Ivan R. Vogelius

Radiation Dose-Response Model for Locally Advanced Rectal Cancer After Preoperative Chemoradiation Therapy

PURPOSE Preoperative chemoradiation therapy (CRT) is part of the standard treatment of locally advanced rectal cancers. Tumor regression at the time of operation is desirable, but not much is known about the relationship between radiation dose and tumor regression. In the present study we estimated radiation dose-response curves for various grades of tumor regression after preoperative CRT. METHODS AND MATERIALS A total of 222 patients, treated with consistent chemotherapy and radiation therapy techniques, were considered for the analysis. Radiation therapy consisted of a combination of external-beam radiation therapy and brachytherapy. Response at the time of operation was evaluated from the histopathologic specimen and graded on a 5-point scale (TRG1-5). The probability of achieving complete, major, and partial response was analyzed by ordinal logistic regression, and the effect of including clinical parameters in the model was examined. The radiation dose-response relationship for a specific grade of histopathologic tumor regression was parameterized in terms of the dose required for 50% response, D50,i, and the normalized dose-response gradient, γ50,i. RESULTS A highly significant dose-response relationship was found (P=.002). For complete response (TRG1), the dose-response parameters were D50,TRG1=92.0 Gy (95% confidence interval [CI] 79.3-144.9 Gy), γ50,TRG1=0.982 (CI 0.533-1.429), and for major response (TRG1-2) D50,TRG1&2=72.1 Gy (CI 65.3-94.0 Gy), γ50,TRG1&2=0.770 (CI 0.338-1.201). Tumor size and N category both had a significant effect on the dose-response relationships. CONCLUSIONS This study demonstrated a significant dose-response relationship for tumor regression after preoperative CRT for locally advanced rectal cancer for tumor dose levels in the range of 50.4-70 Gy, which is higher than the dose range usually considered.

Radiobiological risk estimates of adverse events and secondary cancer for proton and photon radiation therapy of pediatric medulloblastoma.

Abstract Introduction. The aim of this model study was to estimate and compare the risk of radiation-induced adverse late effects in pediatric patients with medulloblastoma (MB) treated with either three-dimensional conformal radiotherapy (3D CRT), inversely-optimized arc therapy (RapidArc® (RA)) or spot-scanned intensity-modulated proton therapy (IMPT). The aim was also to find dose-volume toxicity parameters relevant to children undergoing RT to be used in the inverse planning of RA and IMPT, and to use in the risk estimations. Material and methods. Treatment plans were created for all three techniques on 10 pediatric patients that have been treated with craniospinal irradiation (CSI) at our institution in 2007–2009. Plans were generated for two prescription CSI doses, 23.4 Gy and 36 Gy. Risk estimates were based on childhood cancer survivor data when available and secondary cancer (SC) risks were estimated as a function of age at exposure and attained age according to the organ-equivalent dose (OED) concept. Results. Estimates of SC risk was higher for the RA plans and differentiable from the estimates for 3D CRT at attained ages above 40 years. The risk of developing heart failure, hearing loss, hypothyroidism and xerostomia was highest for the 3D CRT plans. The risks of all adverse effects were estimated as lowest for the IMPT plans, even when including secondary neutron (SN) irradiation with high values of the neutron radiation weighting factors (WRneutron). Conclusions. When comparing RA and 3D CRT treatment for pediatric MB it is a matter of comparing higher SC risk against higher risks of non-cancer adverse events. Considering time until onset of the different complications is necessary to fully assess patient benefit in such a comparison. The IMPT plans, including SN dose contribution, compared favorably to the photon techniques in terms of all radiobiological risk estimates.

A literature-based meta-analysis of clinical risk factors for development of radiation induced pneumonitis

Abstract Introduction. The risk of developing side effects after radiotherapy is not only dependent on radiation dose, but may also be affected by patient-related risk factors. Here we perform a literature-based meta-analysis to estimate the effect of various clinical risk factors on the incidence of symptomatic radiation pneumonitis (RP). Material and methods. A systematic review of English language articles in the Pubmed, Embase and Cochrane controlled trials registers. Studies with the mesh term “radiation pneumonitis” or the search term “radiation pneumonitis” were included. Additional studies were identified by manual searching of the references. Studies reporting crude incidence or odds ratios (OR) for radiation pneumonitis vs. age, disease location, smoking status, chemotherapy schedule or comorbidity were included. A systematic overview (meta-analysis) was conducted to synthesize data across multiple studies. Results. Significant risk factors for RP were: older age (OR = 1.7, p < 0.0001); disease located in mid-lower lung (OR = 1.9, p = 0.002); presence of comorbidity (OR = 2.3, p = 0.007). Ongoing smoking was found to protect against RP (OR = 0.6, p = 0.008). History of smoking tended to protect against RP (OR = 0.7, p = 0.06). Sequential (rather than concomitant) chemotherapy scheduling (OR = 1.6, p = 0.01) increased RP risk, but treatment intensity and patients selection are likely confounders. Conclusion. This systematic overview revealed several clinical risk factors for RP that have not been unambiguously identified in the literature. These risk factors should be considered when defining dose-volume constraints for radiation treatment plan optimization.

