Extending hypofractionated stereotactic body radiotherapy to tumours larger than 70cc - effects and side effects.

BACKGROUND AND PURPOSE: Stereotactic body radiotherapy (SBRT) for tumours ≥5 cm is poorly studied and its utility and feasibility is uncertain. We here report the Karolinska experience of SBRT in this setting. MATERIAL AND METHODS: All patients had a gross tumour volume (GTV) ≥70 cc, a prescribed physical dose of at least 40 Gy and received treatment between 1995-2012. RESULTS: We included 164 patients with 175 tumours located in the thorax (n = 86), the liver (n = 27) and the abdomen (n = 62) and treated with a median prescribed dose (BEDα/ß 10Gy) of 80 Gy (71.4-113). One- and 2- year local control rates were 82% and 61%. In multivariate analyses, minimum dose to the GTV and histological subtype were associated with local control. Renal cell carcinoma (RCC) histology showed the most favourable local control - 94% at 2 years for all histologies. Thirty-seven patients experienced grade 3-5 toxicity most likely related to SBRT. Seven of the ten patients with grade 5 toxicity, had a centrally located tumour in the thorax. CONCLUSION: SBRT of tumours >5 cm in diameter may be an option for peripherally located lung and abdominal tumours. Histological origin and tumour location should be considered before treatment.

Radiation-induced brachial plexus toxicity after SBRT of apically located lung lesions.

Purpose: To evaluate the rate and dose response of brachial plexus toxicity post stereotactic body radiation therapy (SBRT) of apically situated lung lesions. Material/methods: We retrospectively identified all patients with apically located tumors, defined by the epicenter of the tumor being located superiorly to the aortic arch, and treated with SBRT between 2008 and 2013. Patients with a shorter follow-up than 6 months were excluded. Primary aim was to evaluate radiation-induced brachial plexopathy (RIBP). Dose to the plexus was assessed by a retrospective delineation of the brachial plexus on the CT used for treatment planning. Then, Dmax, D0.1cc, D1cc and D3.0cc of the brachial plexus were collected from the dose-volume histograms (DVH) and recalculated to the biologically effective dose (BED) using α/ß = 3 Gy. A normal tissue complication probability (NTCP) model, based on four different dose-volume parameters (BED3,max, BED3,0.1cc, BED3,1.0cc, BED3,3.0cc) was fitted to the data. Results: Fifty-two patients with 56 apically located tumors were identified. Median prescription dose per fraction was 15 Gy (range 6-17) and median number of fractions was 3 (3-10). With a median follow-up of 30 months (6.1-72) seven patients experienced maximum grade 2 (scored 3 times) or 3 (scored 4 times) RIBP after a median of 8.7 months (range 4.0-31). Three patients had combined symptoms with pain, sensory and motor affection and four patients had isolated pain. Median BED3,max for the patients experiencing RIBP was 381 Gy (range 30-524) versus BED3,max of 34 Gy (range 0.10-483) for the patients without RIBP. The NTCP models showed a very high predictive ability (area under the receiver operating characteristic curve (AUC) 0.80-0.88). Conclusion: SBRT of apically located lung lesions may cause severe neurological symptoms; for a three-fraction treatment, we suggest that the maximum dose to the plexus should be kept ≤30 Gy (130 Gy BED3).

Risk of Acute Testicular Failure After Preoperative Radiotherapy for Rectal Cancer: A Prospective Cohort Study.

OBJECTIVE: The aim of this study was to assess the acute effect of preoperative RT for rectal cancer on endocrine testicular function. BACKGROUND: Preoperative radiotherapy (RT) enhances local control and cancer-specific survival in patients treated for rectal cancer. In case series, a negative acute effect on Leydig cell function has been reported. METHODS: This prospective cohort study included 168 males with rectal or prostate cancer stage I-III. Males treated with preoperative RT and surgery for rectal cancer formed the exposed group (n = 93). Males treated with surgery alone were assigned to the unexposed group (n = 75). The androgen levels were assessed at baseline and after preoperative RT. The exposure was quantified with the treatment planning system to estimate the cumulative testicular dose (TD). The risk of low T (serum T < below 8 nmol/L) was the primary endpoint. Secondary endpoints were serum testosterone (T), bioavailable T, luteinizing hormone (LH), and the LH-T ratio. RESULTS: The baseline levels of androgens were not related to exposure status or type of cancer. The proportion of low T increased from 14.6% at baseline to 35.4% after RT, relative risk 2.41 (95% CI 1.57 to 3.71, P < 0.001). Preoperative RT resulted in a significant decrease of serum and bioavailable T and a significant increase of LH and LH-T ratio. The decline in serum and bioavailable T was related to the TD. CONCLUSIONS: Preoperative RT for rectal cancer results in dose-dependent primary testicular failure increasing the risk of hypogonadism at the time of surgery by 2.4 times (number needed to harm = 5).

