Serum CYFRA 21-1 Level as a Prognostic Marker for Extensive Disease Small Cell Lung Cancer.

BACKGROUND/AIM: Pretreatment serum cytokeratin 19 fragment (CYFRA21-1) level predicts outcomes in patients with non-small cell lung cancer; however, little is known about the clinical value of serum CYFRA21-1 level in patients with small cell lung cancer (SCLC). The aim of this study was to evaluate the prognostic value of pretreatment serum CYFRA21-1 level in patients with extensive disease (ED)-SCLC treated using platinum-doublet chemotherapy. PATIENTS AND METHODS: We retrospectively analyzed the pretreatment serum CYFRA21-1 levels of patients with ED-SCLC who were treated using first-line platinum-doublet chemotherapy. RESULTS: A total of 98 patients were analyzed. The patients with a high CYFRA21-1 level (≥7.0 ng/ml) (n=29) had significantly shorter progression-free survival (PFS) and overall survival (OS) than the patients with low CYFRA21-1 levels (n=67) [median PFS=118 days vs. 125 days, respectively (p=0.018); median OS=213 days vs. 295 days, respectively (p=0.046)]. In addition, high CYFRA21-1 level was associated with a high refractory relapse rate. CONCLUSION: Serum CYFRA21-1 level may be a prognostic marker for patients with ED-SCLC treated with platinum-doublet chemotherapy.

Five-Fraction Radiosurgery Using a Biologically Equivalent Dose of a Single Fraction of 24 Gy for a 3-cm Parasagittal Para-Central Sulcus Brain Metastasis From Adenocarcinoma of the Cecum.

An isolated single brain metastasis (BM) is an extremely rare manifestation of failure in patients with cecal adenocarcinoma (CAC). Total en bloc resection (while preserving function) of a 3-cm BM involving both the primary motor and sensory cortexes presents a conundrum: achieving long-term local control and safety of such a BM is also challenging for stereotactic radiosurgery (SRS). We describe the case of a 3.1-cm BM from CAC in the left parasagittal para-central sulcus region, which was treated using five-fraction SRS with a biologically effective dose (BED) of 81.6 Gy. In the SRS, the gross tumor volume (GTV, 7.14 cm3) was defined based on computed tomography (CT)/T1/T2 matching (enhancing lesion 11.66 cm3), and 98.7% of the GTV (CT/T2 mass) was covered with 43.6 Gy (58% isodose) using volumetric-modulated arcs. The maximum tumor response was partial (19.7% of the prior GTV) and sustained for 15.2 months, leaving minor neurological symptoms. However, the patient developed neurological worsening at six months, attributed to adverse radiation effects with a CT/T1/T2 mismatch, for which medical management, including the addition of bevacizumab (BEV), was effective for one year. Multi-fraction SRS with a high marginal and internal BED and sequential systemic therapy, including BEV, can be a minimally invasive, efficacious, and durable treatment option for a large CAC-BM involving the central sulcus. Early co-administration of BEV following SRS, dose escalation to the GTV boundary, and more than five fractions of SRS may be considered to improve the efficacy and safety further.

Nineteen-Month Immunity to Adverse Radiation Effects Following 5-Fraction Re-radiosurgery With 43.6 Gy for Local Progression After Prior 3-Fraction Radiosurgery for Brain Metastasis From Pan-Negative Lung Adenocarcinoma.

Clinical management of patients with local control failure following stereotactic radiosurgery (SRS) for brain metastasis (BM) can be frequently challenging. Re-irradiation with multi-fraction (fr) SRS by using a biological effective dose of ≥80 Gy, based on the linear-quadratic formula with an alpha/beta ratio of 10 (BED10), can be an efficacious option for such a scenario with the BED10 of <80 Gy. However, its long-term safety beyond one year remains unclear. In this report, we describe the case of a patient with a single metachronous BM from lung adenocarcinoma (LAC), without major genetic alterations, in which re-SRS with 43.6 Gy/5 fr (BED10 81.6 Gy) for local progression, following prior 3-fr SRS of the BM, resulted in sustained regression without any local adverse radiation effects (AREs) for 19 months. The BM with a gross tumor volume (GTV) of 1.12 cm3 in the left parietal lobe was initially treated with SRS of 27 Gy/3 fr (50% isodose). Despite steroid administration for nivolumab-induced bullous pemphigoid associated with transient elevation of tumor markers, the BM showed local progression with T1/T2 matching at 38.3 and eight months after SRS and discontinuation of nivolumab, respectively. In the 5-fr re-SRS, 99% of the GTV (1.18 cm3) was covered with 43.6 Gy (63% isodose). However, along with the thoracic disease progression, multiple new BMs developed 15.5 months after the re-SRS, for which volumetric-modulated arc-based whole brain radiotherapy (WBRT) was administered, with simultaneously integrated boosts to 17 lesions and moderate dose attenuation in the pre-irradiated region. However, concurrent administration of gemcitabine and WBRT might have led to persistent severe anorexia for 2.5 months. The patient died 10.8 years after the initial chemotherapy. The relatively small GTV with the superficial location may have rendered the re-irradiated region immune to AREs after the high BED10 re-SRS. Long-term survival can be achieved by chemoimmunotherapy in patients with pan-negative LAC, with limited systemic metastases who are unfit for targeted agents. Therefore, SRS for limited BMs in such scenarios should aim for complete local tumor eradication beyond a partial response in either a first-line or re-irradiation setting.

Volumetric-Modulated Arc-Based Re-radiosurgery With Simultaneous Reduced-Dose Whole-Brain Irradiation for Local Failures Following Prior Radiosurgery of Brain Oligometastases From Small Cell Lung Cancer.

