Optimal Fractionation Schedule Research Articles

The Quest for Optimal Fractionation Schedules in Stereotactic Radiotherapy.

In stereotactic radiotherapy (SRT), treatment with a single high dose is usually feasible as it spares the surrounding normal tissues, especially for intracranial lesions. However, single-fraction treatment may not be ideal in terms of efficacy. Single-dose treatment is particularly inefficient for tumors with hypoxia. Generally, tumors with a size of over 1 cm in diameter are considered to contain hypoxic cells, but the radioresistance of hypoxic cells can be partly overcome by fractionation owing to the reoxygenation of hypoxic tumor cells between fractions. In this article, we discuss the radiobiological characteristics of fractionated stereotactic irradiation (STI). And, based on our observations, we recommend that a dose of 54-60 Gy in six-eight fractions delivered two or three times a week for lung and other tumors larger than 2 cm in diameter is the ideal method of SRT.

Effect of heterogeneous radiosensitivity on the optimal fractionation in radiotherapy

Purposeto determine optimal fractionation schedule which provides maximum biologically effective dose (BED) in the targeted tumor in the case of heterogeneous radiosensitivity of malignant cells in combination with a spatially varying sparing factor for the organ at risk. Methodsthe mathematical framework used in the current study is based on the linear-quadratic (LQ) model with heterogeneous parameters alpha and beta for malignant cells. To determine optimal fractionation, we consider changes in BED in the treatment target (BEDtar) under the condition of fixed BED in the affected normal tissue (BEDnt). Resultswe demonstrate both analytically and via numerical calculations that there exists an optimal number of fractions for which biologically effective dose in the uniformly irradiated target is at maximum. It is also shown that dependence of BEDtar on number of fractions is generally non-monotonic and is affected by the variances σα and σβ of the alpha and beta radiosensitivities, respectively. In a particular case when σα and σβ are sufficiently small, expression for the optimal target dose which maximizes BEDtar was derived analytically. Conclusionthe obtained results demonstrate that in the presence of heterogeneous alpha and beta in the tumor, hypofractionation can either increase or decrease BEDtar depending on the variances σα and σβ. Consequently, intratumor heterogeneity is an important factor which can affect radiobiological comparison of different fractionation regimens.

Thoracic radiotherapy for extensive-stage small-cell lung cancer: what is the optimal dose and timing?

Small-cell lung cancer (SCLC) is a neuroendocrine tumor that represents about 12–20% of all lung cancers. Most of the SCLC patients present with extensive-stage (ES) disease. Primary therapy for ES-SCLC is 4–6 cycles of platinum-based chemotherapy (CT) followed by prophylactic cranial irradiation (PCI) in selected cases. Although the response rate to CT is approximately 60–70%, median survival times are very limited. The main problem of ES-SCLC patients after CT is intra-thoracic tumor recurrence since 75% of the patients had persisting intra-thoracic disease after CT, and approximately 90% of the patients had intra-thoracic progressive disease within the first year after diagnosis. Such high rate of intra-thoracic disease progression explains the need of local treatment in selected patients. There are three randomized studies and two meta-analyses evaluating the role of thoracic radiotherapy (TRT) in patients with ES-SCLC who responded to CT. Two of the randomized trials and one of the meta-analyses showed survival benefit of TRT. According to the results of relevant studies, the patients who responded to CT and have intra-thoracic residual disease after CT, who had limited metastatic sites (≤ 2), and who have good performance status and limited weight loss have more benefit from TRT. We need novel studies evaluating the optimal dose fractionation schedules, optimal timing of RT, impact of time interval between RT and CT, immunotherapy and RT combinations, and number of CT cycles.

Single-fraction stereotactic versus standard conventional multifraction radiation for predominantly non-spine bone metastases: A randomized phase II trial.