Accuracy of the dose-shift approximation in estimating the delivered dose in SBRT of lung tumors considering setup errors and breathing motions.

INTRODUCTION: Geometrical uncertainties can result in a delivered dose to the tumor different from that estimated in the static treatment plan. The purpose of this project was to investigate the accuracy of the dose calculated to the clinical target volume (CTV) with the dose-shift approximation, in stereotactic body radiation therapy (SBRT) of lung tumors considering setup errors and breathing motion. The dose-shift method was compared with a beam-shift method with dose recalculation. MATERIAL AND METHODS: Included were 10 patients (10 tumors) selected to represent a variety of SBRT-treated lung tumors in terms of tumor location, CTV volume, and tumor density. An in-house developed toolkit within a treatment planning system allowed the shift of either the dose matrix or a shift of the beam isocenter with dose recalculation, to simulate setup errors and breathing motion. Setup shifts of different magnitudes (up to 10 mm) and directions as well as breathing with different peak-to-peak amplitudes (up to 10:5:5 mm) were modeled. The resulting dose-volume histograms (DVHs) were recorded and dose statistics were extracted. RESULTS: Generally, both the dose-shift and beam-shift methods resulted in calculated doses lower than the static planned dose, although the minimum (D98%) dose exceeded the prescribed dose in all cases, for setup shifts up to 5 mm. The dose-shift method also generally underestimated the dose compared with the beam-shift method. For clinically realistic systematic displacements of less than 5 mm, the results demonstrated that in the minimum dose region within the CTV, the dose-shift method was accurate to 2% (root-mean-square error). Breathing motion only marginally degraded the dose distributions. CONCLUSIONS: Averaged over the patients and shift directions, the dose-shift approximation was determined to be accurate to approximately 2% (RMS) within the CTV, for clinically relevant geometrical uncertainties for SBRT of lung tumors.

Assessment of testicular dose during preoperative radiotherapy for rectal cancer.

BACKGROUND: Radiotherapy (RT) for rectal cancer can have adverse effects on testicular function resulting in azoospermia and low testosterone levels. Variability of testicular dose (TD) due to differences in position of testes has been assessed with scrotal dosimeters and resulted in substantial variability of delivered TD. The aim of this study was to estimate planned and delivered TD using a treatment planning system (TPS). METHODS: In 101 men treated with RT for rectal cancer the cumulative mean TD (mTD) was calculated by TPS based on plan-computed tomography (CT) to evaluate the effect of different predictors on planned TD. The delivered TD was estimated by TPS based on repeated cone-beam CTs in 32 of 101 men to assess within-person variability of planned and delivered TD in a longitudinal analysis. RESULTS: The median planned mTD for short course RT was 0.57 Gy (range 0.06-14.37 Gy) and 0.81 Gy (range 0.36-10.80 Gy) for long course RT. The median planned mTD was similar to the median delivered mTD in the 32 men analysed over the entire course of RT (p=0.84). The mTD did not change significantly over time of planning and delivering RT. The variation in proximity between testes and planning target volume (PTV) was related to within-person variability of mTD in men on the 50th and 75th percentile of mTD and as expected the absolute difference between planned and delivered mTD increased with higher mTD. CONCLUSION: Testicular doses calculated based on plan-CT are an accurate estimation of delivered TD based on repeated cone beam (CB)CT. The within-person variability of TD is related to variation in proximity between testes and PTV in men with moderate to high TD.

Long-term results of a prospective phase II trial of medically inoperable stage I NSCLC treated with SBRT - the Nordic experience.

