Angela Paul

Histology of non-small cell lung cancer predicts the response to stereotactic body radiotherapy

BACKGROUND AND PURPOSEnTo investigate the prognostic impact of different histological subtypes of non-small cell lung cancer (NSCLC) on outcome following stereotactic body radiotherapy (SBRT) for NSCLC patients.nnnMATERIALS AND METHODSnWe analyzed 126 consecutive patients with early-stage adenocarcinoma or squamous cell carcinoma treated with SBRT from 2004 to 2016. Adenocarcinoma patients were further sub-classified as high-risk or low-risk tumors.nnnRESULTSnWith a median follow-up time of 22months, 2-year overall survival (OS), local (LC), and distant control (DC) were 68%, 90% and 79%, respectively. For LC, histologic subtype was identified as major independent prognostic factor (p=0.033): while LC was 81% for squamous cell carcinoma patients, LC was significantly improved for high-risk and even more non-high-risk adenocarcinoma patients with 96% and 100%, respectively (p=0.026). The negative prognostic impact of the histologic subtype squamous cell carcinoma was not evident when patients received SBRT with higher total doses in EQD2 (2Gy equivalent dose): if patients were treated with a total dose in EQD2≥150Gy, no significant difference in LC for histologic subtypes was detected anymore (p=0.355).nnnCONCLUSIONnIn the current study, histologic subtypes of NSCLC predicted local control probabilities following SBRT. Prospective, multi-center studies are needed to evaluate the prognostic impact of histology and consecutively the need for SBRT dose adaptation.

Sequential proton boost after standard chemoradiation for high-grade glioma

PURPOSEnTo retrospectively assess the feasibility and safety of a sequential proton boost following conventional chemoradiation in high-grade glioma (HGG).nnnMETHOD AND MATERIALSnSixty-six consecutive patients with HGG were treated with 50.0u202fGy photons (50.0-50.4u202fGy) in 2.0u202fGy (1.8-2.0u202fGy) fractions, followed by a proton boost with 10u202fGy equivalent (Gy(RBE)) in 2.0 Gy(RBE) fractions. Patients were matched one to one with 66 patients with HGG undergoing conventional radiation therapy (RT) with 60.0u202fGy photons (59.4-60.0u202fGy) in 2.0u202fGy fractions (1.8-2.0u202fGy). Matching criteria were age, WHO grade, Karnofskys performance status, PTV size, temozolomide therapy (each pu202f>u202f0.1). The study assessed progression-free survival (PFS), overall survival (OS), acute treatment-related toxicity (CTCAE v.4.03) and pseudoprogression (RANO criteria).nnnRESULTSnMedian PFS and OS were similar in both treatment groups (bimodality RT, PFS: 8.8u202fmonths [2-32u202fmonths], OS 19.1u202fmonths [4-41u202fmonths]; photon-only RT, PFS: 7.2u202fmonths [2-39u202fmonths], 20.9u202fmonths [3-53u202fmonths]; pu202f=u202f0.430 and pu202f=u202f0.125). The median PTV of the proton boost was significantly smaller than the photon plan PTVs (each pu202f<u202f0.001). Acute toxicity was mild. Toxicity ≥grade 2 was observed in 6 patients (9%) receiving bimodality RT and 9 patients (14%) receiving photon-only RT. Two types of severe adverse events (CTCAE grade 3) occurred solely in the photon-only group: severe increase in intracranial pressure (5%); and generalized seizures (3%). Pseudoprogression was rare, occurring on average 6u202fweeks after radiotherapy, and was balanced in both treatment groups (nu202f=u202f4 each; 8%).nnnCONCLUSIONnDelivering a proton boost to significantly smaller target volumes when compared to photon-only plans, yielded comparable progression and survival rates at lower CTCAE grade 3 acute toxicity rates. Pseudoprogression occurred rarely and evenly distributed in both treatment groups. Thus, bimodality RT was at least equivalent regarding outcome and potentially superior with respect to toxicity in patients with HGG.nnnSUMMARYnTreating patients with HGG with 50.0u202fGy photons in 2.0u202fGy fractions, followed by a proton boost with 10u202fGy(RBE) in 2.0u202fGy(RBE) fractions, is safe and feasible. Severe radiation-induced acute toxicity and pseudoprogression were rare in both treatment groups. Therefore, in this clinical setting, combined proton radiotherapy might be beneficial in terms of further risk reduction for treatment-related side effects. Interestingly, treatment volume reduction using a proton boost led to comparable survival and progression rates with decreased severe treatment-related toxicity compared to conventional photon radiotherapy.

