High Local Control Rates Research Articles

A Pilot Study of Hypofractionated Simultaneous Integrated Boost Radiotherapy in Stage 0-IIIB Breast Cancer Patients

In the UK START and Canadian hypofractionated whole breast radiotherapy (RT) trials, few patients were Black, received prior chemotherapy, or had large breast size, all factors associated with RT-induced breast toxicity. The purpose of this prospective trial was to assess the safety and efficacy of delivering 15 fractions of hypofractionated simultaneous integrated boost (SIB) RT to patients under-represented on trials of hypofractionated breast RT and who have characteristics which increase their risk for local recurrence and cutaneous toxicity from breast RT.We conducted a prospective, single-arm pilot study to evaluate a once daily 15 fraction SIB RT regimen of 39.9 Gy in 2.66 Gy fractions to the breast/chest wall with or without regional nodal irradiation (RNI) and SIB of 8.1 Gy in 0.54 Gy fractions. Women with Stage 0-IIIB breast cancer who had one or more of the following characteristics were approached for enrollment: 1) prior chemotherapy for breast cancer; 2) > 25 cm breast/chest wall separation; 3) non-White race; 4) ≤ 50 years old; or 5) requiring RNI. Primary endpoint was Grade 3 cutaneous toxicity rate by CTCAE v.5. Among patients who received RNI (n = 30), rates of Grade 3 brachial plexopathy by RTOG criteria and 20% or greater increase in arm lymphedema, were additional primary endpoints. Patients were assessed prior to RT, last day of RT, and 3 weeks, 9 weeks and 1 year post RT. Local regional recurrence free survival (LRFS) was a secondary endpoint.Among 74 participants, 57% received prior chemotherapy, 19% had breast/chest wall separation > 25cm, 39% were Black, 36% were ≤ 50 years old, and 41% were prescribed RNI. Median body mass index was 30.0 (range 17.3 - 54.9). Ten patients received post mastectomy RT. One patient developed Grade 3 radiation dermatitis 3 weeks post RT. No other Grade 3 or higher cutaneous toxicities were observed up to 1 year post RT. One patient developed a grade 3 axillary infection 3 weeks post RT, which resolved after intravenous antibiotics. No patients who received RNI developed grade 3 brachial plexopathy or a 20% increase in the ipsilateral arm volume during the study period. With a median follow up of 60 months (range 12-113 months), one in-breast recurrence with simultaneous distant metastases occurred. Two additional patients developed distant metastases alone. The 5-year LRFS and overall survival rates were 98.6% and 98.5%, respectively.Our results indicate that SIB radiation therapy is well-tolerated with acceptable cutaneous toxicity rates up to 1 year post RT even among patients who are at high risk for RT-induced breast side effects. The high rates of local control and overall survival following SIB treatment are promising and support condensed courses of RT in patients who would typically receive a sequential boost due to higher risk for local recurrence.

Fractionated Proton Beam Radiation Therapy and Hearing Preservation for Vestibular Schwannoma: Preliminary Analysis of a Prospective Phase 2 Clinical Trial

Management for vestibular schwannoma (VS) achieves excellent local control, and advances have increasingly focused on long-term serviceable hearing preservation. Fractionated stereotactic radiation therapy (FSRT) is associated with better hearing preservation compared to stereotactic radiosurgery (SRS). Fractionated proton beam radiation therapy (FPRT) may be associated with greater hearing preservation due to unique dosimetric properties of proton radiotherapy.A single institution, prospective, single-arm, phase 2 clinical trial was designed for patients with VS between 2010-2019. All patients received FPRT to a total dose of 50.4-54Gy relative biological effectiveness (RBE) over 28-30 fractions. The primary endpoint was serviceable hearing preservation, defined as Gardner-Robertson (GR) score 1-2, defined as Pure Tone Average (PTA) ≤50dB and Word Recognition Score (WRS) ≥50%, at 5 years compared to a historical rate of serviceable hearing preservation of 65% in patients treated with photon radiation therapy. Other audiometric measures included Otoacoustic Emissions (OAE) and Auditory Brainstem Response (ABR). Preliminary analysis was performed for 20 patients accrued with a minimum follow up of 1.0 year.Twenty patients were accrued with median follow up of 4.0 years (range 1.0-5.0 years), with a median age of 64 years, median RT dose of 50.4 Gy (RBE). Serviceable hearing preservation at 1 year was 53%, primary endpoint was not yet met. Local control at 4 years was 100%. Median cochlea D90 was lower for patients with serviceable hearing at 1 year (median 40.5 Gy (RBE) vs 46.9 Gy (RBE), P = 0.0863). V90, Dmean, Dmin, and other cochlea dosimetric measures were also generally lower, but the associations with hearing preservation at 1 year were not statistically significant. Median PTA at 1-year worsened from 42dB at baseline to 62dB (P < 0.0001), and median WRS at 1-year worsened significantly from 85% to 48% (P < 0.0001); PTA worsening developed earlier than WRS worsening. The rate of OAE absence significantly worsened from 60% at baseline to 100% at 1-year (P = 0.0156). Other audiometric measures, including contralateral PTA, ABR, tympanometry, were not independently associated with hearing preservation. Treatment was well tolerated, with low levels of acute and late-term toxicity; one patient incurred grade one CN V dysfunction, with no grade two or higher CN dysfunction.FPRT for vestibular schwannoma results in high rates of local control with comparable serviceable hearing preservation compared to historical RT series. Audiometric analyses suggest radiation-associated hearing dysfunction is manifested as early PTA worsening followed by WRS worsening.