BACKGROUND: Presentation of long term results of a phase II multicenter Nordic trial of medically inoperable stage I non-small cell lung cancer (NSCLC) treated with stereotactic body radiotherapy (SBRT). MATERIAL AND METHODS: We report the extended outcome, focusing on long-term effects, of a prospective cohort of 57 evaluable patients with peripherally located T1N0M0 (72%) and T2N0M0 (28%) NSCLC, treated with SBRT 15 Gy × 3, prescribed to the 67% isodose line encompassing the PTV. The patients were inoperable due to chronic obstructive pulmonary disease (65%), cardiovascular disease (25%) or other illnesses (3%) or refused surgery (7%). Median Karnofsky score pre-treatment was 80% (70-100%). Late effects were defined as occurring > 36 months. RESULTS: Thirty-eight patients (67%) were relapse free during their entire follow-up. Local control rate at four and five years were 79% (CI 95% 64-95%) and local relapses occurred at 10-76 months post-treatment. Seven local failures were noted, four occurring ≤ 36 months (all T2a-tumors; two isolated and two in combination with out-of-field relapses) and three occurring > 36 months (T1b-tumors n = 3). Thirteen patients had out-of-field failure only as first presentation of recurrence. Overall survival rate and lung cancer-specific survival rate at five years were 30% and 74%, respectively. Toxicity throughout the entire observation period was acceptable without any grade 5 toxicities. Seventeen grade 3-4 toxicities were noted, three presenting > 36 months (rib fracture, dyspnea and ventricle tachycardia). Median follow-up was 41.5 months (3.4-113.0) for the entire cohort and 59.3 months (36.4-113.0) for the 34 patients (60%) with a follow-up of > 36 months. CONCLUSION: Throughout the observation period local control was excellent and toxicity limited with no increase in late presenting local relapses or late treatment-related morbidity. This further supports SBRT as an efficient local treatment modality even in a medically impaired patient cohort.

Survival and tumour control probability in tumours with heterogeneous oxygenation: a comparison between the linear-quadratic and the universal survival curve models for high doses.

BACKGROUND: The validity of the linear-quadratic (LQ) model at high doses has been questioned due to a decreasing agreement between predicted survival and experimental cell survival data. A frequently proposed alternative is the universal survival curve (USC) model, thought to provide a better fit in the high-dose region. The comparison between the predictions of the models has mostly been performed for uniform populations of cells with respect to sensitivity to radiation. This study aimed to compare the two models in terms of cell survival and tumour control probability (TCP) for cell populations with mixed sensitivities related to their oxygenation. METHODS: The study was performed in two parts. For the first part, cell survival curves were calculated with both models assuming various homogeneous populations of cells irradiated with uniform doses. For the second part, a realistic three-dimensional (3D) model of complex tumour oxygenation was used to study the impact of the differences in cell survival on the modelled TCP. Cellular response was assessed with the LQ and USC models at voxel level and a Poisson TCP model at tumour level. RESULTS: For hypoxic tumours, the disputed continuous bend of the LQ survival curve was counteracted by the increased radioresistance of the hypoxic cells and the survival curves started to diverge only at much higher doses than for oxic tumours. This was also reflected by the TCP curves for hypoxic tumours for which the difference in D50 values for the LQ and USC models was reduced from 5.4 to 0.2 Gy for 1 and 3 fractions, respectively, in a tumour with only 1.1% hypoxia and from 9.5 to 0.4 Gy in a tumour with 11.1% hypoxia. CONCLUSIONS: For a large range of fractional doses including hypofractionated schemes, the difference in predicted survival and TCP between the LQ and USC models for tumours with heterogeneous oxygenation was found to be negligible.

The impact of fractionation in SBRT: analysis with the linear quadratic model and the universal survival curve model.

BACKGROUND: Since the impact of fractionation in SBRT has not been systematically investigated, this modelling study was performed to see how the therapeutic window is affected for a range of fractions at target doses commonly administered in SBRT. MATERIAL AND METHODS: Isoeffective tumour-doses (constant cell survival) were calculated with the linear quadratic (LQ) and the universal survival curve (USC) models for 2-20 fractions. The isoeffective tumour-regimes (with α/ß = 10 Gy) were used to calculate the sparing of normal tissues (with α/ß = 3 Gy) for an increasing number of fractions. Sparing was calculated as an increase in cell survival and decrease in normal tissue complication probability (NTCP) as compared to a common scheme with 3 fractions of 22 Gy to the centre of the target [(15 Gy to the periphery of the planning target volume (PTV)]. RESULTS: At a high dose per fraction, above about 15 Gy, the USC model predicted much lower fractionation sensitivity than the LQ model. This holds true for both tumour and normal tissues. The USC model also predicted greater sparing of normal tissues outside the PTV as compared to the LQ model. Especially at dose levels of the order of 30-50% to that in the centre of the target. The decrease in NTCP predicted by the USC model was of the order of 30% for 10 fractions as compared to the NTCP for 3 fractions. With the LQ model the corresponding decrease was of the order of 10%. CONCLUSION: The USC model generally predicts a larger therapeutic window than the LQ model for an increasing number of fractions than today's practice in SBRT.