Estimated risk of cardiovascular disease and secondary cancers with modern highly conformal radiotherapy for early-stage mediastinal Hodgkin lymphoma

BACKGROUND Hodgkin lymphoma (HL) survivors have an increased morbidity and mortality from secondary cancers and cardiovascular disease (CD). We evaluate doses with involved node radiotherapy (INRT) delivered as 3D conformal radiotherapy (3D CRT), volumetric modulated arc therapy (VMAT), or proton therapy (PT), compared with the extensive Mantle Field (MF). PATIENTS AND METHODS For 27 patients with early-stage, mediastinal HL, treated with chemotherapy and INRT delivered as 3D CRT (30 Gy), we simulated an MF (36 Gy), INRT-VMAT and INRT-PT (30 Gy). Dose to the heart, lungs, and breasts, estimated risks of CD, lung (LC) and breast cancer (BC), and corresponding life years lost (LYL) were compared. RESULTS 3D CRT, VMAT or PT significantly lower the dose to the heart, lungs and breasts and provide lower risk estimates compared with MF, but with substantial patient variability. The risk of CD is not significantly different for 3D CRT versus VMAT. The risk of LC and BC is highest with VMAT. For LYL, PT is the superior modern technique. CONCLUSIONS In early-stage, mediastinal HL modern radiotherapy provides superior results compared with MF. However, there is no single best radiotherapy technique for HL-the decision should be made at the individual patient level.

Risk of Developing Cardiovascular Disease After Involved Node Radiotherapy Versus Mantle Field for Hodgkin Lymphoma

PURPOSE Hodgkin lymphoma (HL) survivors are known to have increased cardiac mortality and morbidity. The risk of developing cardiovascular disease after involved node radiotherapy (INRT) is currently unresolved, inasmuch as present clinical data are derived from patients treated with the outdated mantle field (MF) technique. METHODS AND MATERIALS We included all adolescents and young adults with supradiaphragmatic, clinical Stage I-II HL treated at our institution from 2006 to 2010 (29 patients). All patients were treated with chemotherapy and INRT to 30 to 36 Gy. We then simulated a MF plan for each patient with a prescribed dose of 36 Gy. A logistic dose-response curve for the 25-year absolute excess risk of cardiovascular disease was derived and applied to each patient using the individual dose-volume histograms. RESULTS The mean doses to the heart, four heart valves, and coronary arteries were significantly lower for INRT than for MF treatment. However, the range in doses with INRT treatment was substantial, and for a subgroup of patients, with lymphoma below the fourth thoracic vertebrae, we estimated a 25-year absolute excess risk of any cardiac event of as much as 5.1%. CONCLUSIONS Our study demonstrates a potential for individualizing treatment by selecting the patients for whom INRT provides sufficient cardiac protection for current technology; and a subgroup of patients, who still receive high cardiac doses, who would benefit from more advanced radiation technique.

Recurrences after intensity modulated radiotherapy for head and neck squamous cell carcinoma more likely to originate from regions with high baseline [18F]-FDG uptake.

BACKGROUND AND PURPOSE To analyze the recurrence pattern in relation to target volumes and (18)F-fluorodeoxyglucose (FDG) uptake on positron emission tomography in head and neck squamous cell carcinoma (HNSCC) patients treated with definitive chemoradiation. MATERIAL AND METHODS 520 patients received radiotherapy for HNSCC from 2005 to 2009. Among 100 patients achieving complete clinical response and a later recurrence, 39 patients with 48 loco-regional failures had a recurrence CT scan before any salvage therapy. The estimated point of origin of each recurrence was transferred to the planning CT by deformable image co-registration. The recurrence position was then related to the delineated target volumes and iso-SUV-contours relative to the maximum standard uptake value (SUV). We defined the recurrence density as the total number of recurrences in a sub-volume divided by the sum of that volume for all patients. RESULTS 54% (95% CI 37-69%) of recurrences originated inside the FDG-positive volume and 96% (95% CI 86-99%) in the high dose region. Recurrence density was significantly higher in the central target volumes (P<0.0001) and increased with increasing FDG avidity (P=0.036). CONCLUSIONS The detailed pattern-of-failure data analysis suggests that most recurrences occur in the FDG PET positive areas or the solid tumor.

