) decline, control patients meeting QUANTEC goals had a 4.0-point (9.5) decline, and spacer had >0.5 (7.6; P < .01). Previous surgery was not correlated with QOL (P = .8). Across prognostic groups, including age, body mass index, previous surgery, target volume, or quality of radiation plans, there was no statistically significant heterogeneity in the relative benefit of spacer in decreasing the risk of 1× or 2× the minimally important difference declines. ConclusionsThere was little heterogeneity in the likelihood of spacer reducing the risk of declines in bowel QOL across clinical and dosimetric variables. Even for the >95% of plans meeting QUANTEC rectal criteria, hydrogel spacer provided potentially meaningful benefits.

RADIOTHERAPY DOSIMETRIC DATA AND ORAL COMPLICATIONS IN PATIENTS WITH HEAD AND NECK CANCER

Objective To study the relation between the dosimetric parameters of the radiotherapy design protocols for head and neck cancers and the acute oral complications resulting from this treatment. Study Design This was a cross-sectional, quantitative approach. Radiotherapy was planned according to established design protocols. The constraints used were those described in QUANTEC (Quantitative Analyses of Normal Tissue Effects in the Clinic) and the complications were classified based on the CTCAE (National Cancer Institute's Common Criteria Chart of Toxicity). Results Eleven patients participated, most of them male (89%), with a mean age of 60.2 years. The most frequent tumor site was oropharynx (55%) and the degree of staging IV (64%). Among the participants, 73% were smokers and 82% had a habit of drinking alcohol. The most frequent oral complications were dysphagia (91%), xerostomia (82%), mucositis (54%), and oral pain (54%). For the complications dysphagia, xerostomia, and mucositis, relations were found between the dosimetric data and the development of these; for oral pain, the difference between the groups was not significant. Conclusions Dosimetric data are directly related to the development of certain oral complications resulting from radiotherapy treatment for malignant head and neck neoplasms.

Evaluating the predictive value of quantec rectum tolerance dose suggestions on acute rectal toxicity in prostate carcinoma patients treated with IMRT.

To investigate the predictive value of convenience of rectum dosimetry with Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) dose limits, maximum rectum dose (Dmax), total rectal volume (TVrectum), rectal volume included in PTV (VrectumPTV) on Grade 2-3 acute rectal toxicity for utilization in clinical practice. Numerous previous data have reported frequent acute proctitis after external-beam RT of prostate cancer. Predicting toxicity limited with dose information is inadequate in clinical practice due to comorbidities and medications used. Sixty-four non-metastatic prostate cancer patients treated with IMRT were enrolled. Patients were treated to a total dose of 70-76Gy. Rectal dose volume histograms (DVH) of all patients were evaluated retrospectively, and a QUANTEC Score between 0 and 5 was calculated for each patient. The correlation between the rectal DVH data, QUANTEC score, TVrectum, VrectumPTV, rectum Dmax and Grade 2-3 rectal toxicity was investigated. In the whole group grade 1, 2 and 3 acute rectal toxicities were 25%, 18.8% and 3.1%, respectively. In the DVH data, rectum doses of all patients were under RTOG dose limits. Statistically significant correlation was found between grade 2-3 rectal toxicity and TVrectum (p=0,043); however. It was not correlated with QUANTEC score, VrectumPTV and Dmax. Our results were not able to show any significant correlation between increasing convenience with QUANTEC limits and lower rectal toxicity. Conclusively, new dosimetric definitions are warranted to predict acute rectal toxicity more accurately in prostate cancer patients during IMRT treatment.