Dose escalation in oropharyngeal cancer: a comparison of simultaneous integrated boost and brachytherapy boost.

BACKGROUND: Local recurrence is the most common pattern of failure in head and neck cancer. It can therefore be hypothesised that some of these patients would benefit from an intensified local treatment, such as radiation dose escalation of the primary tumour. This study compares treatment and toxicity outcomes from two different boost modalities in oropharyngeal cancer: simultaneous integrated boost (SIB) and brachytherapy boost. METHODS: Two hundred and forty-four consecutive patients treated with > 72 Gy for oropharyngeal squamous cell carcinoma between 2011 and 2018 at our institution were retrospectively analysed. Data on side effects were collected from a local quality registry and supplemented with a review of medical records. Patients receiving a brachytherapy boost first had external beam radiotherapy consisting of 68 Gy in 2 Gy fractions to the gross tumour volume (GTV), and elective radiotherapy to the neck bilaterally. The brachytherapy boost was typically given using pulsed dose rate, 15 fractions and 0.56-0.66 Gy per fraction [total dose in EQD2 = 75.4-76.8 Gy (α/ß = 10)]. The typical dose escalated radiotherapy with external beam radiotherapy only, was delivered using SIB with 74,8 Gy in 2.2 Gy fractions [EQD2 = 76.0 Gy (α/ß = 10)] to the primary tumour, 68 Gy in 2 Gy fractions to GTV + 10 mm margin and elective radiotherapy to the neck bilaterally. RESULTS: Dose escalation by SIB was given to 111 patients and brachytherapy boost to 134 patients. The most common type of cancer was base of tongue (55%), followed by tonsillar cancer (42%). The majority of patients had T3- or T4-tumours and 84% were HPV-positive. The 5-year OS was 72,4% (95% CI 66.9-78.3) and the median follow-up was 6.1 years. Comparing the two different dose escalation modalities we found no significant differences in OS or PFS and these results remained after a propensity-score matched analysis was performed. The analysis of grade ≥ 3 side effects showed no significant differences between the two different dose escalation techniques. CONCLUSIONS: We found no significant differences in survival or grade ≥ 3 side effects comparing simultaneous integrated boost and brachytherapy boost as alternative dose escalation modalities in the treatment of oropharyngeal cancer.

Dose Escalation of Oropharyngeal Cancer: Long-Time Follow-Up and Side Effects.

Previous studies on dose-escalated radiotherapy in head and neck cancer have shown mixed results, and it is not established which patients would benefit from dose escalation. Further, while dose escalation does not appear to increase late toxicity, this needs to be confirmed with longer follow-up. In this study, we analysed treatment outcome and toxicity in 215 patients with oropharyngeal cancer treated with dose-escalated radiotherapy (>72 Gy, EQD2, α/ß = 10 Gy, boost by brachytherapy or simultaneous integrated boost) and a matched cohort of 215 patients treated with standard dose external-beam radiotherapy (68 Gy) between 2011 and 2018 at our institution. The 5-year overall survival (OS) was 77.8% (72.4-83.6) and 73.7% (67.8-80.1) in the dose-escalated and standard dose group, respectively (p = 0.24). Median follow-up was 78.1 (49.2-98.4) and 60.2 (38.9-89.4) months in the dose-escalated and standard dose groups, respectively. Grade ≥3 osteoradionecrosis (ORN) and late dysphagia were more common in the dose-escalated group compared to the standard dose group, with 19 (8.8%) vs. 4 (1.9%) patients developing grade ≥3 ORN (p = 0.001), and 39 (18.1%) vs. 21 (9.8%) patients developing grade ≥3 dysphagia (p = 0.01). No predictive factors to help select patients for dose-escalated radiotherapy were found. However, the remarkably good OS in the dose-escalated cohort, despite a predominance of advanced tumour stages, encourages further attempts to identify such factors.

Radiotherapy-Dose Escalated for Large Volume Primary Tumors-And Cetuximab with or without Induction Chemotherapy for HPV Associated Squamous Cell Carcinoma of the Head and Neck-A Randomized Phase II Trial.