Analysis of Toxicity and Local Control for Ultra-Central Lung Tumors Undergoing Stereotactic Body Radiation Therapy

High toxicity rates have been reported for ultra-central lung tumors undergoing stereotactic body radiation therapy (SBRT). We retrospectively analyze a cohort of patients undergoing five fraction SBRT at our institution for ultra-central tumors defined as GTV abutting the proximal bronchial tree (PBT), aorta or esophagus.All patients treated with SBRT during 2012 to 2018 at a single institution were reviewed to identify ultra-central lesions undergoing 5 fraction SBRT. Cases were identified as GTV abutting PBT, esophagus or aorta. Patients who received at least 800 cGy per fraction were included. The primary endpoint was grade 3+ adverse events attributable to SBRT, based on CTCAE 4.0. Secondary endpoints were local control (LC) and overall survival (OS). Kaplan-Meier analysis was used to estimate LC and OS.A total of 30 patients were identified (Age 39-92), 26 with GTV abutting the PBT, 2 with GTV abutting aorta and 2 with GTV abutting esophagus. Median follow up time was 12.5 months (1 - 58 months). Five fraction doses were 50 Gy (53%), 45 Gy (26.7), 42.5 Gy (10%) and 40 Gy (10%). Tumor size ranged from 0.6 to 4.9cm. Only 1 grade 5 (3.3%) Hemoptysis toxicity was reported 1 year after SBRT and 4 Grade 3+ toxicities (13.3%), including 2 radiation pneumonitis, 1 pleural effusion and 1 large cavitary lesion with 2/4 receiving 50 Gy. LC was 75.5% at 1 year, and 56.8% at 2 years. With BED > 100, 1 year LC was 92.3% and 2 year LC was 82.1%. OS was 89.1% at 1 year, 85.4% at 2 years and 65.7% at 3 years.SBRT achieves high rates of local control at 2 years in our cohort undergoing 5 fraction SBRT with BED > 100 for ultra-central lesions with acceptable grade 3 toxicities, and potential small risk of grade 5 toxicity. Five fraction SBRT remains an acceptable option for ultra-central lesions.

Stereotactic Magnetic Resonance Guided Adaptive Radiation Therapy for Abdominopelvic Metastases

Stereotactic body radiation therapy (SBRT) can be an effective method for treating metastases. However, the proximity of organs at risk (OARs) to the target can limit the safe delivery of ablative doses, particularly in the abdomen and pelvis where there can be significant interfraction and intrafraction motion. Stereotactic magnetic resonance guided adaptive radiation therapy (SMART) may allow for safer delivery of ablative radiation to abdominopelvic metastases. We report the feasibility and early outcomes of patients with abdominopelvic metastases treated with SMART using a 0.35T MR Linac in a (1) retrospective cohort and (2) a prospective phase 1 trial.We identified 44 patients in the retrospective cohort and enrolled 13 patients onto the phase 1 protocol, all with abdominopelvic metastases. Patients with metastases of the liver, kidneys, or adrenal glands were excluded and were enrolled on companion phase 1 trials. Patients were treated between 10/29/19-2/18/21. For the retrospective cohort, dose prescription and coverage were at the discretion of the treating physician, with 67% of sites receiving 40 Gy/5 fractions. For the phase 1 cohort, patients were treated to 40 Gy/5 fractions daily with goal PTV coverage of V40 ≥95% (ideal) and V30 ≥95% (acceptable).Overall, the 44 patients in the retrospective cohort were treated to 49 sites of abdominopelvic disease, and the 13 patients in the phase 1 cohort received treatment to one site of abdominopelvic disease each on protocol. The most common histology was prostate adenocarcinoma (57%). In total, 308 fractions were delivered, with 138 (45%) using a breath hold and 170 (55%) using free breathing. Online adaptation was necessary for 269/308 fractions (87%) to either satisfy critical OAR metrics (62%) or improve target coverage (38%). Additionally, there were two instances when on-board MRI allowed for the detection of bowel which had displaced the target to such a degree as to interfere with safe treatment delivery, even when utilizing adaptive planning. These two treatments were postponed to either later the same day or a subsequent day. Patients spent an average of 61 minutes in the treatment room. With median follow-up of 150 days (interquartile range 90-224 days), there were no deaths and one local failure (a patient with urothelial carcinoma who received 35 Gy/5 fractions at 102 days after start of SBRT). There was one grade ≥3 treatment-related toxicity (colonic hemorrhage in a patient with serous ovarian cancer who received 40 Gy/5 fractions at 86 days after start of SBRT in the setting of thrombocytopenia).SMART is a feasible method for delivering ablative doses of radiation. Adaptive planning was necessary in a large portion of cases. Early data suggest a high rate of local control and low risk of significant toxicity. Longer-term results of the phase 1 protocol will be reported in the future.

Stereotactic Body Radiation Therapy and Immunotherapy in Abdominal and Pelvic Lymph Node Metastases

This study characterizes the efficacy and safety of stereotactic body radiation therapy (SBRT) with immunotherapy in the treatment of abdominal and pelvic lymph node metastases, based on a pooled analysis of three prospective phase I trials. While SBRT is frequently utilized for metastases, its role in the treatment of abdominal and pelvic lymphadenopathy remains unclear. We hypothesize that local control will remain excellent for nodal SBRT, even with prioritization of organ-at-risk (OAR) constraints resulting in undercoverage of target metastases and with omission of elective treatment of regional nodal basins.Patients with widely metastatic solid malignancies were enrolled on three Phase I trials between 2016 and 2020 (total 213 patients). Patients were treated with multisite SBRT (up to 4 sites). Metastases > 65cc were partially treated. Immunotherapy was administered either concurrently or sequentially. Immunotherapy regimens included pembrolizumab, ipilimumab with nivolumab, urelumab with nivolumab, or cabiralizumab with nivolumab. The study cohort included patients who underwent SBRT to at least one lymph node in the abdomen or pelvis, including the inguinal regions. Local control (LC) of irradiated metastases and regional control (RC) of the corresponding nodal basin were determined per RECIST 1.1 guidelines. Overall survival (OS) was calculated using the Kaplan-Meier method. For each irradiated lesion, the mean dose, V95%, and V100% to the ITV and PTV were recorded.A total of 39 patients (mean age 59.2 years) underwent SBRT to 56 abdominal or pelvic lymph node metastases with median follow-up of 16.2 months. The median prescription dose was 45 Gy in 3 fractions. Median lesion volume was 17.0cc. Lymph node sites included 24 para-aortic/retroperitoneal (43%), 9 pelvic (16%), 11 inguinal (20%), 10 gastrohepatic/porta hepatis (18%), and 2 other (4%). Across all patients, the 1-year LC was 90.4%. Even without elective treatment of the corresponding nodal basins, 1-year RC was 81.9% (with only one isolated regional failure without concomitant distant progression). Median OS was 25 months, while 1-year and 2-year OS were 69.9% and 53.2%, respectively. ITV mean dose, V95%, and V100% were 47.3 Gy, 95.3%, and 89.5%, respectively (reported as medians across all 56 metastases). PTV mean dose, V95%, and V100% were 45.5 Gy, 84.2%, and 75.0%, respectively. The overall incidence of grade 3+ toxicity was 10.3%. The incidence of grade 3 colitis was 2.6% and grade 3 hepatitis was 2.6%, with no grade 4-5 colitis/hepatitis events.In this pooled analysis of three prospective trials, SBRT to abdominal or pelvic lymph node metastases with immunotherapy is associated with acceptable toxicity and high rates of LC, even with target undercoverage to meet OAR constraints. This suggests a potential for this approach in clinical practice and study in future trials.