11578 Background: There lacks a consensus as to the optimal radiotherapy dose and fractionation schedule for treating bone metastases. We assessed the relative efficacy of single high-dose stereotactic radiation therapy (SBRT) versus standard multifraction radiation therapy (MFRT) for alleviation of pain in patients with mostly non-spine bone metastases. Methods: This prospective, randomized, single-institution phase II non-inferiority trial enrolled patients with radiologically confirmed painful bone metastases from September 2014 through June 2018. Patients were randomly assigned in a 1:1 ratio to receive either single-fraction SBRT (12 Gy for ≥4-cm lesions or 16 Gy for < 4-cm lesions) versus MFRT to 30 Gy in 10 fractions. Results: The primary endpoint was pain response, defined by international consensus criteria as a combination of pain score and analgesic use (daily morphine-equivalent dose [MED]). Failure of pain response was defined as worsening pain score (≥2 points on a 0-to-10 scale), an increase in morphine-equivalent opioid dose of ≥50%; re-irradiation; or pathologic fracture. Among evaluable patients who received treatment per protocol, the single-fraction SBRT group had more pain responders (CR+PR) at 2 weeks (62% vs. 36% MFRT, P= 0.01), at 1 month (62% vs 36%, P= 0.01), at 3 months (72% vs. 49% MFRT, P= 0.03), and at 9 months (77% vs. 12% MFRT, P= 0.03). No differences were found in treatment-related toxicity or quality of life scores after SBRT versus MFRT; local control rates at 1 year were higher in patients receiving single-fraction SBRT. Conclusions: Delivering high-dose single-fraction SBRT is an effective, convenient treatment option for patients with painful bone metastases. Among evaluable patients, SBRT led to higher rates of pain response (CR+PR) than did MFRT and thus should be considered for patients expected to have relatively long survival. Clinical trial information: ClinicalTrials.gov ID NCT02163226.

Single-Fraction Stereotactic vs Conventional Multifraction Radiotherapy for Pain Relief in Patients With Predominantly Nonspine Bone Metastases

Consensus is lacking as to the optimal radiotherapy dose and fractionation schedule for treating bone metastases. To assess the relative efficacy of high-dose, single-fraction stereotactic body radiotherapy (SBRT) vs standard multifraction radiotherapy (MFRT) for alleviation of pain in patients with mostly nonspine bone metastases. This prospective, randomized, single-institution phase 2 noninferiority trial conducted at a tertiary cancer care center enrolled 160 patients with radiologically confirmed painful bone metastases from September 19, 2014, through June 19, 2018. Patients were randomly assigned in a 1:1 ratio to receive either single-fraction SBRT (12 Gy for ≥4-cm lesions or 16 Gy for <4-cm lesions) or MFRT to 30 Gy in 10 fractions. The primary end point was pain response, defined by international consensus criteria as a combination of pain score and analgesic use (daily morphine-equivalent dose). Pain failure (ie, lack of response) was defined as worsening pain score (≥2 points on a 0-to-10 scale), an increase in morphine-equivalent opioid dose of 50% or more, reirradiation, or pathologic fracture. We hypothesized that SBRT was noninferior to MFRT. In this phase 2 noninferiority trial of 96 men and 64 women (mean [SD] age, 62.4 [10.4] years), 81 patients received SBRT and 79 received MFRT. Among evaluable patients who received treatment per protocol, the single-fraction group had more pain responders than the MFRT group (complete response + partial response) at 2 weeks (34 of 55 [62%] vs 19 of 52 [36%]) (P = .01), 3 months (31 of 43 [72%] vs 17 of 35 [49%]) (P = .03), and 9 months (17 of 22 [77%] vs 12 of 26 [46%]) (P = .03). No differences were found in treatment-related toxic effects or quality-of-life scores after SBRT vs MFRT; local control rates at 1 and 2 years were higher in patients receiving single-fraction SBRT. Delivering high-dose, single-fraction SBRT seems to be an effective treatment option for patients with painful bone metastases. Among evaluable patients, SBRT had higher rates of pain response (complete response + partial response) than did MFRT and thus should be considered for patients expected to have relatively long survival. ClinicalTrials.gov identifier: NCT02163226.

Palliative thoracic radiotherapy near the end of life in lung cancer: A population-based analysis