The leading cause of death for patients with HPV associated squamous cell carcinoma of the head and neck (SCCHN) after treatment with chemoradiotherapy (CRT) nowadays is peripheral metastasis. This study investigated whether induction chemotherapy (IC) could improve progression free survival (PFS) and impact on relapse pattern after CRT. METHODS: Eligible patients in this multicenter, randomized, controlled, phase 2 trial had p16-positive locoregionally advanced SCCHN. Patients were randomized in a 1:1 ratio to either RT with cetuximab (arm B) versus the same regimen preceded by two cycles of taxotere/cisplatin/5-FU (arm A). The RT dose was escalated to 74.8 Gy for large volume primary tumors. Eligibility criteria included patients of 18-75 years, an ECOG performance status 0-1, and adequate organ functions. RESULTS: From January 2011 to February 2016, 152 patients, all with oropharyngeal tumors were enrolled, 77 in arm A and 75 in arm B. Two patients, one in each group, withdrew their consent after randomization, leaving 150 patients for the ITT analysis. PFS at 2 years was 84.2% (95% CI 76.4-92.8) in arm A and 78.4% (95% CI 69.5-88.3) in arm B (HR 1.39, 95% CI 0.69-2.79, p = 0.40). At the time of analysis, there were 26 disease failures, 9 in arm A and 17 in arm B. In arm A, 3 patients had local, 2 regional, and 4 distant relapses as first sites of recurrence, and in arm B, 4, 4, and 9 relapses in corresponding sites. Eight out of 26 patients with disease progression had salvage therapy and 7 were alive NED (no evidence of disease), at 2 years. Locoregional control was 96% in arm A and 97.3% in arm B and OS 93% and 90.5%, respectively. Local failure as first site of recurrence was low, in 4.6% of patients and was similar for T1/T2 and T3/T4 tumors (n.s). Nevertheless, out of 7 patients with primary local failures, 4 were treated with the escalated RT dose. Toxicity was low and similar in the treatment arms. There was one fatal event in arm A where the combined effects of the drugs used in chemotherapy and cetuximab could not be ruled out. CONCLUSIONS: PFS, locoregional control and toxicity did not differ between the two arms, OS was high, and there were few local relapses. In arm B, more than twice as many patients had distant metastasis as the first site of relapse compared to arm A. The response to IC was found to define 29% of patients in arm A who did not have a tumor relapse during follow-up. An escalated dose of 74.8 Gy could mitigate the negative impact of large tumor volume but for some patients, even this intensified treatment was insufficient.

Expanded HILUS Trial: A Pooled Analysis of Risk Factors for Toxicity From Stereotactic Body Radiation Therapy of Central and Ultracentral Lung Tumors.

PURPOSE: Stereotactic body radiation therapy for tumors near the central airways implies high-grade toxic effects, as concluded from the HILUS trial. However, the small sample size and relatively few events limited the statistical power of the study. We therefore pooled data from the prospective HILUS trial with retrospective data from patients in the Nordic countries treated outside the prospective study to evaluate toxicity and risk factors for high-grade toxic effects. METHODS AND MATERIALS: All patients were treated with 56 Gy in 8 fractions. Tumors within 2 cm of the trachea, the mainstem bronchi, the intermediate bronchus, or the lobar bronchi were included. The primary endpoint was toxicity, and the secondary endpoints were local control and overall survival. Clinical and dosimetric risk factors were analyzed for treatment-related fatal toxicity in univariable and multivariable Cox regression analyses. RESULTS: Of 230 patients evaluated, grade 5 toxicity developed in 30 patients (13%), of whom 20 patients had fatal bronchopulmonary bleeding. The multivariable analysis revealed tumor compression of the tracheobronchial tree and maximum dose to the mainstem or intermediate bronchus as significant risk factors for grade 5 bleeding and grade 5 toxicity. The 3-year local control and overall survival rates were 84% (95% CI, 80%-90%) and 40% (95% CI, 34%-47%), respectively. CONCLUSIONS: Tumor compression of the tracheobronchial tree and high maximum dose to the mainstem or intermediate bronchus increase the risk of fatal toxicity after stereotactic body radiation therapy in 8 fractions for central lung tumors. Similar dose constraints should be applied to the intermediate bronchus as to the mainstem bronchi.

Risk for Hemorrhage the First 2 Years After Gamma Knife Surgery for Arteriovenous Malformations: An Update.