Clinical Outcomes of Single-Isocenter Versus Multiple-Isocenter Stereotactic Radiosurgery Techniques for Multiple Brain Metastases

There are multiple technical approaches for stereotactic radiosurgery (SRS) delivery to multiple brain metastases, including single-isocenter (SIT) and multiple-isocenter (MIT) techniques. SIT is increasing employed to streamline treatment planning and delivery in the setting of multiple brain metastases such that a single radiosurgery plan is generated to treat all metastases simultaneously, rather than generating and delivering separate plans for each metastasis. In this study, we compare clinical outcomes using a single-isocenter versus multiple-isocenter approaches for treating multiple brain metastases amenable to single fraction radiosurgery.This is a single-institution, retrospective review of patients treated from 2017-2019 with intact brain metastases treated using a SIT or MIT with linear accelerator-based SRS. The typical prescription dose was 18 Gy in 1 fraction prescribed to the 80-90% isodose line. Time from end of treatment to local failure or radionecrosis (RN) for each lesion was recorded. On the per-lesion basis, local control (LC) and freedom-from-radionecrosis (FFR), were estimated with Kaplan Meier method and compared between SIT and MIT group via log-rank test. Evidence of RN was defined as radiographic evidence of cerebral edema surrounding a treated lesion with associated clinical symptoms. Multivariable analysis using Cox proportional-hazard regression was used to establish potential predictors for RN, and significance assessed by Likelihood ratio test.104 patients with a total of 437 metastases (80% supratentorial and 20% infratentorial) were included. 232 lesions were treated with a SIT approach, ranging from 2-13 (median 5) intact metastases treated per treatment course. Median radiographic follow up time was 6.4 months for SIT lesions and 10.7 months for MIT lesions. Primary malignancies included non-small cell lung cancer (n = 41), breast cancer (n = 33), melanoma (n = 14), gastrointestinal cancer (n = 6), head and neck cancer (n = 5), and kidney cancer (n = 5). On a per-lesion basis, 6-month LC was 97% for SIT and 99% for MIT (P = 0.12). On a per-lesion basis, 6-month FFR was 96% for SIT and 96% for MIT (P = 0.81). Fourteen patients developed symptomatic RN leading to steroid treatment in 7 patients, laser interstitial thermal therapy in 2 patients, anti-VEGF therapy in 3 patients, and continued observation in 2 patients. The only multivariable predictor for developing RN was increasing PTV size (HR 1.76, P < 0.01).These data indicate high rates of LC and low rates of RN for both MIT and SIT for SRS. Efficient and effective treatment planning and delivery for the treatment of multiple metastases with a single isocenter improves the clinical feasibility of delivering initial and subsequent radiosurgery courses for patients, allowing for optimal integration with systemic therapy in patients with metastatic disease.J. Deng: Employee; UCLA.M.K. Li: None. R.R. Savjani: Research Grant; ASTRO-Varian Research Training Fellowship. F. Chu: None. S.E. Tenn: Research Grant; Brain Lab. Honoraria; Brain Lab. C. Lee: Stock; Varian Medical Systems. N. Agazaryan: Honoraria; Brainlab and Novalis Accreditation. Consultant; Brainlab and Novalis Accreditation. expert panel member; Brainlab and Novalis Accreditation. I. Yang: Consultant; Baxter, Brain Lab. R. Everson: None. W. Kim: None. N. Pouratian: Research Grant and Speaker; Brain Lab. A.U. Kishan: None. R.K. Chin: None. M.L. Steinberg: None. T.B. Kaprealian: Research Grant and Honoraria; Brain Lab. J.V. Hegde: Research Grant; Soylent.

Ten Fraction Ultra-Central Thoracic Hypofractionated Stereotactic Body Radiotherapy (hfSBRT): An Analysis of Outcomes, Dosimetry, and Toxicity