Radiotherapy for metastatic spinal cord compression with increased radiation doses (RAMSES-01): a prospective multicenter study

BackgroundPatients with metastatic spinal cord compression (MSCC) and favorable survival prognoses can benefit from radiation doses greater than 30Gy in 10 fractions in terms of improved local progression-free survival (LPFS) and overall survival (OS).Methods/designThis prospective study mainly investigates LPFS after precision radiotherapy (volumetric modulated arc therapy or stereotactic body radiotherapy) with 18 × 2.33Gy in 3.5 weeks. LPFS is defined as freedom from progression of motor deficits during radiotherapy and an in-field recurrence of MSCC following radiotherapy. The maximum relative dose allowed to the spinal cord is 101.5% of the prescribed dose, resulting in an equivalent dose in 2Gy-fractions (EQD2) for radiation myelopathy is 45.5Gy, which is below the tolerance dose of 50Gy according to the Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC). The EQD2 of this regimen for tumor cell kill is 43.1Gy, which is 33% higher than for 30Gy in 10 fractions (EQD2 = 32.5Gy). Primary endpoint is LPFS at 12 months after radiotherapy. Secondary endpoints include the effect of 18 × 2.33Gy on motor function, ambulatory status, sensory function, sphincter dysfunction, LPFS at other follow-up times, overall survival, pain relief, relief of distress and toxicity. Follow-up visits for all endpoints will be performed directly and at 1, 3, 6, 9 and 12 months after radiotherapy. A total of 65 patients are required for the prospective part of the study. These patients will be compared to a historical control group of at least 235 patients receiving conventional radiotherapy with 10x3Gy in 2 weeks.DiscussionIf precision radiotherapy with 18 × 2.33Gy results in significantly better LPFS than 10x3Gy of conventional radiotherapy, this regimen should be strongly considered for patients with MSCC and favorable survival prognoses.Trial registrationClinicaltrials.gov NCT04043156. Registered 30-07-2019.

Cardiac death after breast radiotherapy and the QUANTEC cardiac guidelines

BackgroundBreast/chest wall irradiation (RT) increases risk of cardiovascular death. International Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) guidelines state for partial heart irradiation a “V25Gy <10% will be associated with a <1% probability of cardiac mortality” in long-term follow-up after RT. We assessed whether women treated with breast/chest wall RT 10-years ago who died of cardiovascular disease (CVD) violated QUANTEC guidelines. Materials/methodsA population-based database identified all cardiovascular deaths in women with early-stage breast cancer <80 years, treated with adjuvant breast/chest wall RT from 2002 to 2006. Ten-year rate of cardiovascular death was calculated using a Kaplan-Meier method. Patients were matched on a 2:1 basis with controls that did not die of CVD. For left-sided cases, the heart and left anterior descending (LAD) artery were retrospectively delineated. Dose-volume histograms were calculated, and heart V25Gy compared to QUANTEC guidelines. Results5249 eligible patients received breast/chest wall RT from 2002 to 2006: 76 (1.4% at 10-years) died of CVD by June 2015. Forty-two patients received left-sided RT (1.7% CVD death at 10-years), 34 right-sided RT (1.3% at 10-years). Heart V25Gy did not exceed 10% in any left-sided cases. No cardiac dosimetry parameter distinguished left-sided cases from controls. ConclusionsQUANTEC guidelines were not violated in any patient that died of CVD after left-sided RT. The risk of radiation induced cardiac death at 10-years appears to be very low if MHD is <3.3 Gy and maximum LAD dose (EQD23 Gy) is <45.4 Gy. Further studies are needed to evaluate heart and LAD constraints in the CT-planning era.

The sensitivity of patient-specific IMRT QA methods in detecting systematic errors: field-by-field versus single-gantry-angle composite

This study evaluated the effect of small systematic errors, such as those from a multileaf collimator (MLC), on the quality of intensity modulated radiotherapy (IMRT) treatment plan delivery. Two IMRT quality assurance (QA) verification techniques, field-by-field (FBF) and singe-gantry-angle composite (SGAC), were performed to evaluate both original and modified plans using a 2D ion chamber array detector. The dose distributions measured by the array detector for both FBF and SGAC were compared with the dose distribution calculated by the treatment planning system (TPS). FBF was found to be more sensitive than SGAC at detecting small systematic errors such as the opening and closing of the MLC’s segments, which were evaluated with respect to a gamma-index of 3%/3 mm and 2%/2 mm. The systematic errors involved in closing the segments of the anterior field by 2 mm and 3 mm showed a significant difference compared with the original field (unmodified): 83.1 ± 1.7% and 42.9 ± 1.9% gamma-index passing rates, respectively, for FBF. For SGAC, the magnitude of closing the MLC by 2 mm remained unnoticed and resulted in a 95.1 ± 2.61% gamma-index passing rate. Opening the MLC by 2 mm gave a false negative, but more than 5% of the rectum received 75 Gy, which exceeded the tolerance radiation dose recommended by the Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC).