BACKGROUND: Knowledge about the natural course of brain arteriovenous malformations (AVMs) have increased during the past 20 years, as has the number of AVMs treated, especially larger ones. It is thus timely to again analyze the risk for hemorrhage after Gamma Knife Surgery (GKS). OBJECTIVE: To confirm or contradict conclusions drawn 20 years ago regarding factors that affect the risk for post-GKS hemorrhage. METHODS: The outcome after GKS was studied in 5037 AVM patients followed for up to 2 years. The relation between post-treatment hemorrhage rate and a number of patient, AVM, and treatment parameters was analyzed. The results were also compared with the results from our earlier study. RESULTS: The annual post-treatment hemorrhage rate was 2.4% the first 2 years after GKS. Large size, low treatment dose, and old age were independent risk factors for AVM hemorrhage. After having compensated for the factors above, peripheral AVM location and female sex, at least during their child bearing ages, were factors associated with a lower post-GKS hemorrhage rate. CONCLUSION: Large AVMs (>5 cm 3 ) treated with low doses (≤16 Gy) had higher and small AVMs treated with high doses a lower risk for hemorrhage as compared with untreated AVMs. This was detectable within the first 6 months after GKS. No difference in hemorrhage rate could be detected for the other AVMs. Based on our findings, it is advisable to prescribe >16 Gy to larger AVMs, assuming that the risk for radiation-induced complications can be kept at an acceptable level.

NTCP modelling of lung toxicity after SBRT comparing the universal survival curve and the linear quadratic model for fractionation correction.

BACKGROUND: In SBRT of lung tumours no established relationship between dose-volume parameters and the incidence of lung toxicity is found. The aim of this study is to compare the LQ model and the universal survival curve (USC) to calculate biologically equivalent doses in SBRT to see if this will improve knowledge on this relationship. MATERIAL AND METHODS: Toxicity data on radiation pneumonitis grade 2 or more (RP2+) from 57 patients were used, 10.5% were diagnosed with RP2+. The lung DVHs were corrected for fractionation (LQ and USC) and analysed with the Lyman- Kutcher-Burman (LKB) model. In the LQ-correction α/ß = 3 Gy was used and the USC parameters used were: α/ß = 3 Gy, D(0) = 1.0 Gy, [Formula: see text] = 10, α = 0.206 Gy(-1) and d(T) = 5.8 Gy. In order to understand the relative contribution of different dose levels to the calculated NTCP the concept of fractional NTCP was used. This might give an insight to the questions of whether "high doses to small volumes" or "low doses to large volumes" are most important for lung toxicity. RESULTS AND DISCUSSION: NTCP analysis with the LKB-model using parameters m = 0.4, D(50) = 30 Gy resulted for the volume dependence parameter (n) with LQ correction n = 0.87 and with USC correction n = 0.71. Using parameters m = 0.3, D(50) = 20 Gy n = 0.93 with LQ correction and n = 0.83 with USC correction. In SBRT of lung tumours, NTCP modelling of lung toxicity comparing models (LQ,USC) for fractionation correction, shows that low dose contribute less and high dose more to the NTCP when using the USC-model. Comparing NTCP modelling of SBRT data and data from breast cancer, lung cancer and whole lung irradiation implies that the response of the lung is treatment specific. More data are however needed in order to have a more reliable modelling.

Estimation of delivered dose to lung tumours considering setup uncertainties and breathing motion in a cohort of patients treated with stereotactic body radiation therapy.

INTRODUCTION: Dose-response relationships for local control of lung tumours treated with stereotactic body radiotherapy (SBRT) have proved ambiguous, however, these have been based on the prescribed or planned dose. Delivered dose to the target may be a better predictor for local control. In this study, the probability of the delivered minimum dose to the clinical target volume (CTV) in relation to the prescribed dose was estimated for a cohort of patients, considering geometrical uncertainties. MATERIALS AND METHODS: Delivered doses were retrospectively simulated for 50 patients treated with SBRT for lung tumours, comparing two image-guidance techniques: pre-treatment verification computed tomography (IG1) and online cone-beam computed tomography (IG2). The prescribed dose was typically to the 67% isodose line of the treatment plan. Simulations used in-house software that shifted the static planned dose according to a breathing motion and sampled setup/matching errors. Each treatment was repeatedly simulated, generating a multiplicity of dose-volume histograms (DVH). From these, tumour-specific and population-averaged statistics were derived. RESULTS: For IG1, the probability that the minimum CTV dose (D98%) exceeded 100% of the prescribed dose was 90%. With IG2, this probability increased to 99%. CONCLUSIONS: Doses below the prescribed dose were delivered to a considerably larger part of the population prior to the introduction of online soft-tissue image-guidance. However, there is no clear evidence that this impacts local control, when compared to previous published data.