<h3>Purpose/Objective(s)</h3> Treatment of ultra-central thoracic tumors, defined as tumors in which direct tumor abutment or planning target volume (PTV) overlap with the primary bronchial tree, great vessels or esophagus exists, remains challenging due to concern for treatment related toxicity and relative lack of dosimetric data to organs at risk (OARs). We report clinical outcomes, toxicity and dosimetric data for ultra-centrally located tumors. <h3>Materials/Methods</h3> Sixty-one ultra-centrally located lung tumors treated at a single institution between November 2009 and March 2017 were retrospectively reviewed. Overall survival (OS), progression free survival (PFS), and local control (LC) were calculated. Incidence and grade of treatment related toxicity were evaluated. Treatment dosimetry was analyzed. <h3>Results</h3> Median age at time of treatment was 70 years (38 to 96 years). Median follow up time was 14 months (1 to 102 months). Individuals underwent hfSBRT for primary (n = 21, 34%), limited metastatic (n = 17, 28%), or recurrent (n = 23, 38%) disease. Median treatment dose was 65 Gy (40 to 70 Gy), corresponding to a biologically effective dose (BED) of 107.25 Gy (56 to 119 Gy). Median PTV was 66cc (4 to 592cc). One- and three-year OS, PFS, and LC were 60%/24%, 37%/19%, and 84%/62% respectively. On univariate analysis, only treatment of locally recurrent disease was negatively correlated with LC (<i>P</i> = 0.026). This did not translate to inferior PFS or OS (<i>P</i> = 0.34 and 0.49 respectively). Median esophageal, maximum dose (Dmax) was 35 Gy, with a median V40 of 0cc. Median primary bronchial tree Dmax was 60 Gy, with a median V52 of 1.05cc. Median great vessel Dmax was 71 Gy, with a median V55.7 of 0.42cc. Grade 2 or higher pneumonitis was reported in 12 individuals (20%). This corresponded to 13% of individuals undergoing initial hfSBRT, and 30% of individuals undergoing re-irradiation (<i>P</i> = 0.09). Grade 3 or higher toxicity was reported in seven individuals (11%). This correlated to two grade 3 incidences of pneumonitis (one re-irradiation, one initial hfSBRT), one grade 3 esophagitis during re-irradiation (Dmax of 57.8 and V40 of 6.3cc), one grade 3 bronchial/tracheal fistula during initial hfSBRT (Dmax of 79.1 and V52 of 3.68cc), and three grade 5 hemoptysis events (all during re-irradiation). One hemoptysis event was categorized as "possibly" related to treatment, while the remaining two events were categorized as "unlikely" related to treatment with clear bronchoscopic or radiographic evidence of disease progression identified. <h3>Conclusion</h3> Our results demonstrate that 10-fraction ultra-central thoracic SBRT can be effectively administered with high rates of LC, favorable dosimetry, and acceptable rates of toxicity. Caution with re-treatment of ultracentral disease must be taken as this may be associated with increased toxicity, and inferior tumor control.

Sites of First Progression in the Randomized PET-Boost Trial for Patients With Locally Advanced NSCLC

<h3>Purpose/Objective(s)</h3> Curative intent conventional chemoradiotherapy for patients with locally advanced NSCLC is typically associated with high progression rates. In the PET-Boost trial, individualized dose escalation utilizing hypofractionation and functional imaging was tested as a strategy to improve local control. Here we report on sites of first recurrence. <h3>Materials/Methods</h3> We conducted a multi-institutional phase II study (NCT01024829). Patients with stage II-III NSCLC were randomized to receive either a boosted dose to the primary tumor (PT) as a whole (arm A) or to a region inside the PT with high FDG-uptake (> 50%SUV_max) (arm B). Boosted dose was delivered in 24 fractions of 3.0 Gy up to 5.4 Gy, limited by predefined OAR limits. Individualized isotoxic treatment plans were produced by equalizing the mean lung dose. Concurrent/sequential/no chemotherapy was allowed. This trial was conducted before immunotherapy became standard adjuvant treatment. Follow-up (PET/)CT-scans were scheduled at 3, 6, 12 and 18-months. The trial had a phase II, "pick the winner", non-comparative design with freedom from local failure rate at 1-year as primary endpoint. Overall survival was estimated using the Kaplan-Meier method. Local and regional failures (LF, RF) were assessed by central review of chest-CT scans. Distant metastases (DM) were reported by local investigators. LF, RF and DM are reported as site of first recurrence. Cumulative incidence rates of first recurrence site were, in competing risk with death, estimated by Aalen-Johansen method. <h3>Results</h3> Between April 2010 and Sept 2017, 54 patients were randomized to arm A and 53 to arm B. Majority of patients had a good performance status (WHO 0-1, 93%), stage III disease (82%) and were treated with concurrent-chemotherapy (72%). In arms A and B respectively, median PT GTV was 99 cc (IQR 67-175) and 115 cc (IQR 64-179). Median fraction dose was 3.25 Gy to PTV_{whole PT} and 3.5 Gy to PTV_50%SUVmax, resulting in median total planned physical dose 78 Gy and 84 Gy respectively. Central review identified 9 patients with missing scans, and 8 not-evaluable scans at 1 year (n = 4 due to surgery, n = 4 due to atelectasis, inflammation or fibrosis). Median FU for LF and RF was 12.6 months. At time of analysis, 36 and 39 patients had experienced a recurrence or died. In arms A and B respectively, the 1-year cumulative incidence rates (reported with 95% CI) for LF as site of first recurrence were 1.9% (0-6%) and 1.9% (0-6%), for RF 1.9% (0-6%) and 5.7% (0-12%), for DM 37.4% (24-50%) and 35.8% (23-49%), and for simultaneous multiple sites 3.7% (0-8%) and 1.9% (0-6%). Median FU for OS was 70.4 months. In arms A and B respectively, estimated 1-year survival was 77% and 62%. <h3>Conclusion</h3> While high local control rates were achieved in this phase II trial of hypofractionated dose escalation in patients with stage II-III NSCLC, distant metastases were frequently seen in this patient cohort with large primary tumors.

SBRT for the Treatment of Isolated Local Recurrence of Resected Pancreatic Cancer