ObjectivesPalliative thoracic radiotherapy (RT) can improve quality of life for patients with advanced lung cancer, but treatment can be associated with acute toxicity and symptomatic relief may take several weeks. The optimal fractionation schedule is not known. Delivery of RT near the end of life (EOL) is an emerging indicator of poor quality care. The aim of this study was to determine utilization of palliative thoracic RT in the last 4 weeks of life, and factors associated with its use, in patients with incurable lung cancer in a population-based healthcare system. Materials and methodsAll patients with lung cancer in British Columbia treated with palliative thoracic RT in 2014 and 2015 were identified. Associations between starting a course of palliative thoracic RT within 4 weeks of death and patient/treatment characteristics were assessed using univariate and multivariate logistic regression analysis. Results1676 courses of palliative thoracic RT were delivered to 1584 lung cancer patients. Median survival was 20 weeks. 12% of palliative thoracic RT courses were delivered in the last 4 weeks of life, with short fractionation schedules and simple RT planning techniques used more frequently near EOL. Of RT courses delivered in the last 4 weeks of life 89% were courses of 1 – 5 fractions, 75% were completed as prescribed and 94% involved simple 1–2 field RT techniques. Receipt of RT in the last 4 weeks of life was associated with male gender, younger age, poor performance status, metastatic disease, small cell carcinoma histology and no prior chemotherapy. ConclusionFurther study and standardization of quality indicators for palliative RT utilization near EOL is required. Whilst clarification occurs, physicians should consider the prognosis of patients with incurable lung cancer and the realistic expectation of benefit from palliative thoracic RT when considering treatment indications and fractionation schedules.

A phase I dose-escalation trial of stereotactic ablative body radiotherapy for non-spine bone and lymph node metastases (DESTROY-trial)

BackgroundIn an oligometastatic setting, metastasis-directed treatment could render patients disease free, possibly for a protracted interval. Stereotactic ablative radiotherapy (SABR) is one of the treatment modalities that can be offered to these patients. In addition, the radiobiological qualities of SABR are promising for the use in perceived radioresistant tumours. There is also emerging evidence that SABR can stimulate the immune response, and a specific therapeutic window may exist for the optimal use of radiotherapy as an immune adjuvant. However, when SABR is considered for non-spine bone or lymph node metastases, the optimal fractionation schedule is not yet known.MethodsThe DESTROY-trial is a non-randomized prospective phase I trial determining a regimen of choice for patients with non-spine bone and lymph node metastases. A total of 90 patients will be included in three different treatment regimens. They will be offered stereotactic ablative radiotherapy in 5, 3 or 1 fractions. Dose-limiting toxicity will be recorded as primary endpoint. Acute and late toxicity, local response and local recurrence, and progression-free survival are secondary endpoints. Liquid biopsies will be collected throughout the course of this study from the second fractionation schedule on.DiscussionDespite its almost universal use in (oligo-)metastatic patients, the level of evidence supporting radical local treatment in general, and stereotactic radiotherapy in particular, is low. This prospective phase I trial will evaluate different SABR regimens for metastases and the differences in immune-stimulatory effects.Trial registrationThe Ethics committee of the GZA Hospitals (B099201732915) approved this study on 05/07/2017. Amendment for translational research was approved on 06/02/2018. Trial registered on Clinicaltrials.gov (NCT03486431) on 03/04/2018 – Retrospectively registered.

Hypo-fractionated stereotactic radiation therapy for lung malignancies by means of helical tomotherapy: report of feasibility by a single-center experience.

Several experiences in the literature report SBRT as an effective treatment option for medically inoperable early stage non-small cell lung cancer (NSCLC) and oligometastatic disease. The optimal fractionation schedules and total dose remain controversial. In this study, we evaluated the safety in terms of toxicity and efficacy of using of 8-10 fractions schedules with Helical Tomotherapy (HT) for primary and metastatic lung lesions. Between March 2014 and May 2016, a total of 39 patients (median age 72years, range 26-91) were treated with HT-SBRT for malignant lung lesions: 22 patients with early stage NSCLC, 17 with oligometastases. Patients received 8-10 fractions with lower daily dose for central and ultracentral lesions. Treatment-related toxicity was evaluated using CTCAE v 4.0 scale. Local control (LC), overall survival (OS) and toxicity rates were prospectively collected. Median duration of RT was 15days (range 10-26days) and no interruption occurred. With a median follow-up of 13months (range 3-29), we reported one G2 pneumonitis (2.6%) and one G2 chest pain (2.6%); no≥G2 esophagitis was registered. Actuarial local control rate was 95.5% both at 12 and 24months for early stage NSCLC and 92.9% both at 12 and 24months for metastatic patients. OS rate was 94.4 and 92.3% at 1year, and 94.4 and 83.9% at 2years in primary and metastatic group, respectively. The use of 8-10 fractions schedule HT-SBRT for lung malignancies results in high LC and OS rates with minimal toxicities reported.

Stereotactic spine radiosurgery: Review of safety and efficacy with respect to dose and fractionation.