First-line and possibly repeated stereotactic radiosurgery (SRS) with preserving whole-brain radiotherapy (WBRT) is an attractive and promising option for synchronous or metachronous limited brain metastases (BMs) from small cell lung cancer (SCLC), for which a modest prescription dose is generally preferred, such as a biological effective dose of ≤60 Gy, based on the linear-quadratic formula with an alpha/beta ratio of 10 (BED10). In addition, the optimal planning scheme for re-SRS for local progression after SRS of BMs from SCLC remains unclear. Herein, we describe a case of limited BMs developing after a partial response to standard chemoradiotherapy (CRT) for limited-stage SCLC. The BMs, including local failures following prior single-fraction (fr) SRS, were re-treated with volumetric-modulated arc-based SRS combined with simultaneous reduced-dose WBRT. The first SRS with 36.3 Gy/3 fr (BED10 80 Gy) for a small BM resulted in a local control of 17.2 months. However, the second SRS with 20 Gy/1 fr (BED10 60 Gy) to the 60% or 85% isodose surface (IDS) covering the gross tumor volume (GTV) of three new BMs with a paradoxical T1/T2 mismatch, that is, a visible mass on T2 larger than an enhancing area, resulted in partial symptomatic local progression of all lesions within 5.2 months, along with the development of two new lesions, despite continued amrubicin monotherapy. In contrast, the third SRS with 53 Gy/10 fr (BED10 81 Gy) to ≤74% IDSs encompassing the GTV boundary resulted in complete responses of all the lesions during six months. However, despite a combined use of WBRT of 25 Gy in the third SRS, symptomatic spinal cerebrospinal fluid dissemination and new BMs developed, the former leading to patient mortality. A BED10 of ≥80 Gy to the GTV margin and a steep dose increase inside the GTV boundary are suitable to ensure excellent local control in SRS for SCLC BMs. Re-SRS with the aforementioned scheme can be an efficacious option for local failures following prior SRS with a BED10 of ≤60 Gy. Modest dose escalation with a simultaneous integrated boost to bulky lesions in the initial CRT may reduce the development of new BM through improved control of the potential source.

Twenty-Month Regression Following Concurrent Conventional Whole-Brain Irradiation and Chemoimmunotherapy for ≥3.8 cm Cerebellar Metastasis From Small Cell Lung Cancer.

Standard whole-brain radiotherapy (WBRT) alone for large brain metastases (BMs) from small cell lung cancer (SCLC) has limited efficacy and durability, and stereotactic radiosurgery (SRS) alone for symptomatic posterior fossa BMs >3 cm with satellite lesions is challenging. Herein, we describe the case of a 73-year-old female presenting with treatment-naïve SCLC and 15 symptomatic multiple BMs, including a ≥3.8-cm cerebellar mass (≥17.7 cm3) and two adjacent lesions; otherwise, the SCLC was confined to the thorax. The patient was initially treated concurrently with conventional WBRT (30 Gy in 10 fractions) without boost and chemoimmunotherapy (CIT) consisting of carboplatin, etoposide, and atezolizumab. Atezolizumab was excluded during irradiation. Five months after WBRT, the large cerebellar lesion had remarkably regressed, and the smaller lesions (≤17 mm) showed complete responses (CRs) without local progression at 20 months. However, six and 16 months after WBRT, the thoracic lesions had progressed, and although amrubicin was administered, four new BMs, including pons involvement, had developed, respectively. Despite the CRs of the four BMs following SRS (49.6 Gy in eight fractions) and the sustained regression of the thoracic lesions, meningeal dissemination and multiple new BMs were evident 3.5 months post-SRS. The small remnant of the large BM and/or newly developed BMs abutting the cerebrospinal fluid (CSF) space could have led to CSF dissemination, the presumed cause of the patient's death. Taken together, concurrent chemo-WBRT and subsequent CIT can provide excellent and durable tumor responses for SCLC BMs, but may not be fully sufficient for BMs ≥3.8 cm. Therefore, in cases with large lesions, focal dose escalation of the large lesions, consolidative thoracic radiotherapy, and dose de-escalation in the macroscopically unaffected brain region may prevent or attenuate CSF dissemination, new BM development, and adverse effects and thus should be considered.

5-Fraction Re-radiosurgery for Progression Following 8-Fraction Radiosurgery of Brain Metastases From Lung Adenocarcinoma: Importance of Gross Tumor Coverage With Biologically Effective Dose ≥80 Gy and Internal Dose Increase.

The criteria for indication of salvage stereotactic radiosurgery (SRS) for local progression following multi-fraction (mf) SRS of brain metastases (BMs) remain controversial, along with the optimal planning scheme. Herein, we described a case of BMs from pan-negative lung adenocarcinoma (LAC), in which the two lesions of local progression following initial eight-fraction (8-fr) SRS were re-treated with 5-fr SRS with the biologically effective dose (BED10) of ≥80 Gy, based on the linear-quadratic (LQ) formula with an alpha/beta ratio of 10. The re-SRS resulted in the alleviation of symptoms and favorable tumor responses with minimal adverse effects during the 7.3-month follow-up. In the lesions of local progression, the gross tumor volume (GTV) coverage with 49.6 Gy (BED10 80 Gy) was generally insufficient, and the GTV dose wes relatively homogeneous with ≥87% isodose covering. In contrast, the 5-fr re-SRS was performed with sufficient GTV coverage with ≤68% isodose of 43 Gy (BED10 80 Gy). Taken together, sufficient GTV coverage with a BED10 of ≥80 Gy and steep dose increase inside the GTV boundary, that is, extremely inhomogeneous GTV dose, are important in 8-fr SRS for ensuring excellent local control of BMs from pan-negative LAC. For local progression following mfSRS that does not fulfill both criteria, re-SRS with the above planning scheme can be an efficacious and safe treatment option for at least six months, especially in cases in which the prior SRS was performed with a dose/fractionation under adequate consideration of brain tolerance. The BED10 seems to be the most suitable for estimating the anti-tumor efficacies of SRS doses in 3-8 fr, similar to that of a single fraction of 24 Gy.