Estimated clinical benefit of protecting neurogenesis in the developing brain during radiation therapy for pediatric medulloblastoma.

We sought to assess the feasibility and estimate the benefit of sparing the neurogenic niches when irradiating the brain of pediatric patients with medulloblastoma (MB) based on clinical outcome data. Pediatric MB survivors experience a high risk of neurocognitive adverse effects, often attributed to the whole-brain irradiation that is part of standard management. Neurogenesis is very sensitive to radiation, and limiting the radiation dose to the hippocampus and the subventricular zone (SVZ) may preserve neurocognitive function. Radiotherapy plans were created using 4 techniques: standard opposing fields, intensity-modulated radiotherapy (IMRT), intensity-modulated arc therapy (IMAT), and intensity-modulated proton therapy (IMPT). Mean dose to the hippocampus and SVZ (mean for both sites) could be limited to 88.3% (range, 83.6%-91.0%), 77.1% (range, 71.5%-81.3%), and 42.3% (range, 26.6%-51.2%) with IMAT, IMRT, and IMPT, respectively, while maintaining at least 95% of the prescribed dose in 95% of the whole-brain target volume. Estimated risks for developing memory impairment after a prescribed dose of 23.4 Gy were 47% (95% confidence interval [CI], 21%-69%), 44% (95% CI, 21%-65%), 41% (95% CI, 22%-60%), and 33% (95% CI, 23%-44%) with opposing fields, IMAT, IMRT, and IMPT, respectively. Neurogenic niche sparing during cranial irradiation of pediatric patients with MB is feasible and is estimated to lower the risks of long-term neurocognitive sequelae. Greatest sparing is achieved with intensity-modulated proton therapy, thus making this an attractive option to be tested in a prospective clinical trial.

Life years lost—comparing potentially fatal late complications after radiotherapy for pediatric medulloblastoma on a common scale

The authors developed a framework for estimating and comparing the risks of various long‐term complications on a common scale and applied it to 3 different techniques for craniospinal irradiation in patients with pediatric medulloblastoma.

Risk factors for radiation-induced hypothyroidism: a literature-based meta-analysis.

A systematic overview and meta‐analysis of studies reporting data on hypothyroidism (HT) after radiation therapy was conducted to identify risk factors for development of HT.

ARTIFACTS IN CONVENTIONAL COMPUTED TOMOGRAPHY (CT) AND FREE BREATHING FOUR-DIMENSIONAL CT INDUCE UNCERTAINTY IN GROSS TUMOR VOLUME DETERMINATION

PURPOSE Artifacts impacting the imaged tumor volume can be seen in conventional three-dimensional CT (3DCT) scans for planning of lung cancer radiotherapy but can be reduced with the use of respiration-correlated imaging, i.e., 4DCT or breathhold CT (BHCT) scans. The aim of this study was to compare delineated gross tumor volume (GTV) sizes in 3DCT, 4DCT, and BHCT scans of patients with lung tumors. METHODS AND MATERIALS A total of 36 patients with 46 tumors referred for stereotactic radiotherapy of lung tumors were included. All patients underwent positron emission tomography (PET)/CT, 4DCT, and BHCT scans. GTVs in all CT scans of individual patients were delineated during one session by a single physician to minimize systematic delineation uncertainty. The GTV size from the BHCT was considered the closest to true tumor volume and was chosen as the reference. The reference GTV size was compared to GTV sizes in 3DCT, at midventilation (MidV), at end-inspiration (Insp), and at end-expiration (Exp) bins from the 4DCT scan. RESULTS The median BHCT GTV size was 4.9 cm(3) (0.1-53.3 cm(3)). Median deviation between 3DCT and BHCT GTV size was 0.3 cm(3) (-3.3 to 30.0 cm(3)), between MidV and BHCT size was 0.2 cm(3) (-5.7 to 19.7 cm(3)), between Insp and BHCT size was 0.3 cm(3) (-4.7 to 24.8 cm(3)), and between Exp and BHCT size was 0.3 cm(3) (-4.8 to 25.5 cm(3)). The 3DCT, MidV, Insp, and Exp median GTV sizes were all significantly larger than the BHCT median GTV size. CONCLUSIONS In the present study, the choice of CT method significantly influenced the delineated GTV size, on average, leading to an increase in GTV size compared to the reference BHCT. The uncertainty caused by artifacts is estimated to be in the same magnitude as delineation uncertainty and should be considered in the design of margins for radiotherapy.