Re-Irradiation for Head and Neck Cancer: Cumulative Dose to Organs at Risk and Late Side Effects.

Re-irradiation in head and neck cancer is challenging, and cumulative dose constraints and dose/volume data are scarce. In this study, we present dose/volume data for patients re-irradiated for head and neck cancer and explore the correlations of cumulative dose to organs at risk and severe side effects. We analyzed 54 patients re-irradiated for head and neck cancer between 2011 and 2017. Organs at risk were delineated and dose/volume data were collected from cumulative treatment plans of all included patients. Receiver-operator characteristics (ROC) analysis assessed the association between dose/volume parameters and the risk of toxicity. The ROC-curve for a logistic model of carotid blowout vs. maximum doses to the carotid arteries showed AUC = 0.92 (95% CI 0.83 to 1.00) and a cut-off value of 119 Gy (sensitivity 1.00/specificity 0.89). The near-maximum dose to bones showed an association with the risk of osteoradionecrosis: AUC = 0.74 (95% CI 0.52 to 0.95) and a cut-off value of 119 Gy (sensitivity 1.00/specificity 0.52). Our analysis showed an association between cumulative dose to organs at risk and the risk of developing osteoradionecrosis and carotid blowout, and our results support the existing dose constraint for the carotid arteries of 120 Gy. The confirmation of these dose-response relationships will contribute to further improvements of re-irradiation strategies.

The HILUS-Trial-a Prospective Nordic Multicenter Phase 2 Study of Ultracentral Lung Tumors Treated With Stereotactic Body Radiotherapy.

INTRODUCTION: Stereotactic body radiation therapy of thoracic tumors close to the central airways implies risk of severe toxicity. We report a prospective multicenter phase 2 trial for tumors located less than or equal to 1 cm from the proximal bronchial tree with primary end point of local control and secondary end point of toxicity. METHODS: Stereotactic body radiation therapy with 7 Gy × 8 was prescribed to the 67% isodose encompassing the planning target volume. The patients were stratified to group A (tumors ≤ 1 cm from the main bronchi and trachea) or group B (all other tumors). Risk factors for treatment-related death were tested in univariate analysis, and a logistic regression model was developed for fatal bronchopulmonary bleeding versus dose to the main bronchi and trachea. RESULTS: A total of 65 patients (group A/group B, n = 39/26) were evaluated. The median distance between the tumor and the proximal bronchial tree was 0 mm (0-10 mm). The 2-year local control was 83%. Grade 3 to 5 toxicity was noted in 22 patients, including 10 cases of treatment-related death (bronchopulmonary hemorrhage, n = 8; pneumonitis, n = 1; fistula, n = 1). Dose to the combined structure main bronchi and trachea and tumor distance to the main bronchi were important risk factors. Dose modeling revealed minimum dose to the "hottest" 0.2 cc to the structure main bronchi and trachea as the strongest predictor for lethal bronchopulmonary hemorrhage. CONCLUSIONS: On the basis of the presented data, 7 Gy × 8, prescribed to the planning target volume-encompassing isodose, should not be used for tumors located within 1 cm from the main bronchi and trachea. Group B-type tumors may be considered for the treatment on the basis of an individual risk-benefit assessment and a maximum dose to the main bronchi and trachea in the order of 70 to 80 Gy (equivalent dose in 2 Gy fractions).

Stereotactic body radiation therapy for early non-small cell lung cancer.

For patients with early stage non-small cell lung cancer (NSCLC) unsuitable for resection local high-dose radiotherapy is the treatment of choice. In modern series even with escalated conformal radiotherapy local control rates of about 55% remain disappointing. Within the last years, stereotactic radiotherapy has been shown an effective treatment approach for early stage malignant lung tumors, combining the accurate focal dose delivery by stereotactic techniques with the biological advantages of dose escalated hypofractionated radiotherapy. Typical treatment regimens include three to five fractions over 1-2 weeks or 1 single fraction as radiosurgery. With adequate staging procedures including FDG-PET-CT scan and a low probability of subclinical involvement of unsuspicious locoregional lymph nodes, the concept is to irradiate the primary T1/2 tumor alone. Recent data report local control rates of up to 90%, with favorable results especially for patients in good general condition. Less than 10% of all patients develop isolated tumor recurrences in regional lymph nodes. Three-year survival is significantly improved to more than 80% when biological effective doses of more than 100 Gy are applied to patients in good conditions. Systemic tumor recurrence still is a major problem, making an additional systemic chemotherapy interesting for selected patients after hSRT, such as those younger than 75 years.