Pediatric Normal Tissue Effects in the Clinic (PENTEC): An International Collaboration to Analyse Normal Tissue Radiation Dose–Volume Response Relationships for Paediatric Cancer Patients

With advances in multimodality therapy, childhood cancer cure rates approach 80%. However, both radiotherapy and chemotherapy can cause debilitating or even fatal late adverse events that are critical to understand, mitigate or prevent. QUANTEC (Quantitative Analysis of Normal Tissue Effects in the Clinic) identified radiation dose constraints for normal tissues in adults and pointed out the uncertainties in those constraints. The range of adverse events seen in children is different from that in adults, in part due to the vulnerability/characteristics of radiation damage to developing tissues, and in part due to the typical body sites affected by childhood cancer that lead to collateral irradiation of somewhat different normal tissues and organs compared with adults. Many childhood cancer survivors have a long life expectancy and may develop treatment-induced secondary cancers and severe organ/tissue injury 10, 20 or more years after treatment. Collaborative long-term observational studies and clinical research programmes for survivors of paediatric and adolescent cancer provide adverse event data for follow-up periods exceeding 40 years. Data analysis is challenging due to the interaction between therapeutic and developmental variables, the lack of radiation dose–volume data and the fact that most childhood malignancies are managed with combined modality therapy. PENTEC (Pediatric Normal Tissue Effects in the Clinic) is a volunteer research collaboration of more than 150 physicians, medical physicists, mathematical modellers and epidemiologists organised into 18 organ-specific working groups conducting a critical review and synthesis of quantitative data from existing studies aiming to: (1) establish quantitative, evidence-based dose/volume/risk guidelines to inform radiation treatment planning and, in turn, improve outcomes after radiation therapy for childhood cancers; (2) explore the most relevant risk factors for toxicity, including developmental status; (3) describe specific physics and dosimetric issues relevant to paediatric radiotherapy; and (4) propose dose–volume outcome reporting standards for publications on childhood cancer therapy outcomes. The impact of other critical modifiers of normal tissue radiation damage, including chemotherapy, surgery, stem cell transplantation and underlying genetic predispositions are also considered. The aims of the PENTEC reports are to provide clinicians with an analysis of the best available data to make informed decisions regarding radiation therapy normal organ dose constraints for planning childhood cancer treatment, and to define future research priorities.

Normal Tissue Complication Probability (NTCP) modeling and validation of quantitative analysis of normal tissue effects in the clinic (QUANTEC) guideline using quality of life questionnaire for parotid gland during head and neck radiotherapy