<h3>Purpose/Objective(s)</h3> Following curative resection for pancreatic ductal adenocarcinoma (PDAC), there are high rates of local recurrence. The optimal treatment of patients with isolated local recurrence (ILR) – recurrence in the abdomen without distant metastases – is not known. This study evaluated stereotactic body radiation therapy (SBRT) as a treatment option for ILR. <h3>Materials/Methods</h3> A multi-institutional retrospective analysis was performed on patients with ILR of PDAC following oncologic surgical resection treated with SBRT. Patient demographics, tumor and prior treatment characteristics, details of recurrence, SBRT treatment design and dosimetry, and patient follow-up and toxicity data were recorded from the medical record. Progression and overall survival estimates were calculated using cumulative incidence and Kaplan-Meier models, respectively. <h3>Results</h3> Between January 2010 and December 2020, 34 patients (17 males and 17 females, median age 69 years) were treated at five institutions in the United States. At the time of initial resection, most patients had T3 tumors (71%) and involved lymph nodes (71%). 31 of 34 (91%) patients underwent a Whipple procedure and 3 (9%) had a distal pancreatectomy. The R0 resection rate was 68%. 29% and 85% received neoadjuvant or adjuvant chemotherapy, respectively; and 12% and 27% had prior neoadjuvant or adjuvant radiation courses around the time of initial surgical resection. Median time to ILR was 18.7mos. The most common location of recurrence was in the pancreatic remnant or near the superior mesenteric artery. All patients underwent 5-fraction photon (28 patients) or proton (6 patients) SBRT to a median dose of 3500cGy (range 3000-4000cGy) with a median BED of 5950cGy (α/β = 10). Median follow-up after SBRT was 3.05 years. The 1-year and 2-year cumulative incidence of cancer progression were 72% (95% CI 56-93%) and 92% (95% CI 76-100%). Distant metastasis was the most common site of first recurrence (15 of 23 recurrences, 65%). 6 patients (25%) had local failure as site of first recurrence. Prior radiation was not associated with increased risk of progression after SBRT (HR 1.31 95% CI 0.56-3.07, <i>P</i> = 0.54). 1-year and 2-year overall survival was 64% (95% CI 49-84%) and 40% (95% CI 25-64%), with a median survival of 1.2 years from time of SBRT. Four patients (12%) developed grade 3 toxicities within one year after completion of SBRT. There were no grade 4-5 toxicities. <h3>Conclusion</h3> For treatment of PDAC ILR after surgical resection, SBRT was well tolerated and offered high rates of local tumor control with low treatment-related toxicity.

Local Control in Tumor-Targeted Dose Escalation for Localized Prostate Cancer

Tumor-targeted dose escalation may improve biochemical disease-free survival in patients with localized prostate cancer. We report outcomes of dose escalation using a strategy of simultaneous integrated boost or HDR brachytherapy boost.Eighty patients with localized prostate cancer with gross tumor volume (GTV) identified on multiparametric magnetic resonance imaging (mpMRI) were enrolled in this phase 2 non-randomized trial (2012-2016). Patients with GTV > 5mm and less than 33% of total prostate volume were eligible. All patients received whole gland prostate volumetric arc therapy (VMAT), 76 Gy in 38 fractions. GTV dose escalation was delivered by integrated boost VMAT (IB-VMAT) of 95 Gy in 38 fractions (n = 40); or MR-guided HDR boost of 10 Gy in 1 fraction (n = 40). Choice of dose escalation strategy was by physician and/or patient choice. The primary end-point was 3-year local control rates determined by MR-guided biopsy and/or MRI alone. Toxicity data was collected using CTCAE v.4.0. Risk group categorization was similar between the arms; 5% low-, 75% intermediate-, and 20% high-risk. Three patients received 6-months ADT.Median (IQR) follow-up was 55.2 months (48.1-71.4). The overall 5-year biochemical failure-free survival was 92% (95% CI, 85-99), with 5 patients developing biochemical relapse (BCR); 1 IB-VMAT, 4 HDR boost. Local control data was available for 66 patients who agreed to the 3-year post-treatment biopsy (20) or MRI alone (46); 32 in IB-VMAT and 34 in HDR boost. Local control in the boost volume was achieved in 61 patients. One patient in the IB-VMAT arm had persistent disease on biopsy, and subsequently developed late BCR. Intraprostatic relapse outside the GTV was seen in 4 patients at last follow-up; 1 treated with IB-VMAT and 3 with HDR boost. All 4 patients developed BCR. Late G2 genitourinary (GU) toxicity was 22.5% and 27.5% in IB-VMAT and HDR boost, respectively. Late G2 gastrointestinal (GI) toxicity was 5% in each arm. Two G3 (1 GI, 1 GU) toxicities were seen in IB-VMAT.Dose escalation to mpMRI-defined GTV provided high rates of local and biochemical control with limited severe late toxicity. Intraprostatic failures outside the boost volume appeared to correlate with BCR, which suggests that dose escalation to other subclinical intraprostatic regions may be required. Further characterization using molecular classification, beyond usual clinical parameters, may be warranted in order to improve local control.

Three-Year Experience of a Multidisciplinary Central Nervous System Clinic Model for Radiation Oncology and Neurosurgery (RADIANS) in a Community Hospital Setting

As academic centers partner and establish healthcare systems with community hospitals, delivery of subspecialty, multidisciplinary care in community hospital settings remains a challenge. Improving outcomes for central nervous system (CNS) disease is related to integrated care between neurosurgery (NS) and radiation oncology (RadOnc) specialties. Our multidisciplinary community hospital-based clinic, RADIANS, previously reported high patient approval of simultaneous evaluation with NS and RadOnc physicians. Three-year experience is now reported. Prospectively collected clinical and demographic patient data over three years was done, and surveys administered. Descriptive statistics reported as mean and percentages for patient characteristics, diagnosis, treatment and outcomes. Between August 2016 and August 2019, 101 patients were evaluated. Mean age and distanced traveled was 61.2 years, and 54.9 miles, respectively. Patient Satisfaction Score was 4.79 (0-5 Scale, 5-very satisfied). Most common referral source was medical oncologists. Seventy-two patients had malignant CNS disease (brain mets 28; spine mets 27; both 6; primary brain 9; primary spine 2), 29 had benign CNS disease. Post-evaluation treatment: radiation therapy (RT) only (n=29), neurosurgery (NS) only (n=16), both RT and NS (n=22), and no RT/NS intervention (n=34). Fractionated stereotactic radiosurgery was most common RT delivered; craniotomy with tumor resection was most common NS performed. Treatment outcomes: local control=61/67 (91%); radiation necrosis or radiation-induced myelitis=2/51 (3.9%). The RADIANS multidisciplinary community hospital-based CNS clinic model is first of its kind to be reported, continuing strong patient approval at extended follow-up. Data indicates the model serves as a regional referral center, delivering evidence-based treatment modalities for complex CNS disease in community hospital settings, yielding high rates of local control and low rates of grade 3 or 4 radiation-induced toxicity.