Overlapping volumes in re-irradiation for head and neck cancer - an important factor for patient selection.

BACKGROUND: There is a lack of consensus concerning the definition of re-irradiation and re-irradiation volumes in head and neck cancer (HNC). The aim of the present study is to introduce a more strict definition of the re-irradiated volume that might better predict the risk of serious side-effects from treatment. METHODS: Fifty-four consecutive patients re-irradiated for HNC cancer were retrospectively analysed. CT images were deformably registered and the dose distributions accumulated after conversion to EQD2. Patients with a cumulative dose of ≥100 Gy in the overlapping volume (V100) were included in the study. Survival data and radiation-related acute and late toxicities were recorded. RESULTS: The overall survival of all included patients at 2 and 5 years was 42.6 and 27.3% respectively and the progression free survival at 2 and 5 years was 32.5 and 28.5% respectively. The overall rate of any event of severe (grade ≥ 3) acute and late toxicity was 26 and 51%, respectively. We found that severe acute toxicity was more common in patients who had a larger overlapping volume (V100 > mean) where 43% of the patients experienced grade ≥ 3 acute toxicity, compared to the patients with smaller overlapping volumes (V100 < mean) where only 11% had severe toxicity (p = 0.02). The seemingly high rates of late toxicity in the present study could be due to the use of a more strict definition of re-irradiation. In previous studies also patients with low dose overlap are included and our results imply that there is a risk that previous studies might have overestimated the risk-benefit ratio in re-irradiation of HNC. CONCLUSIONS: Our study describes the outcome of a patient material where a more strict definition of the re-irradiated volume is used. With this definition, which could better describe the volume of highest risk for serious complications, we found that larger such overlapping volumes result in an increase in severe acute side-effects. A clear definition of re-irradiation and re-irradiation volumes is of utmost importance for future studies of HNC to make results from different studies comparable.

Modeling of Xerostomia After Radiotherapy for Head and Neck Cancer: A Registry Study.

AIM: Data from a local quality registry are used to model the risk of late xerostomia after radiotherapy for head and neck cancer (HNC), based on dosimetric- and clinical variables. Strengths and weaknesses of using quality registry data are explored. METHODS: HNC patients treated with radiotherapy at the Karolinska University hospital are entered into a quality registry at routine follow up, recording morbidity according to a modified RTOG/LENT-SOMA scale. Other recorded parameters are performance status, age, gender, tumor location, tumor stage, smoking status, chemotherapy and radiotherapy data, including prescribed dose and organ-at-risk (OAR) dose. Most patients are entered at several time points, but at variable times after treatment. Xerostomia was modeled based on follow-up data from January 2014 to October 2018, resulting in 753 patients. Two endpoints were considered: maximum grade ≥2 (XERG≥2) or grade ≥3 (XERG≥3) late xerostomia. Univariate Cox regression was used to select variables for two multivariate models for each endpoint, one based on the mean dose to the total parotid volume (Dtot) and one based on the mean dose to the contralateral parotid (Dcontra). Cox regression allows the estimation of the risk of xerostomia at different time points; models were presented visually as nomograms estimating the risk at 9, 12, and 24 months respectively. RESULTS: The toxicity rates were 366/753 (49%) for XERG≥2 and 40/753 (5.3%) for XERG≥3. The multivariate models included several variables for XERG≥2, and dose, concomitant chemotherapy and age were included for XERG≥3. Induction chemotherapy and an increased number of fractions per week were associated with a lower risk of XERG≥2. However, since the causality of these relationships have limited support from previous studies, alternative models without these variables were also presented. The models based on the mean dose to the total parotid volume and the contralateral parotid alone were very similar. CONCLUSION: Late xerostomia after radiotherapy can be modeled with reasonable predictive power based on registry data; models are presented for different endpoints highly relevant in clinical practice. However, the risk of modeling indirect relationships, given the unavoidably heterogeneous registry data, needs to be carefully considered in the interpretation of the results.