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Background: The spine is the most frequent location of bone metastases. Local treatment aims at palliation of pain and, given the increased likelihood of long-term cancer survival, at local control. Kyphoplasty and intraoperative radiotherapy (Kypho-IORT) provided instantaneous pain relief in 70% of patients at the first day after the intervention and resulted in local control rates of > 93% at 1 year in a recently conducted phase I/II trial. To assess its clinical value, we designed a phase III trial which tests Kypho-IORT against the most widespread standard-of-care, external beam radiotherapy (EBRT), in patients with painful vertebral metastases., Methods: This phase III study includes patients ≥50 years of age with up to 4 vertebral metastases and a pain score of at least 3/10 points on the visual/numeric analogy scale (VAS). Patients randomized into the experimental arm (A) will undergo Kypho-IORT (Kyphoplasty plus IORT with 8 Gy prescribed to 13 mm depth). Patients randomized into the control arm (B) will receive EBRT with either 30 Gy in 10 fractions or 8 Gy as a single dose. The primary end point is pain reduction defined as at least - 3 points on the VAS compared to baseline at day 1. Assuming that 40% of patients in the Kypho-IORT arm and 5% of patients in the control arm will achieve this reduction and 20% will drop out, a total of 54 patients will have to be included to reach a power of 0.817 with a two-sided alpha of 0.05. Secondary endpoints are evaluation of the percentage of patients with a pain reduction of at least 3 points at 2 and 6 weeks, local tumor control, frequency of re-intervention, secondary fractures/sintering, complication rates, skin toxicity/wound healing, progression-free survival (PFS), overall survival (OS) and quality of life., Discussion: This trial will generate level 1 evidence on the clinical value of a one-stop procedure which may provide instantaneous pain relief, long-term control and shortened intervals to further adjuvant (systemic) therapies in patients with spinal metastases., Trial Registration: Registered with ClinicalTrials.gov, number: NCT02773966 (Registration date: 05/16/2016).

Background: The median time to recurrence of glioblastoma (GB) following multimodal treatment is ∼7 mo. Nearly all cancers recur locally, suggesting that augmenting local treatments may improve outcomes., Objective: To investigate whether intraoperative radiotherapy (IORT) to the resection cavity is safe and effective., Methods: INTRAGO was a phase I/II trial to evaluate the safety and tolerability of IORT with 20 to 40 Gy of low-energy photons in addition to standard radiochemotherapy (ClinicalTrials.gov ID, NCT02685605). The primary endpoint was safety as per occurrence of dose-limiting toxicities. Secondary endpoints were progression-free survival (PFS) and overall survival (OS). We also performed an exploratory analysis of the local PFS (L-PFS), defined as recurrence within 1 cm of the treated margin., Results: Fifteen patients were treated at 3 dose levels. Of these, 13 underwent incomplete resection, 6 had unresected satellites, and 3 did not receive per-protocol treatment (PPT). The MGMT promoter was unmethylated in 10 patients. The median follow-up was 13.8 mo. The majority of grade 3 to 5 adverse events were deemed unrelated to IORT. Five cases of radionecrosis were observed, 2 were classified as grade 3 events. Other grade 3 events judged related to radiotherapy (external-beam radiotherapy and/or IORT) were wound dehiscence (n = 1), CSF leakage (n = 1), cyst formation (n = 1). No IORT-related deaths occurred. The median PFS was 11.2 mo (95% confidence interval [CI]: 5.4-17.0) for all patients and 11.3 mo (95% CI: 10.9-11.6) for those receiving PPT. The median L-PFS was 14.3 mo (95% CI: 8.4-20.2) for all patients and 17.8 mo (95% CI: 9.7-25.9) for those receiving PPT. The median OS was 16.2 mo (95% CI: 11.1-21.4) for all patients and 17.8 mo (95% CI: 13.9-21.7) for those receiving PPT., Conclusion: These data suggest that IORT is associated with manageable toxicity. Considering the limitations of a 15-patient phase I/II trial, further studies aimed at assessing an outcome benefit are warranted.

Background: Glioblastoma multiforme (GBM) is the most frequent primary malignant brain tumor in adults. Despite multimodal therapies, almost all GBM recur within a narrow margin around the initial resected lesion. Thus, novel therapeutic intensification strategies must target both, the population of dispersed tumor cells around the cavity and the postoperative microenvironment. Intraoperative radiotherapy (IORT) is a pragmatic and effective approach to sterilize the margins from persistent tumor cells, abrogate post-injury proliferative stimuli and to bridge the therapeutic gap between surgery and radiochemotherapy. Therefore, we have set up INTRAGO, a phase I/II dose-escalation study to evaluate the safety and tolerability of IORT added to standard therapy in newly diagnosed GBM. In contrast to previous approaches, the study involves the application of isotropic low-energy (kV) x-rays delivered by spherical applicators, providing optimal irradiation properties to the resection cavity., Methods/design: INTRAGO includes patients aged 50 years or older with a Karnofsky performance status of at least 50% and a histologically confirmed (frozen sections) supratentorial GBM. Safety and tolerability (i.e., the maximum tolerated dose, MTD) will be assessed using a classical 3 + 3 dose-escalation design. Dose-limiting toxicities (DLT) are wound healing deficits or infections requiring surgical intervention, IORT-related cerebral bleeding or ischemia, symptomatic brain necrosis requiring surgical intervention and early termination of external beam radiotherapy (before the envisaged dose of 60 Gy) due to radiotoxicity. Secondary end points are progression-free and overall survival., Trial Registration: The study is registered with clinicaltrials.gov, number: NCT02104882 (Registration Date: 03/26/2014).

