Retreatment Dose Research Articles

Glofitamab monotherapy retreatment in patients with heavily pre-treated relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL): Results from a phase I/II study.

7020 Background: Fixed-duration glofitamab, a CD20xCD3 T-cell engaging bispecific antibody with a novel 2:1 configuration, has demonstrated efficacy and manageable safety in a Phase I/II study (NCT03075696) in heavily pre-treated patients (pts) with R/R NHL (Dickinson. N Engl J Med 2022). We report efficacy and safety data for pts with R/R NHL retreated with glofitamab monotherapy after response to initial glofitamab treatment. Methods: Pts who completed initial treatment and achieved complete response (CR), partial response (PR), or stable disease were eligible for retreatment after documented progression. Initial treatment included obinutuzumab pre-treatment (Gpt) 7 days before the first glofitamab dose, then glofitamab intravenously at either a fixed dose of 0.015–25mg (14- or 21-day cycles) or step-up dosing (2.5mg, then 10mg in Cycle [C] 1, followed by a target dose of 16 or 30mg [C2 onward, 21- day cycles]) for up to 12 cycles. Retreatment was administered at the escalation dose received or at the highest glofitamab dose cleared in the study at time of retreatment, with Gpt 7 days before the first glofitamab dose. As with initial treatment, retreatment was permitted for 12 cycles or until progression or unacceptable toxicity, whichever occurred first. Results: As of Sept 4, 2023, 13 pts (diffuse large B-cell lymphoma [DLBCL], n=4; follicular lymphoma [FL], n=4; mantle cell lymphoma [MCL], n=2; transformed FL [trFL], n=2; high grade B-cell lymphoma, n=1) had received glofitamab retreatment (retreatment dose: 10mg, n=1; 10/16mg, n=1; 2.5/10/30mg, n=11). Median age was 63.0 years (range: 44–81). With initial treatment, 9 pts had CR and 4 pts had PR (best response by investigator). Median time from end of initial treatment to initiation of retreatment was 13.0 months (range: 4.1–27.4). Median number of retreatment cycles received was 5 (range: 2–12). During retreatment, 9 pts (69.2%) responded: CR, 38.5% (FL, n=2; trFL, n=1; MCL, n=2); PR, 30.8% (FL, n=1; trFL, n=1; DLBCL, n=2). Of the 5 pts with CR at retreatment, 3 pts had CR and 2 pts had PR with initial treatment. Of the 4 pts with PR at retreatment, 3 pts had CR and 1 pt had PR with initial treatment. Median retreatment follow-up time was 25.9 months and 5 pts had responses ongoing at data cut-off (FL, n=2; MCL, n=2; trFL, n=1). The safety profile for glofitamab retreatment was consistent with prior reports of glofitamab monotherapy in R/R NHL (Hutchings. J Clin Oncol 2021). Cytokine release syndrome occurred in 7 pts (53.8%; all Grade 1/2). Exploratory data on B-cell pharmacodynamics, CD20 expression, and T-cell status before retreatment will be presented. Conclusions: Glofitamab monotherapy retreatment was efficacious in heavily pre-treated pts with R/R NHL who responded to initial glofitamab treatment before subsequent progression. The safety profile was consistent with that of initial treatment. Clinical trial information: NCT03075696 .

Brentuximab Vedotin Retreatment in Patients with Relapsed or Refractory Classical Hodgkin Lymphoma or Peripheral T-Cell Lymphoma: A Retrospective United States Claims Analysis.

Brentuximab vedotin (BV) monotherapy (BV-M) and combination (BV-C) therapies are safe and effective for classical Hodgkin lymphoma (cHL) and CD30-expressing peripheral T-cell lymphomas (PTCLs). Although the sample sizes have been small (12-29 patients), in clinical studies, response rates of 53-88% have been reported for BV retreatment in patients with an initial BV response. We evaluated the real-world characteristics and treatment patterns of cHL/PTCL patients who received BV and were retreated in the United States. Symphony Health Patient Claims (11/2013-1/2022) were retrospectively analyzed to identify cHL/PTCL patients treated with BV and retreated with BV-M, BV-C, or non-BV therapy. Patient characteristics were described by retreatment, and predictors of BV-M retreatment were identified. Among the cHL and PTCL patients treated with BV (n = 6442 and 2472, respectively), 13% and 12%, respectively, were retreated with BV; the median times from initial BV to BV-M retreatment were 5 and 7 months, respectively; and the numbers of BV-M retreatment doses were 4 and 5, respectively. Among cHL patients, the predictors of BV-M retreatment were age (18-39 vs. ≥60 years), sex (women vs. men), and previous stem cell transplantation (yes vs. no). Among PTCL patients, the only predictor of BV-M retreatment was systemic anaplastic large-cell lymphoma subtype (yes vs. no). Real-world data support clinical study results suggesting earlier BV treatment be considered, as BV retreatment may be an option.