Whole brain radiation therapy alone versus radiosurgery for patients with 1–10 brain metastases from small cell lung cancer (ENCEPHALON Trial): study protocol for a randomized controlled trial

BackgroundConventional whole brain radiotherapy (WBRT) has been established as the treatment standard in patients with cerebral metastases from small-cell lung cancer (SCLC), however, it has only modest efficacy and limited prospective data is available for WBRT as well as local treatments such as stereotactic radiosurgery (SRS).Methods/designThe present single-center prospective randomized study, conducted at Heidelberg University Hospital, compares neurocognitive function, as objectively measured by significant deterioration in Hopkins Verbal Learning Test – Revised total recall at 3xa0months. Fifty-six patients will be randomized to receive either SRS of all brain metastases (up to ten lesions) or WBRT. Secondary endpoints include intracranial progression (local tumor progression and number of new cerebral metastases), extracranial progression, overall survival, death due to brain metastases, local (neurological) progression-free survival, progression-free survival, changes in other cognitive performance measures, quality of life and toxicity.DiscussionRecent evidence suggests that SRS might be a promising treatment option for SCLC patients with brain metastases. The present trial is the first to prospectively investigate the treatment response, toxicity and neurocognition of WBRT and SRS in SCLC patients.Trial registrationClinicaltrials.gov NCT03297788. Registered September 29, 2017.

Robotic Radiosurgery for Brain Metastases Diagnosed With Either SPACE or MPRAGE Sequence (CYBER-SPACE)—A Single-Center Prospective Randomized Trial

BACKGROUNDnStereotactic radiosurgery (SRS) of brain metastases (BM) is recommended in oligometastatic scenarios as a less toxic treatment alternative to whole-brain radiotherapy. Recent findings support SRS for patients with multiple (>3) BM. Furthermore, advances in MR imaging have facilitated the detection of very small BM, as advances in SRS technology have facilitated the highly conformal and simultaneous treatment of multiple target lesions.nnnOBJECTIVEnTo compare efficacy and toxicity of repeated frameless robotic SRS of up to 10 simultaneous BM through a single-center prospective randomized trial.nnnMETHODSnTwo hundred patients will be randomized and receive imaging and treatment based on either the highly sensitive SPACE (sampling perfection with application optimized contrasts using different flip angle evolution) or the MPRAGE (magnetization-prepared rapid gradient-echo) magnetic resonance imaging sequence. If during follow-up new metastases are detected, treatment is repeated. The primary endpoint is reached when a patient develops more than 10 simultaneous new BM and is thus deemed unsuitable for further SRS. Overall survival will be assessed as secondary endpoint. Quality of life and neurocognition will be evaluated every 3 mo using CANTAB tests and EORTC (European Organisation for Research and Treatment of Cancer) questionnaires.nnnEXPECTED OUTCOMESnWe expect to show that repeated SRS based on sensitive imaging can delay intracranial dissemination while preserving neurocognitive function and quality of life.nnnDISCUSSIONnThe present study is the first to prospectively assess the benefit of sensitive imaging and repeated stereotactic irradiation in the treatment of patients with multiple BM. It represents a novel approach, where in a palliative setting advanced technology in treatment and diagnostics is employed to improve tumor control while also reducing toxicity and preserving quality of life.

Evaluation of Stereotactic Radiotherapy of the Resection Cavity After Surgery of Brain Metastases Compared to Postoperative Whole-Brain Radiotherapy (ESTRON)—A Single-Center Prospective Randomized Trial

BACKGROUNDnNeurosurgical resection is recommended for symptomatic brain metastases, in oligometastatic patients or for histology acquisition. Without adjuvant radiotherapy, roughly two-thirds of the patients relapse at the resection site within 24 mo, while the risk of new metastases in the untreated brain is around 50%. Adjuvant whole-brain radiotherapy (WBRT) can reduce the risk of both scenarios of recurrence significantly, although the associated neurocognitive toxicity is substantial, while stereotactic radiotherapy (SRT) improves local control at comparably low toxicity.nnnOBJECTIVEnTo compare locoregional control and treatment-associated toxicity for postoperative SRT and WBRT after the resection of 1 brain metastasis in a single-center prospective randomized study.nnnMETHODSnFifty patients will be randomized to receive either hypofractionated SRT of the resection cavity and single- or multisession SRT of all unresected brain metastases (up to 10 lesions) or WBRT. Patients will be followed-up regularly and the primary endpoint of neurological progression-free survival will be assessed by magnetic resonance imaging (MRI). Quality of life and neurocognition will be assessed in 3-mo intervals using standardized tests and EORTC questionnaires.nnnEXPECTED OUTCOMESnWe expect to show that postoperative SRT of the resection cavity and further unresected brain metastases is a valid means of improving locoregional control over observation at less neurocognitive toxicity than caused by WBRT.nnnDISCUSSIONnThe present study is the first to compare locoregional control as well as neurocognitive toxicity for postoperative SRT and WBRT in patients with up to 10 metastases, while utilizing a highly sensitive and standardized MRI protocol for treatment planning and follow-up.