Local Control Failure After Five-Fraction Stereotactic Radiosurgery Alone for Symptomatic Brain Metastasis From Squamous Cell Lung Carcinoma Despite 43 Gy to Gross Tumor Margin With Internal Steep Dose Increase and Tumor Shrinkage During Irradiation.

Five-fraction (fr) stereotactic radiosurgery (SRS) is increasingly being applied to large brain metastases (BMs) >2-3 cm in diameter, for which 30-35 Gy is the commonly prescribed dose. Since 2018, to further enhance both safety and efficacy, we have limited the five-fr SRS to approximately ≤3 cm BMs and adopted our own modified dose prescription and distribution: 43 and 31 Gy cover the boundaries of the gross tumor volume (GTV) and 2 mm outside the GTV, respectively, along with a steep dose increase inside the GTV boundary, that is, an intentionally very inhomogeneous GTV dose. Herein, we describe a case of symptomatic BM treated with five-fr SRS using the above policy, which resulted in a maximum tumor response with nearly complete remission (nCR) followed by gradual tumor regrowth despite obvious tumor shrinkage during irradiation. A 71-year-old man who had previously undergone surgery for squamous cell carcinoma (SCC) of the lungs presented with right-sided hemiparesis attributed to the para-falcine BM (27 mm in maximum diameter, 5.38 cm3). The BM was treated with five-fr SRS, with 99.2% of the GTV covered with 43 Gy and 59% isodose. Neurological symptoms improved during SRS, and obvious tumor shrinkage and mitigation of perilesional edema were observed upon completion of SRS. No subsequent anti-cancer pharmacotherapy was administered due to idiopathic pulmonary fibrosis (IPF). Despite a maximum response with nCR at four months, the tiny residual enhancing lesion gradually enlarged from 7.7 months to 22.7 months without neurological worsening. Although a consistent T1/T2 mismatch suggested the dominance of brain radionecrosis, 11C-methionine positron emission tomography showed increased uptake in the enhancing lesion. Pathological examination after total lesionectomy at 24.6 months revealed viable tumor tissue. Post-SRS administration of nintedanib for IPF may have provided some anti-tumor efficacy for lung SCC and may mitigate the adverse effects of SRS. The present case suggests that even ≥43 Gy with ≤60% isodose to the GTV boundary and ≥31-35 Gy to the 2 mm outside the GTV are insufficient to achieve long-term local tumor control by five-fr SRS alone in some large BM from lung SCC.

Five-Fraction Stereotactic Radiosurgery With Non-Contrast-Enhanced MRI-Based Target Definition and Moderate Dose Spillage Margin for Limited Brain Metastases With Impaired Renal Function.

In stereotactic radiosurgery (SRS) planning for brain metastases (BMs), the target volume is usually defined as an enhancing lesion based on contrast-enhanced (CE) magnetic resonance images (MRI) and/or computed tomography (CT) images. However, contrast media (CM) are unsuitable for certain patients with impaired renal function. Herein, we describe two limited BM cases not amenable to CM, which were treated with five-fraction (fr) SRS, without whole brain radiotherapy (WBRT), through a target definition based on non-CE-MRI. These included synchronous and partly symptomatic four BMs from esophageal squamous cell carcinoma (Case 1) and one presymptomatic regrowing lesion after WBRT for BMs from lung adenocarcinoma (Case 2). In both cases, all BMs were visualized as well-demarcated mass lesions almost distinguishable from the affected parenchyma on non-CE-MRI, particularly on T2-weighted images (WI). The gross tumor volume (GTV) was defined mainly based on T2-WI under a comprehensive comparison of non-CE-T1/T2-WIs and CT for SRS planning under image co-registration and fusion. Stereotactic radiosurgery was implemented with volumetric modulated arcs using a 5-mm leaf width multileaf collimator, for both of which 5 fr was selected, considering the maximum tumor volume and the effects from WBRT, respectively. Dose distribution was designed to ensure a moderate dose attenuation margin outside the GTV boundary and a concentrically-laminated steep dose increase inside the GTV boundary. Specifically, the peripheries of the GTV and 2 mm outside the GTV boundary were covered by ≥43 Gy with <70% isodose relative to the maximum dose and ≥31 Gy, respectively. The not-too-steep dose spillage margin can cover potentially invisible tumor invasion outside the GTV and other inherent uncertainties regarding target definition and irradiation accuracy. Post-SRS tumor responses were excellent clinically and/or radiographically with mild adverse radiation effects in Case 2. In limited BM cases unsuitable to CM, multi-fraction SRS with non-CE-MRI-based GTV definition and sufficient GTV dose along with moderate dose spillage margin would be a valuable treatment option for selected cases, with the entire GTV boundaries being almost visible on non-CE-MRI.

Five-Year Sustained Complete Remission With Minimal Adverse Effects Following Radiosurgery for 2-cm Brain Metastasis With Deep Eloquent Location From Lung Adenocarcinoma Despite Low Marginal Dose and High 12 Gy Volume.