1482: Re-irradiation in non-small cell lung cancer: overall survival longer with higher retreatment dose

1482: Re-irradiation in non-small cell lung cancer: overall survival longer with higher retreatment dose

Diagnostic utility of lung ultrasound in predicting the need for surfactant therapy in preterm neonates with respiratory distress.

Lung ultrasound is an accurate and early predictor for surfactant replacement therapy in respiratory distress syndrome (RDS) as compared to clinical parameters and chest x-ray. However, lung pathologies for respiratory distress at birth have overlapping symptomatology and low middle-income countries have a higher incidence of congenital pneumonia, in addition to RDS, making the immediate diagnosis difficult. Thus, there is a need for assessing a cutoff for lung ultrasound scores in the given setting. The primary objective was to determine the diagnostic accuracy of the lung ultrasound score (LUS) in predicting the need for surfactant therapy in preterm neonates with respiratory distress. Secondary objectives were to correlate LUS with corresponding oxygen saturation to the fraction of inspired oxygen ratio (SpO2/FiO2), arterial/Alveolar oxygen pressure ratio (a/A), and chest x-ray (CXR) findings. A prospective observational study was carried out at a tertiary-level neonatal intensive care unit in India in 2022 enrolling 100 neonates <34 weeks gestational age with respiratory distress at birth. After initial stabilization of the neonate, LUS was performed and baseline parameters were noted. Surfactant was administered as per the 2019 European Consensus guidelines and LUS was repeated after 6 h of therapy. The mean gestation of enrolled neonates was 31.06 ± 2.12 weeks and the mean birthweight was 1,412 ± 391 g. Approximately 58% were diagnosed with RDS and 30% had congenital pneumonia. Surfactant was administered to 40% of neonates. The cutoff LUS for surfactant therapy was 7 [area under the curve (AUC) 0.977; 95% CI, 0.947-1; P < 0.001; with sensitivity 92.5%, specificity 96.67%, PPV 94.87%, and NPV 95.08%] and the cutoff LUS for the second dose of surfactant was 10 (AUC 0.964; 95% CI, 0.913-1; P < 0.001). The score decreased by 3.24 (2.44-4.05) after 6 h of the first dose and correlated significantly with SpO2/FiO2 ratio (-0.750), a/A ratio (-0.650), and CXR findings (0.801). The study predicted an optimal LUS cutoff of 7 and 10 for the need for the first dose of surfactant and re-treatment, respectively, in neonates <34 weeks gestational age with respiratory distress.

Overcoming the challenges of drug development in platinum-resistant ovarian cancer.

The definition of "platinum-resistant ovarian cancer" has evolved; it now also reflects cancers for which platinum treatment is no longer an option. Standard of care for platinum-resistant ovarian cancer is single-agent, non-platinum chemotherapy with or without bevacizumab, which produces modest response rates, with the greatest benefits achieved using weekly paclitaxel. Several recent phase 3 trials of pretreated patients with prior bevacizumab exposure failed to meet their primary efficacy endpoints, highlighting the challenge in improving clinical outcomes among these patients. Combination treatment with antiangiogenics has improved outcomes, whereas combination strategies with immune checkpoint inhibitors have yielded modest results. Despite extensive translational research, there has been a lack of reliable and established biomarkers that predict treatment response in platinum-resistant ovarian cancer. Additionally, in the platinum-resistant setting, implications for the time between the penultimate dose of platinum therapy and platinum retreatment remain an area of debate. Addressing the unmet need for an effective treatment in the platinum-resistant setting requires thoughtful clinical trial design based on a growing understanding of the disease. Recent cancer drug approvals highlight the value of incorporating molecular phenotypes to better define patients who are more likely to respond to novel therapies. Clinical trials designed per the Gynecologic Cancer InterGroup recommendations-which advocate against relying solely upon the platinum-free interval-will help advance our understanding of recurrent ovarian cancer response where platinum rechallenge in the platinum-resistant setting may be considered. The inclusion of biomarkers in clinical trials will improve patient stratification and potentially demonstrate correlations with biomarker expression and duration of response. With the efficacy of antibody-drug conjugates shown for the treatment of some solid and hematologic cancers, current trials are evaluating the use of various novel conjugates in the setting of platinum-resistant ovarian cancer. Emerging novel treatments coupled with combination trials and biomarker explorations offer encouraging results for potential strategies to improve response rates and prolong progression-free survival in this population with high unmet need. This review outlines existing data from contemporary clinical trials of patients with platinum-resistant ovarian cancer and suggests historical synthetic benchmarks for non-randomized trials.