Background:Stereotactic body radiotherapy (SBRT) is an emerging treatment option for spinal metastases with demonstrated efficacy in the upfront, postoperative, and re-treatment settings, as well as for tumor histologies considered radioresistant. Uncertainty exists regarding the optimal dose and fractionation schedule, with single and multifraction regimens commonly utilized.Methods:A literature search of the PubMed and Medline databases was conducted to identify papers specific to spine SBRT and the effect of varying dose/fractionation regimens on outcomes. Bibliographies of relevant papers were searched for further references, and international spine SBRT experts were consulted.Results:Local control rates generally exceed 80% at 1 year, while high rates of pain control have been attained. There is insufficient evidence to suggest superiority of either single or multiple fraction regimens with respect to local control and pain control. Low rates of toxicity have been reported, assuming strict dose constraints are respected. Radiation myelopathy may be the most morbid toxicity, although the rates are low. The risk of vertebral compression fracture appears to be associated with higher doses per fraction such as those used in single-fraction regimens. The Spinal Instability Neoplastic Score should be considered when evaluating patients for spine SBRT, and prophylactic stabilisation may be warranted. Pain flare is a relatively common toxicity which may be mediated with prophylactic dexamethasone. Because of the treatment complexity and potentially serious toxicities, strict quality assurance should occur at the organizational, planning, dosimetric, and treatment delivery levels.Conclusion:Both single and multifraction regimens are safe and efficacious in spine SBRT for spinal metastases. There may be advantages to hypofractionated treatment over single-fraction regimens with respect to toxicity. Ongoing investigation is underway to define optimal dose and fractionation schedules.

Consensus guidelines for postoperative stereotactic body radiation therapy for spinal metastases: results of an international survey.

OBJECTIVE Although postoperative stereotactic body radiation therapy (SBRT) for spinal metastases is increasingly performed, few guidelines exist for this application. The purpose of this study is to develop consensus guidelines to promote safe and effective treatment for patients with spinal metastases. METHODS Fifteen radiation oncologists and 5 neurosurgeons, representing 19 centers in 4 countries and having a collective experience of more than 1300 postoperative spine SBRT cases, completed a 19-question survey about postoperative spine SBRT practice. Responses were defined as follows: 1) consensus: selected by ≥ 75% of respondents; 2) predominant: selected by 50% of respondents or more; and 3) controversial: no single response selected by a majority of respondents. RESULTS Consensus treatment indications included: radioresistant primary, 1-2 levels of adjacent disease, and previous radiation therapy. Contraindications included: involvement of more than 3 contiguous vertebral bodies, ASIA Grade A status (complete spinal cord injury without preservation of motor or sensory function), and postoperative Bilsky Grade 3 residual (cord compression without any CSF around the cord). For treatment planning, co-registration of the preoperative MRI and postoperative T1-weighted MRI (with or without gadolinium) and delineation of the cord on the T2-weighted MRI (and/or CT myelogram in cases of significant hardware artifact) were predominant. Consensus GTV (gross tumor volume) was the postoperative residual tumor based on MRI. Predominant CTV (clinical tumor volume) practice was to include the postoperative bed defined as the entire extent of preoperative tumor, the relevant anatomical compartment and any residual disease. Consensus was achieved with respect to not including the surgical hardware and incision in the CTV. PTV (planning tumor volume) expansion was controversial, ranging from 0 to 2 mm. The spinal cord avoidance structure was predominantly the true cord. Circumferential treatment of the epidural space and margin for paraspinal extension was controversial. Prescription doses and spinal cord tolerances based on clinical scenario, neurological compromise, and prior overlapping treatments were controversial, but reasonable ranges are presented. Fifty percent of those surveyed practiced an integrated boost to areas of residual tumor and density override for hardware within the beam path. Acceptable PTV coverage was controversial, but consensus was achieved with respect to compromising coverage to meet cord constraint and fractionation to improve coverage while meeting cord constraint. CONCLUSIONS The consensus by spinal radiosurgery experts suggests that postoperative SBRT is indicated for radioresistant primary lesions, disease confined to 1-2 vertebral levels, and/or prior overlapping radiotherapy. The GTV is the postoperative residual tumor, and the CTV is the postoperative bed defined as the entire extent of preoperative tumor and anatomical compartment plus residual disease. Hardware and scar do not need to be included in CTV. While predominant agreement was reached about treatment planning and definition of organs at risk, future investigation will be critical in better understanding areas of controversy, including whether circumferential treatment of the epidural space is necessary, management of paraspinal extension, and the optimal dose fractionation schedules.