In single-fraction (sf) stereotactic radiosurgery (SRS) for brain metastases (BM) from lung adenocarcinoma (LAC), a marginal dose of ≥22-24 Gy is generally deemed desirable for achieving long-term local tumor control, whereas symptomatic brain radionecrosis significantly increases when the surrounding brain volume receiving ≥12 Gy (V12 Gy) exceeds >5-10 cm3, especially in a deep location. Here, we describe a 75-year-old male with a single LAC-BM of 20 mm in diameter, with a deep eloquent location, which was treated with sfSRS followed by erlotinib, resulting in sustained local complete remission (CR) with minimal adverse radiation effect at nearly five years after sfSRS. The LAC harbored epidermal growth factor receptor (EGFR) mutation. The gross tumor volume (GTV) was defined based on contrast-enhanced computed tomography (CECT) alone. sfSRS was implemented 11 days after planning CECT acquisition. The original GTV had some under- and over-coverage of the enhancing lesion. The D98% values of corrected GTV (cGTV) (3.08 cm3) and 2-mm outside the cGTV were 18.0 Gy with 55% isodose and 14.8 Gy, respectively. The irradiated isodose volumes, including the GTV, receiving ≥22 Gy and ≥12 Gy were 2.18 cm3 and 14.32 cm3, respectively. Erlotinib was administered 13 days after sfSRS with subsequent dose adjustments over 22 months. There was a remarkable tumor response and subsequent nearly CR of the BM were observed at 2.7 and 6.3 months, respectively, with the tumor remnant being visible as a tiny cavitary lesion located in the cortex of the post-central gyrus at 56.4 months. The present case suggests the existence of: (i) extremely radio- and tyrosine kinase inhibitor (TKI)-sensitive LAC-BM for which sfSRS of ≤18 Gy combined with EGFR-TKI is sufficient for attaining long-term CR; and (ii) long-term brain tolerance following sfSRS despite high 12 Gy volume and deep eloquent location in the late 70s The moderate marginal dose of the GTV, the main location of the BM in the cerebral cortex, and the excellent tumor responses with sufficient extrication from the mass effect may render the BM immune to late adverse radiation effect.

Gradual and Remarkable Tumor Shrinkage Following Seven-Fraction Stereotactic Radiosurgery Alone With a Marginal Dose of 48.3 Gy for Large Lobar Possibly Intra-sulcal Brain Metastasis From Renal Cell Carcinoma.

Brain metastases (BMs) from renal cell carcinoma (RCC) have the tendency of slow and insufficient tumor shrinkage along with prolongation of massive peritumoral edema following stereotactic radiosurgery (SRS). Herein, we describe a case of large lobar RCC-BM, with possible intra-sulcal location, treated with 7-fraction (fr) SRS without subsequent anti-cancer medication, which resulted in gradual and remarkable tumor shrinkage with extrication from the mass effect. A 59-year-old woman was incidentally diagnosed with bilateral RCC associated with multiple lung metastases and subsequently presented with symptomatic single BM of 32 mm in the maximum diameter (9.54 cm3) two months later while vacillating. A biopsy of the kidney showed clear cell carcinoma. The patient was deemed medically inoperable for BM due to unfit conditions, including severe deep venous thromboses and thrombocytopenia. Considering the tumor volume, irregular tumor configuration, non-superficial location, and mass effect, 98% of the gross tumor volume (GTV D98%) was covered by 48.3 Gy in 7 fr with 64% isodose. Dose distribution was optimized with volumetric modulated arcs with the affirmative allowance of very inhomogeneous GTV dose. Anti-cancer medication was limited to nivolumab plus ipilimumab followed by everolismus 12 days before and during SRS, respectively. Subsequently, the patient transitioned to palliative care due to a declining general condition. Although long-term administration of steroids was required, gradual and marked tumor shrinkage (1.25 cm3, 13.1% of the initial volume) and mitigation of the peritumoral edema was observed during six months after SRS. The main location of the initial BM was deemed as intra-sulcal in the intraparietal sulcus and originated in the cerebral cortex. The patient died nine months after SRS. The gradual but remarkable tumor response obtained with 7-fr SRS alone, in this case, provides a basis to further optimize fractionated SRS dosage to enhance efficacy and safety for large and/or symptomatic RCC-BMs not amenable to immediate surgical removal, in combination with anti-cancer pharmacotherapy, if feasible, including tyrosine kinase inhibitors, which may enhance efficacy against BM and mitigate adverse effects relevant to high dose SRS.

Modified Dynamic Conformal Arcs With Forward Planning for Radiosurgery of Small Brain Metastasis: Each Double Arc and Different To-and-Fro Leaf Margins to Optimize Dose Gradient Inside and Outside the Gross Tumor Boundary.

Dynamic conformal arcs (DCA) are a widely used technique for stereotactic radiosurgery (SRS) of brain metastases (BM) using a micro-multileaf collimator (mMLC), while the planning design and method considerably vary among institutions. In the usual forward planning of DCA, the steepness of the dose gradient outside and inside the gross tumor volume (GTV) boundary is simply defined by the leaf margin (LM) setting to the target volume edge. The dose fall-off outside the small GTV tends to be excessively precipitous, especially with an MLC of 2.5-mm leaf width, which is predisposed to the insufficient coverage of microscopic brain invasion and other inherent inaccuracies. Meanwhile, insufficient dose increase inside the GTV boundary, i.e., less inhomogeneous GTV dose, likely leads to inferior and less sustainable tumor response. The more inhomogeneous GTV dose is prone to the steeper dose gradient outside the GTV and vice versa. Herein, we describe an alternative simply modified DCA (mDCA) planning that was uniquely devised to optimize the dose gradient outside and inside the GTV boundary for further enhancing and consolidating local control of small BM. For a succinct exemplification, a 10-mm spherical target was assumed as a GTV for DCA planning using a 2.5-mm mMLC. The benchmark plan was generated by adding a 0-mm LM to the GTV edge by assigning a single fraction of 30 Gy to the isocenter, in which the GTV coverage by 24 Gy with 80% isodose surface (IDS) was 96%, i.e., D96%, while the coverage of GTV + isotropic 2 mm volume by 18 Gy with 60% IDS was 70%, with the D98% being 12 Gy with 40% IDS, viz., too steep dose fall-off outside the GTV boundary. Alternatively, the increase of LM with or without decreasing the isocenter dose enables the increase of the GTV + 2 mm coverage by 18 Gy while resulting in an inadequate GTV dose with either a less inhomogeneous dose or an excessive marginal dose. Meanwhile, in the newly devised mDCA planning, every single arc was converted to a double to-and-fro arc with different LM settings under the same spatial arrangement, which enabled GTV + 2 mm volume coverage with 18 Gy while preserving the GTV marginal dose and inhomogeneity similar to those for the benchmark plan. Additionally, the different collimator angle (CA) setting for the to-and-fro arcs led to further trimming of the dose conformity. The limitations of general forward planning with only adjusting the LM for every single arc were demonstrated, which can be a contributing factor for local tumor progression of small BM. Alternatively, the mDCA with each double to-and-fro arc and different LM and CA settings enables optimization of the dose gradient both outside and inside the GTV boundary according to the planners' intent, e.g., moderate dose spillage margin outside the GTV and steep dose increase inside the GTV boundary.