Neoadjuvant Concurrent Radiotherapy and Chemotherapy in Early Breast Cancer Patients: Long-Term Results of a Prospective Phase II Trial.

Simple SummaryThe originality of this prospective study is to use radiation therapy in association with chemotherapy before surgery and permit patients to preserve their breasts or to undergo immediate reconstruction. This neoadjuvant strategy can therefore allow one-stage breast reconstructive surgery, the so-called “reverse technique”.Background: Neoadjuvant concurrent radiochemotherapy makes it possible to increase the breast conservation rate. This study reports the long term outcome of this treatment. Methods: From 2001 to 2003, 59 women with T2–3 N0–2 M0 invasive breast cancer (BC) not amenable to upfront breast conserving treatment (BCS) were included in this prospective, non-randomized phase II study. Chemotherapy (CT) consisted of four cycles of continuous 5-FU infusion and Vinorelbine. Starting concurrently with the second CT cycle, normofractionated RT was delivered to the breast and LN. Breast surgery was then performed. Results: Median follow-up (FU) was 13 years [3–18]. BCS was performed in 41 (69%) patients and mastectomy in 18 patients, with pathological complete response rate of 27%. Overall and distant-disease free survivals rates at 13 years were 70.9% [95% CI 59.6–84.2] and 71.5% [95% CI 60.5–84.5] respectively. Loco regional and local controls rates were 83.4% [95% CI 73.2–95.0] and 92.1% [95% CI 83.7–100], respectively. Late toxicity (CTCAE-V3) was assessed in 51 patients (86%) with a median follow-up of 13 years. Fifteen presented grade 2 fibrosis (29.4%), 8 (15.7%) had telangiectasia, and 1 had radiodermatitis. Conclusions: This combined treatment provided high long-term local control rates with limited side-effects.

Reirradiation With Stereotactic Radiosurgery After Local or Marginal Recurrence of Brain Metastases From Previous Radiosurgery

Brain metastases represent a major indication for stereotactic radiosurgery (SRS), but further study is needed regarding repeat SRS (SRS2) after local or marginal recurrence after prior SRS (SRS1). We report local tumor control (LC) after SRS2 and identify predictors of radiation necrosis (RN) and symptomatic RN (SRN). Patients had biopsy-proven non-small cell lung cancer and at least 1 brain metastasis previously treated with SRS. SRS2 was performed from 2015 to 2020 and required overlap of the prescription isodose lines with those from SRS1. Patients treated with preoperative SRS were excluded. Primary endpoints were LC by Response Assessment in Neuro-oncology criteria, RN, and SRN. From 8 institutions, 102 patients with 123 treated lesions were included. SRS2 was performed at a median 12 months after SRS1. SRS2 delivered a median 18 Gy (interquartile range [IQR], 16-18) margin dose to the 50% (IQR, 50%-70%) isodose line, maximum dose of 30.5 Gy (IQR, 25.0-36.0), and V12Gy of 3.38 cm3 (IQR, 0.83-7.64). One-year and 2-year LC were 79% and 72%, respectively. Local tumor control was improved with tumor volume ≤1 cm3 (P < .005). There were 25 (20%) cases of RN and 9 (7%) cases of SRN. For SRS1 and SRS2, SRN rates were higher with maximum doses ≥40 Gy or SRS2 V12Gy >9 cm3 (P < .025 for each). SRS1 and SRS2 maximum dose ≥40 Gy was also predictive of increased RN (P < .05 for each). Prior immunotherapy was not predictive of RN or SRN. Repeat SRS afforded a high rate of local tumor control and a low rate of SRN. At SRS2, V12Gy ≤9 cm3 and maximum dose <40 Gy may reduce the risks of RN and SRN. These results are most applicable to lesions with approximately 1 cm3 volume and 1-year interval between SRS courses.

Outcomes Following Hypofractionated Stereotactic Radiotherapy to the Cavity After Surgery for Melanoma Brain Metastases

AimsHypofractionated stereotactic radiotherapy (HSRT) to the cavity after surgical resection of brain metastases improves local control. Most reported cohorts include few patients with melanoma, a population known to have high rates of recurrence and neurological death. We aimed to assess outcomes in patients with melanoma brain metastases who received HSRT after surgery at two Australian institutions. Materials and methodsA retrospective analysis was carried out including patients treated between January 2012 and May 2020. HSRT was recommended for patients with melanoma brain metastases at high risk of local recurrence after surgery. Treatment was delivered using appropriately commissioned linear accelerators. Routine follow-up included surveillance magnetic resonance imaging brain every 3 months for at least 2 years. Primary outcomes were overall survival, local control, incidence of radiological radionecrosis and symptomatic radionecrosis. ResultsThere were 63 cavities identified in 57 patients. The most common HSRT dose prescriptions were 24 Gy in three fractions and 27.5 Gy in five fractions. The median follow-up was 32 months in survivors. Local control was 90% at 1 year, 83% at 2 years and 76% at 3 years. Subtotal brain metastases resection (hazard ratio 12.5; 95% confidence interval 1.4–111; P = 0.0238) was associated with more local recurrence. Overall survival was 64% at 1 year, 45% at 2 years and 40% at 3 years. There were 10 radiological radionecrosis events (16% of cavities) during the study period, with 5% at 1 year and 8% at 2 years after HSRT. The median time to onset of radiological radionecrosis was 21 months (range 6–56). Of these events, three became symptomatic (5%) during the study period at a median time to onset of 26 months (range 21–32). ConclusionCavity HSRT is associated with high rates of local control in patients with melanoma brain metastases. Subtotal resection strongly predicts for local recurrence after HSRT. Symptomatic radionecrosis occurred in 5% of cavities but increased to 8% of longer-term survivors.