Local Control After Stereotactic Body Radiation Therapy for Early-Stage Non-Small Cell Lung Cancer: A Tale of 2 Schedules?

Stereotactic body radiation therapy (SBRT) for early-stage (T1-3, N0, and M0) non-small cell lung cancer (NSCLC) generally yields excellent local control rates. The optimal dose and fractionation schedule remains unknown, especially for the treatment of central tumors. At our institution, we typically treat early-stage NSCLC patients with 10-11 Gy x 5 fractions for central tumors and 18-20 Gy x 3 fractions for non-central tumors. We present our institutional experience with SBRT for early-stage NSCLC and examine if local control rates vary with SBRT schedule. We identified patients who were treated with SBRT for early-stage NSCLC between September 2009 and May 2015. Patients with T1-3, N0, M0 tumors were eligible. Patients with more advanced disease, lung nodules attributed to other diagnoses, or missing follow-up data were excluded. Actuarial local control rates and freedom from progression rates for the entire cohort and for subsets treated with 10-11 Gy x 5 (Schedule A) and 18-20 Gy x 3 (Schedule B) were calculated using the Kaplan-Meier method. Comparisons were made using log-rank testing. Toxicity grading was performed using Common Terminology Criteria for Adverse Events (CTCAE) or Radiation Therapy Oncology Group (RTOG) criteria. Sixty-one patients met all inclusion criteria. With a median follow-up of 15.0 months, four local failures were observed, and fifteen patients developed progressive disease. Actuarial local control rates at 1 and 2 years were 98% and 92%, respectively. Four out of 29 patients receiving Schedule A experienced local failure, compared to 0 out of 32 patients receiving Schedule B. The 2-year actuarial local control rate for patients treated with Schedule A was 83%, compared to 100% for patients treated with Schedule B (log-rank P=0.040). Actuarial freedom from progression rates at one and two years were 88% and 67%, respectively. The 2-year actuarial freedom from progression rate for patients treated with Schedule A was 64%, compared to 70% for patients treated with Schedule B (log-rank P=0.079). Mean tumor diameter was 2.5 cm for tumors treated with Schedule A and 1.9 cm for tumors treated with Schedule B (unpaired t-test P=0.011). No grade 3 or higher acute or late toxicities were observed. SBRT for early-stage NSCLC yields excellent rates of local control, with progression most often occurring at regional and/or distant sites. 10-11 Gy x 5 schedule and increased tumor size were associated with increased probability of local failure. Additional studies with higher numbers of local failures will be necessary to fully characterize the interplay between SBRT schedule and/or tumor size as predictive factors.

Radiobiology of hypofractionated stereotactic radiotherapy: what are the optimal fractionation schedules?

In hypofractionated stereotactic radiotherapy (SRT), high doses per fraction are usually used and the dose delivery pattern is different from that of conventional radiation. The daily dose is usually given intermittently over a longer time compared with conventional radiotherapy. During prolonged radiation delivery, sublethal damage repair takes place, leading to the decreased effect of radiation. In in vivo tumors, however, this decrease in effect may be counterbalanced by rapid reoxygenation. Another issue related to hypofractionated SRT is the mathematical model for dose evaluation and conversion. The linear–quadratic (LQ) model and biologically effective dose (BED) have been suggested to be incorrect when used for hypofractionation. The LQ model overestimates the effect of high fractional doses of radiation. BED is particularly incorrect when used for tumor responses in vivo, since it does not take reoxygenation into account. Correction of the errors, estimated at 5–20%, associated with the use of BED is necessary when it is used for SRT. High fractional doses have been reported to exhibit effects against tumor vasculature and enhance host immunity, leading to increased antitumor effects. This may be an interesting topic that should be further investigated. Radioresistance of hypoxic tumor cells is more problematic in hypofractionated SRT, so trials of hypoxia-targeted agents are encouraged in the future. In this review, the radiobiological characteristics of hypofractionated SRT are summarized, and based on the considerations, we would like to recommend 60 Gy in eight fractions delivered three times a week for lung tumors larger than 2 cm in diameter.