An Extremely Inhomogeneous Gross Tumor Dose is Suitable for Volumetric Modulated Arc-Based Radiosurgery with a 5-mm Leaf-Width Multileaf Collimator for Single Brain Metastasis.

Introduction Single or multi-fraction (mf) stereotactic radiosurgery (SRS) is an indispensable treatment option for brain metastases (BMs). The integration of volumetric modulated arc therapy (VMAT) into linac-based SRS is expected to further enhance efficacy and safety and to expand the indications for the challenging type of BMs. However, the optimal treatment design and relevant optimization method for volumetric modulated arc-based radiosurgery (VMARS) remain unestablished with substantial inter-institutional differences. Therefore, this study was conducted to determine the optimal dose distribution suitable for VMARS of BMs, especially regarding dose inhomogeneity of the gross tumor volume (GTV). The GTV boundary, not margin-added planning target volume, was regarded as a basis for planning optimization and dose prescription. Materials and methods This was a planning study for the clinical scenario of a single BM. Eight sphere-shaped objects with diameters of 5-40 mm in 5-mm increments were assumed as GTVs. The treatment system included a 5-mm leaf width multileaf collimator (MLC) Agility® (Elekta AB, Stockholm, Sweden) and a dedicated planning system Monaco® (Elekta AB). The prescribed dose (PD) was uniformly assigned to just cover 98% of the GTV (D98%). Three VMARS plans with different dose inhomogeneities of the GTV were generated for each GTV: the % isodose surfaces (IDSs) of GTV D98%, normalized to 100% at the maximum dose (Dmax), were ≤70% (extremely inhomogeneous dose, EIH); ≈80% (inhomogeneous dose, IH); and ≈90% (rather homogeneous dose, RH). VMARS plans were optimized using simple and similar cost functions. In particular, no dose constraint to the GTV Dmax was assigned to the EIH plans. Results Intended VMARS plans fulfilling the prerequisites were generated without problems for all GTVs of ≥10 mm, whereas 86.4% was the lowest IDS for the D98% for 5-mm GTV. Therefore, additional plans for 9- and 8-mm GTVs were generated, which resulted in 68.6% and 75.1% being the lowest IDSs for the D98% values of 9- and 8-mm GTVs, respectively. The EIH plans were the best in terms of the following: 1) dose conformity, i.e., minimum spillage of PD outside the GTV; 2) moderate, not too excessive, dose attenuation outside the GTV, i.e., appropriate marginal dose 2-mm outside the GTV boundary as a function of GTV size; and 3) lowest dose of the surrounding normal tissue outside the GTV. In contrast, the RH plans were the worst based on all of the aforementioned measures. Conclusions On the assumption of uniform dose assignment to the GTV margin, a very inhomogeneous GTV dose is basically the most suitable for SRS of BMs in terms of 1) superior dose conformity; 2) minimizing the dose of the surrounding normal tissue outside the GTV; and 3) moderate dose spillage margin outside the GTV with a tumor volume-dependent rational increase, i.e., appropriate dose of the common PTV boundary. The concentrically laminated steep dose increase inside the GTV boundary for the EIH plan may also be advantageous for achieving superior tumor response, although early and excessive GTV shrinkage caused by the EIH plan during mfSRS can lead to surrounding brain injury.

Ten-Fraction Stereotactic Radiosurgery With Different Gross Tumor Doses and Inhomogeneities for Brain Metastasis of >10 cc: Treatment Responses Suggesting Suitable Biological Effective Dose Formula for Single and 10 Fractions.