Stereotactic body radiotherapy to treat breast cancer oligometastases: A systematic review with meta-analysis

ObjectivesStereotactic ablative radiotherapy (SABR) has been reported to be an effective treatment for oligometastatic disease from different primary cancer sites. Here we assess the effectiveness and safety of SABR for oligometastatic breast cancer patients by performing a meta-analysis. MethodsFollowing PRISMA and MOOSE guidelines, a systematic review and meta-analysis was performed. Eligible studies were identified on Medline, Embase, Cochrane Library, and annual meetings proceedings from 1990 to June 2021. A meta-regression analysis was performed to assess if there was a correlation between moderator variables and outcomes, and a p-value <0.05 was considered significant. ResultsTen studies met criteria for inclusion, comprising 467 patients and 653 treated metastases. The 1- and 2-year local control rates were 97% (95% CI 95–99%), and 90% (95% CI 84–94%), respectively. Overall survival (OS) was 93% (95% CI 89–96%) at 1 year, 81% (95% CI 72–88%) at 2 years. The rate of any grade 2 or 3 toxicity was 4.1 % (95% CI 0.1–5%), and 0.7% (0–1%), respectively. In the meta-regression analysis, only prospective design (p = 0.001) and bone-only metastases (p = 0.01) were significantly associated with better OS. In the subgroup analysis, the OS at 2y were significantly different comparing HER2+, HR+/HER2(-) and triple negative breast cancer 100%, 86% and 32%, p = 0.001. For local control outcomes, hormone receptor status (p = 0.01) was significantly associated on meta-regression analysis. ConclusionSABR for oligometastatic breast cancer is safe and associated with high rates of local control. Longer follow-up of existing data and ongoing prospective trials will help further define the role of this management strategy.

New enzyme-targeting radiosensitizer (KORTUC II) treatment for locally advanced or recurrent breast cancer.

Kochi oxydol radiation therapy for unresectable carcinomas II (KORTUC II) is currently the most widely used radiosensitizer in Japan. This sensitizer is a solution consisting of 0.83% sodium hyaluronate and 0.5% hydrogen peroxide. The mixture is injected intratumorally just before radiation therapy (RT) several times. KORTUC II has the effect of neutralizing antioxidant enzymes, while increasing the oxygen tension into the tumor tissue, and achieves marked local effects without notable adverse events. The present report describes cases in which KORTUC II was used to treat patients with locally advanced breast cancer (LABC) or recurrent breast cancer (LRBC). The present study included 30 patients with LABC (n=9) or LRBC (n=21) aimed at local control of tumors, who were followed up for ≥3 months after treatment. The irradiation dose and extent fields were determined by the attending physicians considering various patient factors, such as a performance status, prognosis and presence or absence of adjuvant therapy. The median irradiation dose was 60.4 Gy3.5 (43.6-76.1 Gy3.5) based on the calculation of equivalents of 2 Gy fractions, and the median total number of sensitizer injections was 5 (2-7) times. The median maximum tumor shrinkage was 97.0% and 15 patients (50%) were assessed to have achieved a clinical complete response. The proportion with loco-regional control at 1, 2 and 3 years was 100, 94.7 and 75.4%, respectively, and progression free survival after RT at 1 and 2 years was 59.0 and 24.1%, respectively. KORTUC II exhibited high rates of local tumor control for LABC and LRBC. KORTUC II is expected to be an inexpensive and promising RT method because it is safe and has an excellent radio-sensitizing effect.

Predicting the effect of indirect cell kill in the treatment of multiple brain metastases via single-isocenter/multitarget volumetric modulated arc therapy stereotactic radiosurgery.

PurposeDue to spatial uncertainty, patient setup errors are of major concern for radiosurgery of multiple brain metastases (m‐bm) when using single‐isocenter/multitarget (SIMT) volumetric modulated arc therapy (VMAT) techniques. However, recent clinical outcome studies show high rates of tumor local control for SIMT‐VMAT. In addition to direct cell kill (DCK), another possible explanation includes the effects of indirect cell kill (ICK) via devascularization for a single dose of 15 Gy or more and by inducing a radiation immune intratumor response. This study quantifies the role of indirect cell death in dosimetric errors as a function of spatial patient setup uncertainty for stereotactic treatments of multiple lesions.Material and MethodsNine complex patients with 61 total tumors (2‐16 tumors/patient) were planned using SIMT‐VMAT with geometry similar to HyperArc with a 10MV‐FFF beam (2400 MU/min). Isocenter was placed at the geometric center of all tumors. Average gross tumor volume (GTV) and planning target volume (PTV) were 1.1 cc (0.02–11.5) and 1.9 cc (0.11–18.8) with an average distance to isocenter of 5.4 cm (2.2–8.9). The prescription was 20 Gy to each PTV. Plans were recalculated with induced clinically observable patient setup errors [±2 mm, ±2o] in all six directions. Boolean structures were generated to calculate the effect of DCK via 20 Gy isodose volume (IDV) and ICK via 15 Gy IDV minus the 20 Gy IDV. Contributions of each IDV to the PTV coverage were analyzed along with normal brain toxicity due to the patient setup uncertainty. Induced uncertainty and minimum dose covering the entire PTV were analyzed to determine the maximum tolerable patient setup errors to utilize the ICK effect for radiosurgery of m‐bm via SIMT‐VMAT.ResultsPatient setup errors of 1.3 mm /1.3° in all six directions must be maintained to achieve PTV coverage of the 15 Gy IDV for ICK. Setup errors of ±2 mm/2° showed clinically unacceptable loss of PTV coverage of 29.4 ± 14.6% even accounting the ICK effect. However, no clinically significant effect on normal brain dosimetry was observed.ConclusionsRadiosurgery of m‐bm using SIMT‐VMAT treatments have shown positive clinical outcomes even with small residual patient setup errors. These clinical outcomes, while largely due to DCK, may also potentially be due to the ICK. Potential mechanisms, such as devascularization and/or radiation‐induced intratumor immune enhancement, should be explored to provide a better understanding of the radiobiological response of stereotactic radiosurgery of m‐bm using a SIMT‐VMAT plan.