Introduction: Radiation therapy is the main treatment method for head and neck cancers, which comprise 3–5% of all cancers. A major side effect of this treatment is complication of the parotid glands, i.e. xerostomia, which occurs at relatively low doses. This complication leads to mouth dryness which is the most common problem for head and neck cancer survivors. There are different grades of xerostomia and severe xerostomia is defined as a long-term reduction in the function of salivary gland to less than 25% relative to the pre-radiotherapy baseline value. The grading of xerostomia is usually assessed by patient self-reports carried out by the quality of life questionnaire (QoL), designed based on indigenous criteria and internationally recognized protocols. In recent years several studies have focused on normal tissue complication probability (NTCP) modeling of xerostomia using quality of life questionnaires with or without functional analysis based on various standard model parameters. Lyman (LKB) model is commonly used to predict the normal tissue complication probability (NTCP). This model uses the patient’s calculated dose volume histogram of (DVH) of an organ at risk (OAR) and the dose response curve parameters. The quantitative analysis of normal tissue effects in the clinic (QUANTEC) effort is to refine the guidelines based on 3D dose/volume and outcome data. According to QUANTEC guideline to limit the severity of xerostomia, maximum dose received by one or both of parotid glands should be 20 Gy and 25 Gy (20/25 Gy), respectively. The aim of this study was to evaluate the NTCP model parameters for all grades of acute parotid complications using the LKB model during head and neck conformal radiotherapy treatment and using a QoL questionnaire. Materials and Methods: 50 patients with head and neck cancer who have been referred for radiotherapy to Milad Hospital in Isfahan, Iran, were selected. QoL questionnaire datasets of patients with squamous cell carcinoma and lymph node cancers beside the parotids were within the radiation field were analyzed. The European organization for research and treatment of cancer (EORTC) QLQ HN35 was used in three stages (before, during and at the end of treatment). Prescribed dose per fraction was modified to 2 Gy/fraction equivalent dose for each patients. The LKB model with DVH reduction to form the equivalent uniform dose (EUD), known as LEUD was used. The model parameters of TD50 (Tolerance Dose 50%) and m was assessed by fitting the patient reported complication data to the normal tissue complication probability (NTCP) curve. Results: One patient (2%) at stage 2 and 5 patients (10%) at stage 3 experienced grade 3 xerostomia. The dose-response curves (LKB model) for occurrence of xerostomia was fitted to the QoL data which were collected at stages 2 and 3. These parameters were TD50 =23.3Gy, m =1 and TD50 =21.6 Gy, m =1 at stage 2 and stage 3, respectively. Conclusion: The agreement between the NTCP modeling based on QoL questionnaire data and the QUANTEC guidelines, confirms the cutoff values of 20/25 Gy to spare the parotid gland.

Is SBRT Boost Feasible for PET Positive Lymph Nodes for Cervical Cancer? Evaluation using Tumor Control Probability and QUANTEC Criteria

PurposeThis study aimed to examine the feasibility of stereotactic body radiation therapy (SBRT) as an external beam radiation therapy boost to positron emission tomography (PET) positive lymph nodes (LN) in patients with cervical cancer and to evaluate overall tumor control probability (TCP) increase. Methods and MaterialsTen patients with cervical cancer and PET positive LN metastasis who received external beam radiation therapy (45 Gy), followed by a 3-dimensional conformal radiation therapy boost (5.4-9 Gy) and tandem-and-ovoid high-dose-rate brachytherapy (16-30 Gy) were retrospectively enrolled in this study. SBRT plans were generated using 21 Gy, 24 Gy, or 30 Gy as a replacement for 3-dimensional conformal radiation therapy boost. The 2 Gy-per-fraction equivalent dose maps were made using an α/β value of 10 for PET positive LNs and 3 for organs at risk (OARs). TCP values were calculated using a logistic TCP model, where 2 input parameters (D50 and Gamma50 = 2) were modeled by 2 clinical outcomes: our institution and the literature. OAR sparing was evaluated using Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC) dose limits. ResultsThirty percent of 10 patients receiving conventional boost experienced recurrence. The TCP of the SBRT schemes was 88% ± 7% (97% ± 2%; 21 Gy), 96% ± 1% (99% ± 0%; 24 Gy), and 99% ± 1% (100% ± 0%; 30 Gy), and the conventional LN-boost TCP value was 25% ± 11% (58% ± 15%) when TCP input parameters were based on published clinical outcome data for LN SBRT treatments (institutional outcome data). The tumor coverage doses (D90) of the SBRT boost plans were on average 32.34 Gyαβ=10 (21 Gy), 37.78 Gyαβ=10 (24 Gy), and 55.54Gyαβ=10 (30 Gy) higher than the conventional LN boost plan. The QUANTEC OAR dose constraints were met for the bladder, rectum, and bowel in all cases for the SBRT LN 21 Gy group, and in 90% and 70% of cases in the SBRT LN 24 Gy and SBRT LN 30 Gy groups, respectively. ConclusionsAn SBRT boost dose of 30 Gy can be delivered without compromising QUANTEC OAR limits. The use of SBRT increases TCP values, regardless of the input parameters.