Stereotactic radiosurgery (SRS) with >5 fractions (fr) has been increasingly adopted to improve local control and safety for brain metastases (BM) of >10 cm3, given the limited brain tolerance of SRS with ≤5 fr. However, the optimal indication and treatment design, including the prescribed dose and distribution for 10 fr SRS, remains uncertain. A single fr of 24 Gy provides approximately 95% of the one-year local tumor control probability. The potential SRS doses in 10 fr that is clinically equivalent to a single fr of 24 Gy regarding anti-tumor effect range from 48.4 to 81.6 Gy as biological effective doses (BED) as a function of the BED model formulas along with the alpha/beta ratios. The most appropriate BED formula in conjunction with an alpha/beta ratio to estimate similar anti-BM effects for single and 10 fr remains controversial. Herein, we describe four cases of symptomatic radiation-naïve BM >10 cm3 (range, 11 to 26 cm3), treated with 10 fr SRS with a standard prescribed dose of 42 Gy, for which modified dynamic conformal arcs were used with forward planning to improve dose conformity. In the first two cases with gross tumor volumes (GTV) of 15.3 and 10.9 cm3, 42 Gy was prescribed to 70%-80% isodose, normalized to 100% at the isocenter, which encompasses the boundary of the planning target volume: GTV + isotropic 1 mm margin. The tumor responses were initially marked regression followed by regrowth within three months in case 1 and no shrinkage with subsequent progression within three months in case 2. In the remaining two cases with larger GTVs of 19.1 and 26.2 cm3, the GTV boundary and 2-3 mm margin-added object volume was covered by 80% and 56% isodoses with 53 Gy and 37 Gy, respectively, to further increase the marginal and internal doses of GTV and to ensure moderate dose spillage outside the GTV, while >1-1.5 mm outside the GTV was covered by 42 Gy with 63% isodose. According to the BED based on the linear-quadratic (LQ) model with an alpha/beta ratio of 10 (BED10), 53 Gy corresponds to approximately 81 Gy in BED10 and 24 Gy in a single fr. Excellent initial maximum tumor response and subsequently sustained tumor regression (STR) were achieved in both cases. Subsequently, enlarging nodules that could not exclude the possibility of tumor regrowth were disclosed within two years, while late adverse radiation effects remained moderate. These dose-effect relationships suggest that a GTV marginal dose of ≥53 Gy with ≤80% isodose would be preferred to effect ≥1-year STR and that further dose escalation of both marginal and internal GTV may be necessary to achieve ≥2-year STR, while GTV of >25 cm3 may be unsuitable for 10 fr SRS in terms of long-term brain tolerance. Among LQ, LQ-cubic, and LQ-linear model formulas and alpha/beta ratios of 10-20, BED10 may be clinically most suitable to estimate a 10 fr SRS dose that provides anti-BM efficacy similar to that for a single fr.

Correlation of Brain Metastasis Shrinking and Deviation During 10-Fraction Stereotactic Radiosurgery With Late Sequela: Suggesting Dose Ramification Between Tumor Eradication and Symptomatic Radionecrosis.

Stereotactic radiosurgery (SRS) with >5 fraction (fr) has been increasingly adopted for brain metastases (BMs), given the current awareness of limited brain tolerance for ≤5 fr. The target volume/configuration change and/or deviation within the cranium during fractionated SRS can be unpredictable and critical uncertainties affecting treatment accuracy, plus the effect of these events on the long-term outcome remains uncertain. Herein, we describe a case of two challenging BMs treated by 10 fr SRS with a unique dose-gradient optimization strategy, in which the large cystic tumor revealed an intriguing correlation of such inter-fractional change with late radiographic sequela, suggesting a dose threshold for attaining long-term local tumor control and being immune to symptomatic brain necrosis. A 63-year-old man presented with two cystic lesions located in the left parietal lobe (19.9 cm3) and pons (1.1 cm3) one month after surgery for esophageal squamous cell carcinoma. The principles for 10 fr SRS were as follows: (1) very inhomogeneous gross tumor volume (GTV) dose covered by 53 Gy, biologically effective dose with an alpha/beta ratio of 10 (BED10) of ≥80 Gy; (2) moderate dose spillage margin outside the GTV boundary: 2-2.5 mm outside the GTV margin was covered by 37 Gy, BED10 of ≈50 Gy; (3) concentrically-laminated, steep dose increase inside the GTV boundary: 2 mm inside the GTV margin was covered by ≥62 Gy, BED10 of ≥100 Gy. At the completion of SRS, the parietal lesion showed significant shrinking and dorsomedial shifting with slight evisceration of the GTV, followed by marked regression of the parietal lesion within four months. At 13.5 months, a cystic change was noted at the dorsal part of the remnant. At 16.7 months, ventral enhancement gradually expanded without enlargement of the dorsal cystic component. On the T2-weighted images, the dorsal low-intensity remnant and ventral iso-intensity blurry-demarcated component were contrasting. Pathological examinations during and after lesionectomy at 17.4 months revealed necrosis only. At 30.5 months, the patient had a left visual field defect without recurrence. In contrast, the pons lesion showed no notable change during 10 fr SRS and nearly complete remission over six months with its sustainment without radiation injury at 30.5 months. Taken together, 10 fr SRS with a sufficient BED10 can provide superior tumor response and safety for BM that is not amenable to ≤5 fr SRS. Although a very inhomogeneous GTV dose can contribute to early and adequate tumor shrinkage and subsequent local tumor eradication, significant tumor shrinkage during fractionated SRS (fSRS) inevitably results in unnecessary higher dose exposure to the surrounding brain, which could lead to late radiation injury requiring intervention. The optimum dose should be determined through further investigation, in consideration of the dynamic and unpredictable nature of the actual absorbed doses to both the tumor and the surrounding brain.

Lung Cancer Complicated by Relapsing Polychondritis.

A 77-year-old man presented with a 1-month history of cough, pharyngeal discomfort, and weight loss. Chest radiography revealed a mass shadow in the right upper lung field. Bronchoscopy showed multiple white nodules along the tracheal cartilage ring. Although adenocarcinoma cells were detected in the mass, several biopsy specimens of the tracheal lesions exhibited no malignancy. 18F-fluorodeoxyglucose positron emission tomography revealed an intense accumulation in the mass, nasal septum, and tracheal cartilage. Furthermore, anti-type II collagen antibody levels were elevated. We finally diagnosed him with lung cancer complicated by relapsing polychondritis. Treatment with oral prednisolone was initiated, followed by sequential chemoradiotherapy for lung cancer.

Fifteen-Fraction Radiosurgery Followed by Reduced-Dose Whole-Brain Irradiation With a Total Biologically Effective Dose of >90-100 Gy for a Locally Invasive Brain Metastasis From Lung Adenocarcinoma With a High Dissemination Potential.