High rate of local control and cure at 10 years after treatment of prostate cancer with external beam radiotherapy and high-dose-rate brachytherapy: a single centre experience

Background and purpose To analyse the cumulative incidence of any failure (AF), prostate cancer-specific failure (PCSF), any death (AD), prostate cancer-specific death (PCSD), and local control in 2387 men with prostate cancer (PC), consecutively treated with combined high-dose-rate brachytherapy (HDRBT) and external beam radiotherapy (EBRT) from 1998 to 2010. Material and methods A retrospective, single-institution study of men with localised PC. The mean age was 66 years and 54.7% had high-risk PC according to the Cambridge prognostic group (CPG) classification. The treatment was delivered as EBRT (2 Gy × 25) and HDRBT (10 Gy × 2) with combined androgen blockade (CAB). The median follow-up was 10.2 years. Results The cumulative incidence of PCSD at 10 years was 5% [CI 95% 0.04–0.06]. The 10 years PCSD per risk group were: low (L) 0.4%, intermediate favourable (IF) 1%, intermediate unfavourable (IU) 4.3%, high-risk favourable (HF) 5.8%, and high-risk unfavourable (HU) 13.9%. The PCSF rate at 10 years was 16.5% [CI 95% 0.15–0.18]. The PCSF per risk group at 10 years were: L 2.5%, IF 5.5%, IU 15.9%, HF 15.6%, and HU 38.99%. PCSF occurred in 399 men, of whom 15% were found to have local failure. The estimated frequency of local failure in the entire cohort was 1.2%. Conclusions HDRBT combined with EBRT is an effective treatment with long-term overall survival and excellent local control for patients with PC. The low rate of local recurrence among men with relapse suggests that these patients were micro metastasised at time of treatment, which calls for improved methods to detect disseminated disease.

Particle Radiotherapy for Skull Base Chondrosarcoma: A Clinical Series from Italian National Center for Oncological Hadrontherapy.

Simple SummarySkull-base chondrosarcoma is a rare locally aggressive or malignant group of cartilaginous neoplasm. The standard of care consists of surgery and high-dose radiation therapy, better if with particle, due to their radioresistance and proximity to organs at risk such as brainstem and optic pathways. Due to the rarity of the tumor and its site, outcomes in terms of local control and toxicity of patients with this malignancy after receiving particle therapy has been documented only in a limited number of series with a restricted number of patients, in particular with regard to carbon ions. The aim of our retrospective study is to assess the role of particle therapy (protons and carbon ions) after surgery in our Institute in skull-base chondrosarcomas. Background: The standard treatment for skull base chondrosarcoma (SB-CHS) consists of surgery and high-dose radiation therapy. Our aim was to evaluate outcome in terms of local control (LC) and toxicity of proton therapy (PT) and carbon ion (CIRT) after surgery. Materials and methods: From September 2011 to July 2020, 48 patients underwent particle therapy (67% PT, 33% CIRT) for SB-CHS. PT and CIRT total dose was 70 GyRBE (relative biological effectiveness) in 35 fractions and 70.4 GyRBE in 16 fractions, respectively. Toxicity was assessed using the Common Terminology Criteria for Adverse Events (CTCAE v5). Results: After a median follow-up time of 38 months, one local failure (2%) was documented and the patient died for progressive disease. Overall, 3-year LC was 98%. One (2%) and 4 (8%) patients experienced G3 acute and late toxicity, respectively. White-matter brain changes were documented in 22 (46%) patients, but only 7 needed steroids (G2). No patients had G3 brain toxicity. No G4–5 complications were reported. We did not find any correlation between high-grade toxicity or white-matter changes and characteristics of patients, disease and surgery. Conclusions: PT and CIRT appeared to be effective and safe treatments for patients with SB-CHS, resulting in high LC rates and an acceptable toxicity profile.

Stereotactic Radiosurgery for Postoperative Metastatic Surgical Cavities: A Critical Review and International Stereotactic Radiosurgery Society (ISRS) Practice Guidelines.

The purpose of this critical review is to summarize the literature specific to single-fraction stereotactic radiosurgery (SRS) and multiple-fraction stereotactic radiation therapy (SRT) for postoperative brain metastases resection cavities and to present practice recommendations on behalf of the ISRS. The Medline and Embase databases were used to apply the Preferred Reporting Items for Systematic Reviews and Meta-Analyses approach to search for manuscripts reporting SRS/SRT outcomes for postoperative brain metastases tumor bed resection cavities with a search end date of July 20, 2018. Prospective studies, consensus guidelines, and retrospective series that included exclusively postoperative brain metastases and had at minimum 100 patients were considered eligible. The Embase search revealed 157 manuscripts, of which 77 were selected for full-text screening. PubMed yielded 55 manuscripts, of which 23 were selected for full text screening. We deemed 8 retrospective series, 1 phase 2 prospective study, 3 randomized controlled trials, and 1 consensus contouring paper appropriate for inclusion. The data suggest that SRS/SRT to surgical cavities with prescription doses of 30 to 50 Gy equivalent effective dose (EQD) 210, 50 to 70 Gy EQD25, and 70 to 90 EQD22 are associated with rates of local control ranging from 60.5% to 91% (median, 80.5%). Randomized data suggest improved local control with single-fraction SRS compared with observation and improved cognitive outcomes compared with whole-brain radiation therapy (WBRT). The toxicity of SRS/SRT in the postoperative setting was limited and is reviewed herein. Although randomized data raise concern for poorer local control after resection cavity SRS than WBRT, these findings may be driven by factors such as conservative prescription doses used in the SRS arm. Retrospective studies suggest high rates of local control after single-fraction SRS and hypofractionated SRT for postoperative brain metastases. With a superior neurocognitive profile and no survival disadvantage to withholding WBRT, the ISRS recommends SRS as first-line treatment for eligible postoperative patients. Emerging data suggest that fractionated SRT may provide superior local control compared with single-fraction SRS, in particular, for large tumor cavity volumes/diameters and potentially for patients with a preoperative diameter greater than 2.5 cm.