Real-time Tumor Oxygenation Changes After Single High-dose Radiation Therapy in Orthotopic and Subcutaneous Lung Cancer in Mice: Clinical Implication for Stereotactic Ablative Radiation Therapy Schedule Optimization

To investigate the serial changes of tumor hypoxia in response to single high-dose irradiation by various clinical and preclinical methods to propose an optimal fractionation schedule for stereotactic ablative radiation therapy. Syngeneic Lewis lung carcinomas were grown either orthotopically or subcutaneously in C57BL/6 mice and irradiated with a single dose of 15Gy to mimic stereotactic ablative radiation therapy used in the clinic. Serial [(18)F]-misonidazole (F-MISO) positron emission tomography (PET) imaging, pimonidazole fluorescence-activated cell sorting analyses, hypoxia-responsive element-driven bioluminescence, and Hoechst 33342 perfusion were performed before irradiation (day -1), at 6hours (day 0), and 2 (day 2) and 6 (day 6) days after irradiation for both subcutaneous and orthotopic lung tumors. For F-MISO, the tumor/brain ratio was analyzed. Hypoxic signals were too low to quantitate for orthotopic tumors using F-MISO PET or hypoxia-responsive element-driven bioluminescence imaging. In subcutaneous tumors, the maximum tumor/brain ratio was 2.87±0.483 at day -1, 1.67±0.116 at day 0, 2.92±0.334 at day 2, and 2.13±0.385 at day 6, indicating that tumor hypoxia was decreased immediately after irradiation and had returned to the pretreatment levels at day 2, followed by a slight decrease by day 6 after radiation. Pimonidazole analysis also revealed similar patterns. Using Hoechst 33342 vascular perfusion dye, CD31, and cleaved caspase 3 co-immunostaining, we found a rapid and transient vascular collapse, which might have resulted in poor intratumor perfusion of F-MISO PET tracer or pimonidazole delivered at day 0, leading to decreased hypoxic signals at day 0 by PET or pimonidazole analyses. We found tumor hypoxia levels decreased immediately after delivery of a single dose of 15Gy and had returned to the pretreatment levels 2days after irradiation and had decreased slightly by day 6. Our results indicate that singlehigh-dose irradiation can produce a rapid, but reversible, vascular collapse in tumors.

Single versus multiple session stereotactic body radiotherapy for spinal metastasis: the risk-benefit ratio.

Spine stereotactic body radiation therapy represents an important advancement in the management of spinal metastases that allows precise delivery of ablative doses of radiation therapy with excellent local control. Although the technique is being increasingly used in clinical practice, the optimal fractionation schedule remains uncertain. In this perspective paper, we review radiobiologic principles that support the use of multiple- versus single-fraction spine stereotactic body radiation therapy schedules and clinical data supporting the multiple-fraction approach. Specifically, we suggest that there may be a local control benefit of fractionation, while helping to limit the risk of toxicities such as vertebral body fracture, pain flare and radiation myelopathy. We conclude with future directions and the need for future study on this important topic.

Brachytherapy in lung cancer: a review

Metastatic non-small cell lung cancer (NSCLC) remains the leading cause of cancer death worldwide. Intraluminal brachytherapy (ILBT) has been shown to improve patients’ symptoms in some studies. However, its role in the palliation of these patients amidst the other local treatment modalities such as external beam radiotherapy (EBRT), laser and photodynamic therapy (PDT) remains unclear. We have completed a systematic review of the literature to evaluate outcomes of patients with lung cancer treated with ILBT alone and/or in combination with other treatment modalities. We have reviewed tumour and symptom response, overall survival (OS) and toxicities of patients treated with diverse fractionation schemes and those treated with a curative intent. Overall, ILBT is associated with improvement of patients’ symptoms in most cases. Its toxicity profile is generally low with small risk of fatal hemoptysis. Further studies are needed to establish an optimal fractionation schedule, although it appears that fractionated treatments (3 fractions) were associated with less toxicity yet similar symptom relief when compared to single fraction treatments. Caution must be taken when prescribing the dose to avoid necrosis and or fistula that may be lead to fatal hemoptysis.

Prognostic factors associated with pain palliation after spine stereotactic body radiation therapy.