A deep-seated, locally infiltrative 5.8-cm brain metastasis (BM) involving the ventricular wall and optic radiation is deemed unamenable for a safe total resection, while preventing tumor seeding. Meanwhile, radiotherapeutic management alone for such a BM close to the brainstem is also challenging. We describe such a BM (gross tumor volume [GTV] 40.3 cm3) from lung adenocarcinoma (LAC), located in the left temporo-occipital lobes, with extensive invasion to the tentorium cerebelli and a high potential for dissemination. The BM was treated with 15-fraction(s) (fr) stereotactic radiosurgery (SRS) followed by whole-brain irradiation (WBI) at 27 Gy/15 fr with a 19-day interval. During the SRS, the solid component away from the tentorium showed obvious shrinkage. The cumulative biologically effective doses (BEDs) of the minimum and D99% of the GTV were ≥92.3 Gy and ≥102.6 Gy, respectively, where the BED was based on the linear-quadratic formula at an alpha/beta ratio of 10 (BED10). Despite a maximum response with nearly complete regression at 7.5 months, local tumor regrowth near the tentorial incisura became gradually apparent from 11.2 to 19.3 months. Salvage re-SRS with 53 Gy/10 fr specific to these lesions resulted in obvious regression at 5.8 months. However, radiation injury concomitant with triventriculomegaly progressed from 7.9 to 13.9 months, eventually leading to meningeal dissemination and patient mortality at 34.6 months. This case demonstrates that a BED10 ≥90-100 Gy in 30 fr to the GTV boundary with a more than two-week interval without combined systemic therapy is insufficient for achieving complete local tumor eradication of a 40-cc LAC-BM. Shorter treatment duration with a steeper dose gradient outside and inside the GTV in the SRS or a volumetric modulated arc-based SRS combined with simultaneously integrated WBI may improve efficacy and safety.

Robotic Radiosurgical Boost After Whole-Brain Radiotherapy for 12 Brain Metastases: En Bloc Consecutive Irradiation With Comprehensively Optimized Single Plan for Eight Lesions Totaling 118 cc.

General radiotherapeutic management for >10 brain metastases (BMs) totaling >100 cm3, including multiple large lesions (>10-30 cm3) in close proximity, demonstrated limited efficacy and/or safety. We describe a case of 12 BMs, summating 122.2 cm3, including a 39.6 cm3 maximum lesion and adjacent ones. The patient had an 8.1-year treatment history for recurrent/metastatic breast cancer refractory to endocrine and chemotherapy. BMs were treated with conventional whole-brain radiotherapy (WBRT) with 30 Gy/10 fractions (fr), followed by an immediate stereotactic radiosurgery (SRS) boost with 27 Gy/5 fr (52-64% isodoses) which covers the gross tumor boundaries of selected eight lesions (total 118.4 cm3). The SRS dose was defined to ensure the cumulative biologically effective dose (BED10) of just ≥80 Gy while minimizing the risk of radiation injury. The SRS was performed using a CyberKnife (CK) robotic system (Accuray Incorporated, Sunnyvale, California, United States) with a variable-sized collimator (10-40 mm), for which en bloc consecutive irradiation, using 215 beams based on a comprehensively optimized single plan (path), was adopted. The treatment time per fraction was ≤45 min (mean 5.6 min per lesion). Afterward, BMs demonstrated remarkable regression over six months, causing the total residual visible lesions of 12.6 cm3 (10.3%) at 11.4 months, despite the absence of obvious lesion shrinkage during the radiotherapy. WBRT, followed by an immediate 5-fr SRS boost with a total BED10 of 80 Gy to large and/or culprit lesions, can be an efficacious and safe treatment option for multiple BMs, totaling >120 cm3. En bloc consecutive irradiation with a single path provides overwhelmingly more efficient delivery for treating multiple lesions using CK in terms of irradiation time and comprehensive reduction of normal brain dose compared to individual planning. Volumetric-modulated arc-based >10-fr SRS with simultaneously integrated reduced-dose WBRT may be an alternative to further enhance efficacy and safety.

Frameless Co-Registration of Biplane 2D Digital Subtraction Angiography Whole Frames and 3D Rotational Angiography-Based Cone-Beam Computed Tomography Angiogram on Dedicated Software for Stereotactic Radiosurgery of Cranial Vascular Malformations.

PURPOSE: Given its high spatial resolution and vasculature selectivity, the cone-beam computed tomography (CT) angiography (CBCTA) image acquired by selective 3D rotational angiography (3DRA) is the most suitable 3D image for the target definition of stereotactic radiosurgery (SRS) for intracranial arteriovenous malformations (AVMs) and dural arteriovenous fistulas (DAVFs). Furthermore, the relatively low temporal resolution of 3DRA-based CBCTA can be complemented by the stereotactic co-registration of orthogonally paired 2D dynamic digital subtraction angiography (2D-DSA). The integration of 2D-DSA, which is usually limited to one or a few frames for each projection, into CBCTA and/or planning CT can be achieved only by catheter-directed angiography on the day of SRS via a dedicated image localizer under rigid frame fixation to the skull, which imposes substantial burdens on patients. This study aimed to demonstrate a novel, convenient, and significantly less invasive method for the frameless co-registration of biplane 2D-DSA whole frames and CBCTA on commercially available dedicated software, namely, Brainlab® Elements (Brainlab AG, Munich, Germany), and present its prerequisite for successful image fusion. Technical Report: Elements have afforded the following functionality: A 3D vasculature image is automatically extracted as a floating image from any 3D image series containing vascular details and then subsequently co-registered manually and automatically to a selected frame pair of 2D-DSA with a six-degree-of-freedom rigid registration. As a preclinical feasibility study, two anonymous image datasets from patients harboring cerebral AVM and transverse-sigmoid (TS) DAVF were used to verify the accuracy and practicality of Elements for the frameless co-registration of 2D/3D vascular images, particularly on the assumption of clinical workflow for the target delineation of SRS planning. The use of ordinary unsubtracted CBCTA resulted in the insufficient extraction of abutting vessels or vessels that are in close proximity to bony structures, particularly in the case of TS-DAVF, where the fistulous pouch and the affected venous sinuses were adjacent to the cranial bone. By contrast, the amount and selectivity of vasculatures and the accuracy of subsequent image fusion were significantly improved from the subtracted CBCTA. The integration of CBCTA into dynamic 2D-DSA allowed the simultaneous review of both image information by sharing any concerning point and 2D or 3D structures under a common 3D coordinate. CONCLUSIONS: Elements enable the clinically useful frameless co-registration of biplane 2D-DSA whole frames into CBCTA, for which the routine acquisition of both subtracted and unsubtracted CBCTA axial images for ordinary diagnostic purposes is an indispensable prerequisite for successful image fusion and further widespread application. This frameless integration of the 2D/3D angiogram would dramatically enhance both the frame-based and frameless SRS workflow and circumstances by allowing users to forward SRS planning well in advance before SRS, along with the omission of invasive angiography on the day of SRS, and would broaden the implementation of frameless SRS. Furthermore, the comprehensive alternating interactive review of the 2D/3D integrated angiogram leads to a more in-depth quasi-4D understanding of the affected angioarchitectures compared with the separate viewing of each image.