Magnetic resonance guided SBRT reirradiation in locally recurrent prostate cancer: a multicentric retrospective analysis

AimsReirradiation of prostate cancer (PC) local recurrences represents an emerging challenge for current radiotherapy. In this context, stereotactic body radiation therapy (SBRT) allows the delivery of high doses, with curative intent. Magnetic Resonance guided Radiation Therapy (MRgRT) has shown promising results in terms of safety, feasibility and efficacy of delivering SBRT thanks to the enhanced soft tissue contrast and the online adaptive workflow. This multicentric retrospective analysis evaluates the feasibility and efficacy of PC reirradiation, using a 0.35 T hybrid MR delivery unit.MethodsPatients affected by local recurrences of PC and treated in five institutions between 2019 and 2022 were retrospectively collected. All patients had undergone previous Radiation Therapy (RT) in definitive or adjuvant setting. Re-treatment MRgSBRT was delivered with a total dose ranging from 25 to 40 Gy in 5 fractions. Toxicity according to CTCAE v 5.0 and treatment response were assessed at the end of the treatment and at follow-up.ResultsEighteen patients were included in this analysis. All patients had previously undergone external beam radiation therapy (EBRT) up to a total dose of 59.36 to 80 Gy. Median cumulative biologically effective dose (BED) of SBRT re-treatment was 213,3 Gy (103,1-560), considering an α/β of 1.5. Complete response was achieved in 4 patients (22.2%). No grade ≥ 2 acute genitourinary (GU) toxicity events were recorded, while gastrointestinal (GI) acute toxicity events occurred in 4 patients (22.2%).ConclusionThe low rates of acute toxicity of this experience encourages considering MRgSBRT a feasibile therapeutic approach for the treatment of clinically relapsed PC. Accurate gating of target volumes, the online adaptive planning workflow and the high definition of MRI treatment images allow delivering high doses to the PTV while efficiently sparing organs at risk (OARs).

Tumor Control Probability After Radiosurgery of Brain Metastases With and Without Retreatment

To develop and compare tumor-control probability (TCP) models for single-fraction stereotactic radiosurgery (SRS) for brain metastasis (BMs) with and without retreatment. We developed three different schemas to model TCP of BMs treated with linear accelerator-based SRS. Dose to 99% of each planning target volume (PTV D99) and 6-month local control were fit using linear-quadratic-linear (LQ-L) models based on equivalent-dose conversions in 2 Gy (EQD2). The M1 schema had separate LQ-L TCP models for initial dose (M1-initial) and retreatment dose (M1-retreat), and the M2 schema had an LQ-L model using the sum of 50% of the initial SRS dose plus the retreatment SRS dose. The M1-initial and M1-retreat schema modeled local control after first SRS to 48 lesions (patients=22) and second SRS to 46 lesions (patients=21). The M0 schema included a whole data set of 349 lesions (patients=136) receiving first SRS (no retreatment and M1-initial). LQ-L models fitted the data well (χ2=0.059-0.525 and P=0.999-1.000). For M0 and M1-retreat, the fitted models EQD250 and γ50 parameters were similar. The LQ-L fitted EQD250 was ∼8.0 Gy for M0 and M1-retreat, ∼24 Gy for M1-initial, and ∼19 Gy for M2. The model fitted γ50 was 0.1 Gy for M0, M1-retreat, and M2 and 0.5 for M1-initial. For the PTV D99 of 10 and 20 Gy, the steepest to shallowest dose-response or largest change in TCP, that is, TCP20Gy - TCP10Gy, was observed in M1-initial (0.49) and M2 (0.17). M0 and M1-retreat showed a similar change in TCP of 0.21. The model-fitted parameters predicted the recurrent BMs required a higher threshold dose and had a steeper dose-response for first SRS versus second SRS and M0. Alternatively, the recurrent BMs required ∼2 Gy higher predicted PTV D99 dose for first SRS to achieve the same TCP of 0.75 compared with second SRS and M0. Further investigations on larger patient cohorts are needed for validating our findings in predictive modeling of recurrent BMs.

Effectiveness and safety of retreatment with lutetium Lu 177 DOTATATE in patients with progressive neuroendocrine tumors in the United States: A retrospective real-world study.