OBJECT The number of patients with spinal tumors is rapidly increasing; spinal metastases develop in more than 30% of cancer patients during the course of their illness. Such lesions can significantly decrease quality of life, often necessitating treatment. Stereotactic radiosurgery has effectively achieved local control and symptomatic relief for these patients. The authors determined prognostic factors that predicted pain palliation and report overall institutional outcomes after spine stereotactic body radiation therapy (SBRT). METHODS Records of patients who had undergone treatment with SBRT for either primary spinal tumors or spinal metastases from June 2008 through June 2013 were retrospectively reviewed. Data were collected at the initial visit just before treatment and at 1-, 3-, 6-, and 12-month follow-up visits. Collected clinical data included Karnofsky Performance Scale scores, pain status, presence of neurological deficits, and prior radiation exposure at the level of interest. Radiation treatment plan parameters (dose, fractionation, and target coverage) were recorded. To determine the initial extent of epidural spinal cord compression (ESCC), the authors retrospectively reviewed MR images, assessed spinal instability according to the Bilsky scale, and evaluated lesion progression after treatment. RESULTS The study included 99 patients (mean age 60.4 years). The median survival time was 9.1 months (95% CI 6.9-17.2 months). Significant decreases in the proportion of patients reporting pain were observed at 3 months (p < 0.0001), 6 months (p = 0.0002), and 12 months (p = 0.0019) after treatment. Significant decreases in the number of patients reporting pain were also observed at the last follow-up visit (p = 0.00020) (median follow-up time 6.1 months, range 1.0-56.6 months). Univariate analyses revealed that significant predictors of persistent pain after intervention were initial ESCC grade, stratified by a Bilsky grade of 1c (p = 0.0058); initial American Spinal Injury Association grade of D (p = 0.011); initial Karnofsky Performance Scale score, stratified by a score of 80 (p = 0.002); the presence of multiple treated lesions (p = 0.044); and prior radiation at the site of interest (p < 0.0001). However, when multivariate analyses were performed on all variables with p values less than 0.05, the only predictor of pain at last follow-up visit was a prior history of radiation at the site of interest (p = 0.0038), although initial ESCC grade trended toward significance (p = 0.073). Using pain outcomes at 3 months, at this follow-up time point, pain could be predicted by receipt of radiation above a threshold biologically effective dose of 66.7 Gy. CONCLUSIONS Pain palliation occurs as early as 3 months after treatment; significant differences in pain reporting are also observed at 6 and 12 months. Pain palliation is limited for patients with spinal tumors with epidural extension that deforms the cord and for patients who have previously received radiation to the same site. Further investigation into the optimal dose and fractionation schedule are needed, but improved outcomes were observed in patients who received radiation at a biologically effective dose (with an a/b of 3.0) of 66.7 Gy or higher.

A model for effects of adaptive immunity on tumor response to chemotherapy and chemoimmunotherapy

Complete clinical regressions of solid tumors in response to chemotherapy are difficult to explain by direct cytotoxicity alone, because of low growth fractions and obstacles to drug delivery. A plausible indirect mechanism that might reconcile this is the action of the immune system. A model for interaction between tumors and the adaptive immune system is presented here, and used to examine controllability of tumors through the interplay of cytotoxic, cytostatic and immunogenic effects of chemotherapy and the adaptive immune response. The model includes cytotoxic and helper T cells, T regulatory cells (Tregs), dendritic cells, memory cells, and several key cytokines. Nearly all parameter estimates are derived from experimental and clinical data. Individual tumors are characterized by two parameters: growth rate and antigenicity, and regions of tumor control are identified in this parameter space. The model predicts that inclusion of the immune response significantly expands the region of tumor control for both cytostatic and cytotoxic chemotherapies. Moreover, outside the control zone, tumor growth is delayed significantly. An optimal fractionation schedule is predicted, for a fixed cumulative dose. The model further predicts expanded regions of tumor control when several forms of immunotherapy (adoptive T cell transfer, Treg depletion, and dendritic cell vaccination) are combined with chemotherapy. Outcomes depend greatly on tumor characteristics, the schedule of administration, and the type of immunotherapy chosen, suggesting promising opportunities for personalized medicine. Overall, the model provides insight into the role of the adaptive immune system in chemotherapy, and how scheduling and immunotherapeutic interventions might improve efficacy.