The Incidence and Its Associated Factors Relevant to Brain Radionecrosis That Requires Intervention Following Single or Fractionated Stereotactic Radiosurgery Using Vero4DRT for Brain Metastases.

PURPOSE: Several factors, including the surrounding brain volume receiving specific doses, have hitherto been reported to correlate with brain radionecrosis (BR) after single or fractionated stereotactic radiosurgery (sSRS or fSRS) for brain metastases (BMs); however, those, especially for fSRS, have not yet been fully elucidated. Furthermore, the clinical outcome data of patients with BM treated with SRS using Vero4DRT are extremely limited. Therefore, this study aimed to demonstrate the incidence of BR requiring intervention (BRRI) and its highly correlated factors. MATERIALS AND METHODS: Patients with BMs treated with sSRS or fSRS using Vero4DRT at Toyohashi Municipal Hospital between July 2017 and June 2021 were retrospectively reviewed, of whom patients were available for at least 20 weeks of magnetic resonance imaging follow-up from SRS were included, and analyzed. The prescribed dose fractionation schemes to the planning target volume (PTV) boundary included 24 Gy (sSRS), 35 Gy (5 fractions [fr]), 42 Gy (10 fr), and 30 Gy (3 fr), according to the tumor volume and location. The volume of the surrounding normal brain receiving 84 Gy (V84 Gy, biologically effective dose [BED2] based on a linear-quadratic model with an alpha/beta ratio of 2, single-dose equivalent [SDE] to 12 Gy), V112 Gy (BED2, SDE to 14 Gy) for all lesions, and all irradiated volume, including gross tumor volume (GTV) receiving 81.6 Gy (81.6 Gy vol., BED2) for fSRS were calculated, for which cerebrospinal fluid and bone volumes were cautiously excluded. The diagnosis of tumor progression or BR dominance was based on serial T1/T2 matching. RESULTS: Sixty patients with 120 lesions (65 treated with sSRS and 55 treated with fSRS) were included in the final analysis, with a median follow-up period of 65 weeks. The local control rate at one year was 87.5%. The cumulative incidence of BRRI within two years was 11.5%. The risk of symptomatic BR was significantly higher for V84 Gy >10 cc (p <0.001) and V112 Gy >5 cc (p = 0.021). In the fSRS group, the cumulative incidence of Grade 3 BR and those requiring resection was significantly higher for 81.6 Gy vol. >14 cc (p = 0.003 and p = 0.004, respectively). The coexistence of viable tumor tissue and BR could not be ruled out for enlarging lesions after the nadir response, especially for fSRS, due to a lower BED10 to GTV margin (<80 Gy, BED10). CONCLUSIONS: Stereotactic irradiation with Vero4DRT provided efficacy and safety comparable to previous linear accelerator series, and most of the dose-volume thresholds for BRRI presented in this study were notably lower than those reported in previous studies. This study suggests that the indication of single and up to 5 frSRS should be limited to far smaller tumors than previously acknowledged to ensure long-term safety and efficacy.

Direct intracranial invasion of eccrine spiradenocarcinoma of the scalp: a case report and literature review.

BACKGROUND: Eccrine spiradenocarcinoma (SC), also known as malignant eccrine spiradenoma, is a rare malignant cutaneous adnexal neoplasm arising from long-standing benign eccrine spiradenoma. Malignant skin tumors rarely show direct intracranial invasion. However, once the intracranial structure is infiltrated, curative excision with sufficient margins can become extremely difficult, particularly when the venous sinuses are involved. No effective adjuvant therapies have yet been established. Here, we report an extremely rare case of scalp eccrine SC with direct intracranial invasion, which does not appear to have been reported previously. CASE PRESENTATION: An 81-year-old woman presented with a large swelling on the parietal scalp 12 years after resection of spiradenoma from the same site. The tumor showed intracranial invasion with involvement of the superior sagittal sinus and repeated recurrences after four surgeries with preservation of the sinus. The histopathological diagnosis was eccrine SC. Adjuvant high-precision external beam radiotherapy (EBRT) proved effective after the third surgery, achieving remission of the residual tumor. The patient died 7 years after the first surgery for SC. CONCLUSIONS: Scalp SC with direct intracranial invasion is extremely rare. Radical resection with tumor-free margins is the mainstay of treatment, but the involvement of venous sinuses makes this unfeasible. High-precision EBRT in combination with maximal resection preserving the venous sinuses could be a treatment option for local tumor control.