e16215 Background: Advanced neuroendocrine tumors (NETs) are associated with a very poor prognosis. A regimen of 4 doses of lutetium Lu 177 (177Lu)-DOTATATE has been shown to improve both progression-free survival (PFS) and overall survival (OS) in patients with advanced NETs. This is the first United States (US) study to evaluate the effectiveness and safety of additional doses in patients with progressive NETs. Methods: This was a retrospective chart review of 31 adults with advanced NETs who had undergone initial treatment with up to 4 doses of 177Lu-DOTATATE and who, following disease progression and a period of ≥6 months since the end of initial treatment, were re-treated with ≥1 additional dose at a single US center (2010–2020). Patient characteristics, treatment patterns, and clinical outcomes were evaluated descriptively. Response was evaluated according to RECIST 1.1; toxicity was defined using CTCAE 5.0 criteria. Kaplan–Meier plots were used to evaluate PFS and OS. Results: Of the 31 patients who received 177Lu-DOTATATE re-treatment, 19 (61%) were male and 29 (94%) were white. Overall, patients received a median of 6 doses (4 initial doses and 2 re-treatment doses) and the mean±sd administered activity was 41.9±4.4 GBq. Two patients also went on to receive additional re-treatment (1 and 2 doses, respectively) following a second period of ≥6 months and progression after re-treatment. Best responses of partial response and stable disease were observed in 11 patients (35%) and 20 patients (65%) after initial treatment, and 7 patients (23%) and 14 patients (45%) after re-treatment (Table). The median PFS after initial treatment was 20.2 months and after re-treatment was 9.6 months. The median OS after initial treatment was 42.6 months and after re-treatment was 12.6 months. Hematological parameters decreased significantly during both initial and re-treatment but recovered such that there was no significant difference between the values prior to initial treatment and prior to re-treatment. Clinically significant hematotoxicity occurred in 1 and 3 patients following initial and re-treatment, respectively. No grade 3/4 nephrotoxicity (based on creatinine levels) was observed. Conclusions: Re-treatment with 177Lu-DOTATATE after progression appeared to be well-tolerated and offered disease control in patients with progressive NETs following initial 177Lu-DOTATATE treatment.[Table: see text]

P003 Quality improvement project on rituximab use in rheumatoid arthritis - how do we improve quality and cost effectiveness?

Background/AimsRituximab (RTX) is a chimeric monoclonal antibody against CD20, a transmembrane protein on B lymphocyte surfaces. It is now established as an effective treatment for rheumatoid arthritis (RA). The timing of re-treatment is not well defined and varies widely in clinical practice. Our aim was to assess departmental practice on retreatment doses and frequency of RTX in RA patients. We proposed retreatment with reduced dose (1gm) as compared to the standard dose (1gm x 2, 2 weeks apart). We envisage this would maintain efficacy and lead to significant cost saving for the CCG and Rheumatology department.MethodsData were collected retrospectively over 3 years (2017- 2020) on patients who had received at least one re-treatment RTX dose no less than 24 weeks after first course of standard regime. Information was obtained on patient demographics, serology, disease activity scores, previous treatment, concurrent therapy including steroids, frequency and dosing of RTX.Results50 patients were included with an average age 66 years (range 32- 85), 58% were females, 83% were seropositive and 59% had established erosive disease. Most patients had received prior therapy of non-biologic and biologic DMARDs, methotrexate and anti-TNF being the most used agents in 70% and 52%, respectively. 40% were biologic DMARD naïve mostly due to anti-TNF contraindication. 78% patients were receiving concomitant non-biologic DMARDs, methotrexate being the commonest in 50% patients. 16% were on steroids with dose ≤ to 5mg in 87% of patients. 43% of patients received RTX 6 monthly, 33% 6- 9 monthly and 24% > 9 months. 96% of the patients received 1gm infusion x2, 2 weeks apart.ConclusionOur data showed most patients were receiving standard retreatment regime (1gm x2 fortnightly) at 6 monthly intervals. Previous studies including SMART (Study of Re-treatment With MabThera), SERENE, IMAGE and MIRROR trials suggested reduced dose of RTX had similar clinical efficacy to the standard dose. We optimised retreatment schedule of RTX from 2g to 1g, thereby reducing infection risk, especially in view of the COVID-19 pandemic and achieving significant cost savings. The cost savings over 3-year cycle of treatment for a DGH is of the order of £236,927.P003 Table 1Cost savings over 3-year cycle of treatmentThe prices for a 1000mg in 250mL Sodium Chloride 0.9% infusion of each of the Rituximab biosimilars MabThera Truxima Rixathon £2187.12 (inc. VAT)£963.12 (inc. VAT)£447.12 (inc. VAT) Dose Truxima Cost (£) /dose No. of pts (6 month Freq) No. of pts (6-9 month Freq) No. of pts (9+ month Freq) Total Costs (£) 2g1,926201511Costs over 3-year treatment with (2g)231,149138,689104,017473,855Costs over 3-year treatment with (1g)115,57469,34452,008236,927Disclosure N. Ahmad: None. J. McNally: None.

Drug levels, anti-drug antibodies and B-cell counts were not predictive of response in rheumatoid arthritis patients on (ultra-)low-dose rituximab.