Parenchymal and Functional Lung Changes after Stereotactic Body Radiotherapy for Early-Stage Non-Small Cell Lung Cancer—Experiences from a Single Institution

Introduction This study aimed to evaluate parenchymal and functional lung changes following stereotactic body radiotherapy (SBRT) for early-stage non-small cell lung cancer (NSCLC) patients and to correlate radiological and functional findings with patient and treatment characteristics as well as survival. Materials and methods Seventy patients with early-stage NSCLC treated with SBRT from 2004 to 2015 with more than 1u2009year of CT follow-up scans were analyzed. Incidence, morphology, severity of acute and late lung abnormalities as well as pulmonary function changes were evaluated and correlated with outcome. Results Median follow-up time was 32.2u2009months with 2-year overall survival (OS) of 83% and local progression-free survival of 88%, respectively. Regarding parenchymal changes, most patients only developed mild to moderate CT abnormalities. Mean ipsilateral lung dose (MLD) in biological effective dose and planning target volume size were significantly associated with maximum severity score of parenchymal changes (pu2009=u20090.014, pu2009<u20090.001). Furthermore, both maximum severity score and MLD were significantly connected with OS in univariate analysis (pu2009=u20090.043, pu2009=u20090.025). For functional lung changes, we detected significantly reduced total lung capacity, forced expiratory volume in 1u2009s, and forced vital capacity (FVC) parameters after SBRT (pu2009≤u20090.001). Multivariate analyses revealed SBRT with an MLDu2009≥u20099.72u2009Gy and FVC reduction ≥0.54u2009L as independent prognostic factors for inferior OS (pu2009=u20090.029, pu2009=u20090.004). Conclusion SBRT was generally tolerated well with only mild toxicity. For evaluating the possible prognostic impact of MLD and FVC reduction on survival detected in this analysis, larger prospective studies are truly needed.

Treatment planning for MLC based robotic radiosurgery for brain metastases: plan comparison with circular fields and suggestions for planning strategies

Abstract To evaluate the possible range of application of the new InCise2 MLC for the CyberKnife M6 system in brain radiosurgery, a plan comparison was made for 10 brain metastases sized between 1.5 and 9cm3 in 10 patients treated in a single fraction each. The target volumes consist of a PTV derived by expanding the GTV by 1mm and were chosen to have diversity in the cohort regarding regularity of shape, location and the structures needed to be blocked for beam transmission in the vicinity. For each case, two treatment plans were optimized: one using the MLC and one using the IRIS-collimator providing variable circular fields. Plan re-quirements were: dose prescription to the 70% isodose line (18 or 20Gy), 100% GTV coverage, ≥98% PTV coverage, undisturbed central high dose region (95% of maximum dose) and a conformity index as low as possible. Plan com-parison parameters were: conformity index (CI), high-dose gradient index (GIH), low-dose gradient index (GIL), total number of monitor units (MU) and expected treatment time (TT). For all cases, clinically acceptable plans could be gen-erated with the following results (mean±SD) for CI, GIH, GIL, MU and TT, respectively for the MLC plans: 1.09±0.03, 2.77±0.26, 2.61±0.08, 4514±830MU and 27±5min and for the IRIS plans: 1.05±0.01, 3.00±0.35, 2.46±0.08, 8557±1335MU and 42±7min. In summary, the MLC plans were on average less conformal and had a shallower dose gradient in the low dose region, but a steeper dose gradient in the high dose region. This is accompanied by a smaller vol-ume receiving 10Gy. A plan by plan comparison shows that usage of the MLC can spare about one half of the MUs and one third of treatment time. From these experiences and results suggestions for MLC planning strategy can be de-duced.