TH-AB-BRB-07: A Feasibility Study for Personalized Fractionation Schedule for Lung Cancer

Purpose: Investigate the feasibility of using spatio-temporal optimization, i.e., fractionation schedule optimization combined with IMRT to select the patient-specific fractionation schedule that best maximizes the tumor biologically equivalent dose (BED). Methods and materials: The optimal fractionation schedule for a patient depends on the tumor and organ at-risk (OAR) sensitivity to fraction size (i.e., α/β), the effective tumor doubling time, and the size and location of tumor target relative to one or more OAR. We used a novel spatio-temporal optimization method to identify the number of fractions N that maximizes the tumor BED using 3D BED distribution for sixteen lung phantom cases. The selection of the optimal fractionation schedule used equivalent 30-fraction OAR constraints for the heart (Dmean < 45 Gy), lungs (Dmean < 20 Gy), cord (Dmax < 45 Gy), esophagus (Dmax < 63 Gy), and unspecified tissues (D05 < 63 Gy). To asses plan quality, we considered the min, mean, max and D95 tumor BED and the equivalent uniform dose (EUD) for optimized plans to the corresponding BED values for a conventional IMRT plan (60 Gy in 30 fractions). A sensitivity analysis was performed to assess the effects on optimal fractionation schedule of the effective tumor doubling time (Td = 3–100 days) and lag-time for accelerated repopulation (Tk = 0 to 10 days) Results: For a tumor α/β = 10Gy, tumor max, min, mean, and D95 BED were about 20% larger than the BED for the conventional prescription. The EUD for the optimized fractionation schedule was up to 17% larger than conventional prescription. For fast proliferating tumor (Td < 10 days), there was no significant increase in tumor dose but the treatment course could be shortened, offering convenience for patients and efficient allocation of resources.

Comparison of radiation regimens in the treatment of Glioblastoma multiforme: results from a single institution

BackgroundThe optimal fractionation schedule of radiotherapy (RT) for Glioblastoma multiforme (GBM) is yet to be determined. We aim to compare different fractionation regimens and identify prognostic factors to better tailor RT for newly diagnosed GBM patients.MethodsAll data for patients who underwent surgery for GBM between January 2005 and December 2012 were compiled. Clinical information was collected using patient charts and government registry. Cox analysis was used to identify variables affecting survival and treatment outcome.ResultsThe median follow-up time was 13.2 months. Two hundred and seventy-six patients met the inclusion criteria, including 147 patients in the 60 Gy in 30 fractions (ConvRT) group, 86 patients in the 60 Gy in 20 fractions (HF60) group, and 43 patients in the 40 Gy in 15 fractions (HF40) group. Median survival (MS) was 16.0 months with a median progression-free survival (PFS) of 9.23 months in the ConvRT group. This was comparable to outcome in the HF60 group with MS 15.0 months and a median PFS of 9.1 months. Patients in the HF40 group had MS of 8 months, with a median PFS 5.4 months. Cox analysis showed no significant difference in OS between the ConvRT and HF60 groups but worse outcome in the HF40 group (HR 2.22, P = 0.04). MGMT methylation, extent of resection, use of chemotherapy, and repeat surgery were found to be significant independent prognostic factors for survival.ConclusionsHF60 constitutes a safe RT approach that shows survival comparable to standard RT while allowing for a shorter treatment time.

Adjuvant radiotherapy outcome of stage I testicular seminoma: a single institution study.

PurposeTo analyze treatment outcome and side effects of adjuvant radiotherapy using radiotherapy fields and doses which have evolved over the last two decades in a single institution.Materials and MethodsForty-one patients received radiotherapy after orchiectomy from 1996 to 2007. At our institution, the treatment field for stage I seminoma has changed from dog-leg (DL) field prior to 2003 to paraaortic (PA) field after 2003. Fifteen patients were treated with the classic fractionation scheme of 25.5 Gy at 1.5 Gy per fraction. Other patients had been treated with modified schedules of 25.05 Gy at 1.67 Gy per fraction (n=15) and 25.2 Gy at 1.8 Gy per fraction (n=11).ResultsWith a median follow-up of 112 months, the 5-year and 10-year survival rates were 100% and 96%, respectively, and 5-year and 10-year relapse-free survival rates were both 97.1%. No in-field recurrence occurred. Contralateral seminoma occurred in one patient 5 years after treatment. No grade III-IV acute toxicity occurred. An increased rate of grade 1-2 acute hematologic toxicity was found in patients with longer overall treatment times due to 1.5 Gy per fraction. The rate of grade 2 acute gastrointestinal toxicity was significantly higher with DL field than with PA field and also higher in the 1.8-Gy group than in the 1.5-Gy and 1.67-Gy groups.ConclusionPatients with stage I seminoma were safely treated with PA-only radiotherapy with no pelvic failure. Optimal fractionation schedule needs to be explored further in order to minimize treatment-related toxicity.