The REDO trial (REtreatment with Rituximab in RhEumatoid arthritis: Disease Outcome after Dose Optimisation) showed that ultra-low-dose rituximab (500 mg or 200 mg) was similarly effective to a 1000 mg dosage in the majority of RA patients. This pre-planned secondary analysis investigated (1) associations between rituximab dosage, drug levels, anti-drug antibodies (ADAs) and B-cell counts and (2) the predictive value of pharmacokinetic and pharmacodynamic parameters, and of patient, disease and treatment characteristics in relation to response to ultra-low-dose rituximab. For 140 RA patients from the REDO trial, differences in drug levels, ADAs and B-cell counts were examined at baseline, and at 3 and 6 months after dosing. Treatment response was defined as absence of flare and no extra rituximab or >1 glucocorticoid injection received during follow-up. The association between potential predictors and response was investigated using logistic regression analyses. Lower doses of rituximab resulted in lower drug levels but did not significantly affect ADA levels or B-cell counts, and 3 (10.7%), 12 (20.7%) and 7 (13.0%) patients failed to meet the response criteria in, respectively, the 1000 mg, 500 mg and 200 mg dosage groups. Drug levels, ADAs, B-cell counts, and patient, disease and treatment characteristics were not predictive for response to ultra-low-dose rituximab. The results of this study further support the hypothesis that continued treatment with 500 or 200 mg rituximab is similarly effective to a 1000 mg dosage in RA patients doing well on rituximab. These results, combined with lack of finding a clinical dose-response relationship in the original REDO study, suggest that 200 mg rituximab is not yet the lowest effective rituximab retreatment dose in RA.

Further development of spinal cord retreatment dose estimation: including radiotherapy with protons and light ions

Purpose A graphical user interface (GUI) was developed to aid in the assessment of changes in the radiation tolerance of spinal cord/similar central nervous system tissues with time between two individual treatment courses. Methods The GUI allows any combination of photons, protons (or ions) to be used as the initial, or retreatment, radiotherapy courses. Allowances for clinical circumstances, of reduced tolerance, can also be made. The radiobiological model was published previously and has been incorporated with additional checks and safety features, to be as safe to use as possible. The proton option includes use of a fixed RBE of 1.1 (set as the default), or a variable RBE, the latter depending on the proton linear energy transfer (LET) for organs at risk. This second LET-based approach can also be used for ions, by changing the LET parameters. Results GUI screenshots are used to show the input and output parameters for different clinical situations used in worked examples. The results from the GUI are in agreement with manual calculations, but the results are now rapidly available without tedious and error-prone manual computations. The software outputs provide a maximum dose limit boundary, which should not be exceeded. Clinicians may also choose to further lower the number of treatment fractions, whilst using the same dose per fraction (or conversely a lower dose per fraction but with the same number of fractions) in order to achieve the intended clinical benefit as safely as possible. Conclusions The new GUI will allow scientific-based estimations of time related radiation tolerance changes in the spinal cord and similar central nervous tissues (optic chiasm, brainstem), which can be used to guide the choice of retreatment dose fractionation schedules, with either photons, protons or ions.

PCN132 Cost-Effectiveness Analysis of RE-Treatment with 177lu-Dotatate Versus NO RE-Treatment with 177lu-Dotatate in Patients with Progressive Midgut Neuroendocrine Tumors

To assess the cost-effectiveness of re-treatment with 177Lu-DOTATATE vs. no re-treatment with 177Lu-DOTATATE in patients with progressive midgut neuroendocrine tumors (NET), who initially received peptide receptor radionuclide therapy (I-PRRT) with 177Lu-DOTATATE, from a UK NHS and PSS perspective. The lifetime costs and effectiveness of treatment were simulated using a cohort-based, three-state (progression-free, progressed disease, and death) partition survival model with a 28-days cycle length. Clinical data were derived from the NETTER-1 study for patients without re-treatment and further adjusted for re-treatment based on van der Zwan et al, 2019. Cost inputs included costs for drug acquisition, concomitant medication, administration, disease monitoring and adverse events costs. Effectiveness was valued in quality-adjusted life years (QALYs), with utility weights derived from HRQoL data collected in NETTER-1 study and real world Erasmus study. Costs and effects were discounted at 3.5% per year. Uncertainty was assessed via deterministic and probabilistic sensitivity analyses. At lifetime, the total cost of re-treatment with 177Lu-DOTATATE was £79,433 versus £61,559 for no re-treatment. The total QALYs for re-treatment with 177Lu-DOTATATE vs. no re-treatment were 3.84 and 2.82, respectively. The incremental cost and QALY of re-treatment was £17,874 and 1.02, respectively. The ICER for re-treatment with 177Lu-DOTATATE vs. no re-treatment was £17,553. Number of re-treatment doses of 177Lu-DOTATATE was the key driver of model results. Re-treatment with 177Lu-DOTATATE seems a cost-effective option vs. no re-treatment.

Radiotherapy treatment of spinal metastases in Ibadan: A 9-year review

Background: Metastatic spinal tumors signify disease progression and result in poor quality of life of patients. We are likely to see an increasing burden of spinal metastases due to the global trend of increasing cancer survival. Objective: The objective of this study was to review the pattern of presentation and radiotherapy of metastatic spinal tumors in the Radiation Oncology Department, University College Hospital, Ibadan, Nigeria. Materials and Methods: The radiation therapy records of all patients who received spinal irradiation between January 2007 and December 2015 were retrieved. The extracted data are patients' sociodemographic, clinicopathologic, and treatment factors which include the radiation dose given and retreatment dose. Results: Majority (91.7%) of the patients who had radiotherapy to the spine had metastatic spinal tumors. Male patients accounted for 69.1% of the cases and females accounted for 30.1% resulting in a male–female ratio of 2.23:1. Close to half (45.8%) of the patients were elderly. Prostate cancer (57.3%) and breast cancer (18.8%) were the most common primary sites. The most common involved spinal site was the thoracic region. In all age groups, fewer patients received a short radiotherapy treatment course (totaling 15 Gy or less and within a duration of 1 week) versus long radiotherapy treatment course (other radiation schedules not meeting criteria for short). Conclusion: A high index of suspicion of metastatic spinal cancer is required, particularly for breast and prostate cancers. The authors recommend that more elderly patients should be treated with short-course radiotherapy.

Assessment of the alpha/beta ratio of the optic pathway to adjust hypofractionated stereotactic radiosurgery regimens for perioptic lesions

Hypofractionation has been recently considered as an alternative to improve stereotactic radiosurgery treatments of lesions close to the optic pathways. To estimate the intrinsic benefit from fractionation versus single-dose radiosurgery for perioptic lesions, the value of the alpha/beta ratio of the optic pathways needs to be known. Based on the linear quadratic (LQ) model, hypofractionation versus single-fraction SRS can be justified in cases where parts of the optic apparatus necessarily receive the full therapeutic peripheral dose, if there is a positive difference between α/s of the lesion and the α/s of the surrounding organs at risk. Furthermore, the knowledge of α/s ratios is required to calculate radiobiological dose parameters, such as the biologically effective dose (BED) and single fraction equivalent dose (SFED), and helps estimate normal tissue complication probability (NTCP), dose constraints, and retreatment doses. Only 3 alpha/beta ratios for the visual system have been published so far, varying between -0.6 and 3.06 Gy. The alpha/beta ratio of the optic pathways was estimated from a fraction equivalent plot based on a meta-analysis of 429 studies published between 2000 and June 2018. We included 15 studies with fraction sizes between 1 and 31, considering the following inclusion criteria: at least one well-documented RION case with detailed dosimetric analysis for the visual system, follow-up period (FUP) of at least 24 months, no tumor progression, no prior radiation. Additionally, we included results from our center on 68 hypofractionated treatments and 161 single-fraction SRS treatments for perioptic lesions. The fraction equivalent (FE) plot method revealed an alpha/beta ratio of the optic pathway of 1.03 Gy, confidence interval [-0.38–1.60]. Well-documented RION cases are rare in the literature; there is still not enough data to distinguish between alpha/beta ratios of the optic chiasm, the nerves, and the tracts. Optimized hypofractionation schedules were calculated for the treatment of meningiomas, chordomas, and brain metastases. Compared to single-fraction SRS, a significant intrinsic benefit from hypofractionation can be achieved, not only for perioptic malignant tumors, but for benign lesions as well, because of the very low alpha/beta ratio of the optic system of 1.03 Gy. An increased single fraction equivalent dose of up to 10% for perioptic meningiomas and of more than 25% for malignant tumors can be reached with optimized hypofractionated stereotactic radiosurgery schedules.

Challenges in the re-irradiation of locally advanced head and neck cancers: outcomes and toxicities

To retrospectively review outcomes and toxicities for patients with recurrent head and neck cancer (HNC) undergoing re-irradiation (re-RT). Retrospective review of oncologic outcomes and toxicity data from patients who received head and neck (HN) re-RT with curative intent using intensity-modulated radiation therapy (IMRT) from 2011 to 2016. Common toxicities were scored using Common Terminology Criteria for Adverse Events (CTCAE) V4. Treatment outcomes included progression-free survival (PFS), locoregional control (LRC), and overall survival (OS). Twenty-one patients with HNC were re-irradiated with curative intent. The median follow-up after re-RT was 27.8 months. The median retreatment dose was 66 Gy (range, 60–70), and the median retreatment volume was 194.1 cm3 (range, 52.4–1375.6). The median LRC, PFS, and OS were 10 months, 8.4 months, and 18.1 months, respectively. Patients treated with surgery as a component of primary HN cancer treatment had significantly worse PFS and OS when retreated compared with those initially treated with chemoradiation alone (p = 0.026 and p = 0.005, respectively). Those with stage IVA/B recurrent disease had worse LRC, PFS, and OS compared with stage II/III disease (p = 0.029, p = 0.049, and p = 0.020 respectively). Acute grade ≥ 3 toxicity and late grade ≥ 3 toxicity were 38% and 38%, respectively, with dysphagia being most common (24% acute and 14% late). Re-irradiation with IMRT for locally advanced HN recurrences either definitively or after salvage surgery is feasible, but treatment-related toxicity remains significant. Patients who received surgery as a component of their initial treatment and those with more advanced stage disease may be more difficult to salvage with re-irradiation.

Spinal cord re-treatments using photon and proton based radiotherapy: LQ-derived tolerance doses

Re-treatment, using megavoltage photon radiotherapy, can benefit carefully selected patients with new or recurrent tumours. Such re-treatments may involve the further exposure of tissues such as the brain or spinal cord.A time-dependent model has been developed, which incorporates data from all published radiobiological experiments concerned with the in vivo re-irradiation of the spinal cord using photons. It allows an estimation of the increasing recovery in tissue tolerance with elapsed time after the initial treatment course. In accordance with the experimental evidence, the recovery rate depends on the biological effective dose (BED) of the initial treatment. Various degrees of conservatism have been introduced in the model to allow for potential changes in CNS tissue tolerance due to patient age, chemotherapy, surgery etc.An estimation of the re-treatment dose-fractionation schedule is made easier by the use of a downloadable Graphical User Interface (GUI). Worked examples of its use are given forconventional photon (X-ray) based treatments, and also for protons, where relative biological effectiveness (RBE) considerations must be respected within the BED estimates. The model provides boundary conditions for clinical practice. The responsible clinician can choose to usemore ‘forgiving’ BED values and from this to calculate the re-irradiation dose-fractionation schedule.For protons, greater care is required sincethe inter-relationship between linear energy transfer (LET) and RBE can lead to significant over-dosage relative to accepted CNS tolerance doses, especially with the use of scanned proton beams. LET and RBE factors are important in order to deliver safe and effective re-treatment doses.

Changes in the retreatment radiation tolerance of the spinal cord with time after the initial treatment

Purpose: To estimate, from experimental data, the retreatment radiation ‘tolerances’ of the spinal cord at different times after initial treatment.Materials and methods: A model was developed to show the relationship between the biological effective doses (BEDs) for two separate courses of treatment with the BED of each course being expressed as a percentage of the designated ‘retreatment tolerance’ BED value, denoted and . The primate data of Ang et al. (2001) were used to determine the fitted parameters. However, based on rodent data, recovery was assumed to commence 70 days after the first course was complete, and with a non-linear relationship to the magnitude of the initial BED (BEDinit).Results: The model, taking into account the above processes, provides estimates of the retreatment tolerance dose after different times. Extrapolations from the experimental data can provide conservative estimates for the clinic, with a lower acceptable myelopathy incidence. Care must be taken to convert the predicted value into a formal BED value and then a practical dose fractionation schedule.Conclusions: Used with caution, the proposed model allows estimations of retreatment doses with elapsed times ranging from 70 days up to three years after the initial course of treatment.

POSSIBILITIES OF REIRRADIATION IN PATIENTS WITH RECURRENT SQUAMOUS CELL CARCINOMA OF HEAD AND NECK

Locoregional recurrence is the most frequent cause of death of patients with SCCHN. At present day clear guidance on the irradiation volume, total dose and timing of radiation re-treatment of these patients are missing. 20 patients with histologically confirmed locoregional recurrence of HNSCC, received reirradiation. Median time after primary radiotherapy course was 37 months. The treatment volumes and total doses were formed as follows: GTV (primary lesion and involved lymph nodes, delineated on CT, MRI and 18 F-FDG PET-CT)+CTV (0,5–1,0 cm) + PTV (0,3–0,5 cm) was treated to the total dose equivalent to 66–70 Gy of conventional fractionation, the upper neck (if indicated, levels I–III+PTV 0,5 cm) to 60 Gy, the lower neck (if indicated, levels IV–V+PTV 0,5 cm) — equivalent to 50 Gy. Single doses to these volumes were 2,14–2,21 Gy, 2,0 Gy and 1,8 Gy, respectively. Treatment was planned using IMRT and VMAT techniques with SIB (Simultaneously Integrated Boost). Daily positioning inaccuracy was less than 3 mm at lymph nodes PTV and less than 1 mm in OARs of CNS and optic pathways. 19 of 20 patients received full course of radiation therapy without a break. Radiation toxicity manifested with grade 2 oral and pharyngeal mucositis and grade 2 radiation epidermitis. Relief time of radiation mucositis and dermatitis was the same to primary radiotherapy course. Oneyear OS was 48%. Using technique of SIB with IMRT and VMAT during curative reirradiation of recurrent HNSCC is available with maintaining satisfactory tolerability.

Phase I/II trial evaluating concurrent carbon-ion radiotherapy plus chemotherapy for salvage treatment of locally recurrent nasopharyngeal carcinoma

BackgroundAfter definitive chemoradiotherapy for non-metastatic nasopharyngeal carcinoma (NPC), more than 10% of patients will experience a local recurrence. Salvage treatments present significant challenges for locally recurrent NPC. Surgery, stereotactic ablative body radiotherapy, and brachytherapy have been used to treat locally recurrent NPC. However, only patients with small-volume tumors can benefit from these treatments. Re-irradiation with X-ray—based intensity-modulated radiotherapy (IMXT) has been more widely used for salvage treatment of locally recurrent NPC with a large tumor burden, but over-irradiation to the surrounding normal tissues has been shown to cause frequent and severe toxicities. Furthermore, locally recurrent NPC represents a clinical entity that is more radio-resistant than its primary counterpart. Due to the inherent physical advantages of heavy-particle therapy, precise dose delivery to the target volume(s), without exposing the surrounding organs at risk to extra doses, is highly feasible with carbon-ion radiotherapy (CIRT). In addition, CIRT is a high linear energy transfer (LET) radiation and provides an increased relative biological effectiveness compared with photon and proton radiotherapy. Our prior work showed that CIRT alone to 57.5 GyE (gray equivalent), at 2.5 GyE per daily fraction, was well tolerated in patients who were previously treated for NPC with a definitive dose of IMXT. The short-term response rates at 3–6 months were also acceptable. However, no patients were treated with concurrent chemotherapy. Whether the addition of concurrent chemotherapy to CIRT can benefit locally recurrent NPC patients over CIRT alone has never been addressed. It is possible that the benefits of high-LET CIRT may make radiosensitizing chemotherapy unnecessary. We therefore implemented a phase I/II clinical trial to address these questions and present our methodology and results.Methods and designThe maximal tolerated dose (MTD) of re-treatment using raster-scanning CIRT plus concurrent cisplatin will be determined in the phase I, dose-escalating stage of this study. CIRT dose escalation from 52.5 to 65 GyE (2.5 GyE × 21–26 fractions) will be delivered, with the primary endpoints being acute and subacute toxicities. Efficacy in terms of overall survival (OS) and local progression-free survival of patients after concurrent chemotherapy plus CIRT at the determined MTD will then be studied in the phase II stage of the trial. We hypothesize that CIRT plus chemotherapy can improve the 2-year OS rate from the historical 50% to at least 70%.ConclusionsRe-treatment of locally recurrent NPC using photon radiation techniques, including IMXT, provides moderate efficacy but causes potentially severe toxicities. Improved outcomes in terms of efficacy and toxicity profile are expected with CIRT plus chemotherapy. However, the MTD of CIRT used concurrently with cisplatin-based chemotherapy for locally recurrent NPC remains to be determined. In addition, whether the addition of chemotherapy to CIRT is needed remains unknown. These questions will be evaluated in the dose-escalating phase I and randomized phase II trials.

Stereotactic Body Radiation Therapy as Salvage for Intrathoracic Recurrence in Patients With Previously Irradiated Locally Advanced Non–Small Cell Lung Cancer

The purpose of this study is to provide data on the outcomes of using stereotactic body radiotherapy (SBRT) as a means of salvage for non-small cell lung cancer (NSCLC) relapses previously treated with radiation. The records of 128 consecutive patients treated with thoracic SBRT from 2009 through 2012 were retrospectively reviewed. Twenty-seven patients (29 lesions) treated with prior thoracic radiation for stage IIB-IIIB NSCLC with subsequent recurrences and retreated with SBRT were identified. The median prior radiation dose was 64.8 Gy (range, 45 to 74 Gy) with a median retreatment dose of 50 Gy (range, 30 to 54 Gy), corresponding to a biological equivalent dose of 100 Gy (range, 48 to 151 Gy), at a median time of 13.4 months from prior radiation. The mean follow-up after salvage SBRT was 22 months. Local failure following salvage was 11%, nodal failure was 37%, and distant failure was 30%. The local recurrence-free survival at 2 years was 72%. Out-of-field failure was predictive for worse local control (hazard ratio, 47.38; 95% confidence interval, 5.795-64.899). Progression-free survival at 1 year was 55% and 38% at 2 years. Overall survival at 2 years from SBRT salvage was 79%. Salvage biological equivalent dose ≥100 Gy was predictive of improved progression-free survival (48% vs. 18%, P=0.021) and overall survival (91% vs. 52%, P=0.004) at 2 years. The rate of symptomatic pneumonitis was 63% and chest wall pain reported was 26%. We observed improved outcomes following SBRT as a means of salvage for locally advanced recurrent NSCLC over traditional radiation therapy options. The toxicities were greater than expected from naive lung irradiation, but the adverse effects remained controlled with medications.