Background: Since the results from the randomized TARGIT A trial were published, intraoperative radiotherapy (IORT) is used more often. IORT can be provided as accelerated partial breast irradiation (APBI) or as a boost. The definition of suitable patients for IORT as APBI differs between different national societies (e.g. ESTRO and ASTRO) and different inclusion criteria of trials and so does the eligibility of patients. This analysis identifies eligible patients for IORT according to available consensus statements and inclusion criteria of the ongoing TARGIT trials., Methods: Between 01/03 - 12/09, 1505 breast cancer cases were treated at the breast cancer center at the University Medical Center Mannheim. Complete data sets for age, stage (T, N, and M), histology and hormone receptor status were available in 1108 cases. Parameters to identify eligible patients are as follows: ESTRO: >50 years, invasive ductal carcinoma/other favorable histology (IDC), T1-2 (≤3 cm), N0, any hormone receptor status, M0; ASTRO: ≥60 years, IDC, T1, N0, positive estrogen hormone receptor status, M0; TARGIT E "elderly", risk adapted radiotherapy with IORT followed by external beam radiotherapy in case of risk factors in final histopathology, phase II: ≥70 years, IDC, T1, N0, any hormone receptor status, M0; TARGIT C "consolidation", risk adapted radiotherapy, phase IV: ≥50 years, IDC, T1, N0, positive hormone receptor status, M0; TARGIT BQR "boost quality registry": every age, every histology, T1-2 (max. 3.5 cm), any hormone receptor status, N0/+, M0/+., Results: Out of the 1108 cases, 379 cases (34.2%) were suitable for IORT as APBI regarding the ESTRO and 175 (15.8%) regarding the ASTRO consensus statements. 82 (7.4%) patients were eligible for the TARGIT E trial, 258 (23.3%) for the TARGIT C trial and 671 (60.6%) for the TARGIT BQR registry. According to the consensus statements of ASTRO (45.1%) and ESTRO (41.4%) about half of the eligible patients were treated with IORT as APBI. From the eligible patients fulfilling the criteria for IORT boost (35%) about one third was eventually treated., Conclusions: Patient selection for IORT should be restrictive. For IORT as APBI the TARGIT trials are even more restrictive including patients than the ESTRO and ASTRO consensus statements.

Simple Summary: This multicenter study (n = 1133, inclusion criteria: 3.5 cm maximum tumor size and preoperative indication for a boost) provides detailed data on acute and long-term toxicities in breast cancer patients undergoing breast-conserving surgery combined with an anticipated intraoperative boost with low-energy X-rays followed by whole breast irradiation. Toxicity assessments, based on LENT SOMA criteria, were performed annually up to 10 years of follow-up. IORT boost was completed in 90% and EBRT in 97% of cases. No grade 3 or 4 acute toxicities were observed, with mild acute side effects reported in a small proportion of patients. Chronic toxicities were seen in 16.2% of patients with teleangiectasia, 14.3% with grade ≥ 2 fibrosis, 3.4% with grade ≥ 2 pain, and 1.1% with hyperpigmentation. The results show that the therapy is safe and feasible in terms of toxicity and confirms intraoperative boost as a standard method of boost application in a large prospective cohort. In the context of breast cancer treatment optimization, this study prospectively examines the feasibility and outcomes of utilizing intraoperative radiotherapy (IORT) as a boost in combination with standard external beam radiotherapy (EBRT) for high-risk patients. Different guidelines recommend such a tumor bed boost in addition to whole breast irradiation with EBRT for patients with risk factors for local breast cancer recurrence. The TARGIT BQR (NCT01440010) is a prospective, multicenter registry study aimed at ensuring the quality of clinical outcomes. It provides, for the first time, data from a large cohort with a detailed assessment of acute and long-term toxicity following an IORT boost using low-energy X-rays. Inclusion criteria encompassed tumors up to 3.5 cm in size and preoperative indications for a boost. The IORT boost, administered immediately after tumor resection, delivered a single dose of 20 Gy. EBRT and systemic therapy adhered to local tumor board recommendations. Follow-up for toxicity assessment (LENT SOMA criteria: fibrosis, teleangiectasia, retraction, pain, breast edema, lymphedema, hyperpigmentation, ulceration) took place before surgery, 6 weeks to 90 days after EBRT, 6 months after IORT, and then annually using standardized case report forms (CRFs). Between 2011 and 2020, 1133 patients from 10 centers were preoperatively enrolled. The planned IORT boost was conducted in 90%, and EBRT in 97% of cases. Median follow-up was 32 months (range 1–120, 20.4% dropped out), with a median age of 61 years (range 30–90). No acute grade 3 or 4 toxicities were observed. Acute side effects included erythema grade 1 or 2 in 4.4%, palpable seroma in 9.1%, punctured seroma in 0.3%, and wound healing disorders in 2.1%. Overall, chronic teleangiectasia of any grade occurred in 16.2%, fibrosis grade ≥ 2 in 14.3%, pain grade ≥ 2 in 3.4%, and hyperpigmentation in 1.1%. In conclusion, a tumor bed boost through IORT using low-energy X-rays is a swift and feasible method that demonstrates low rates in terms of acute or long-term toxicity profiles in combination with whole breast irradiation. [ABSTRACT FROM AUTHOR]

In the randomised TARGIT-A trial, risk-adapted targeted intraoperative radiotherapy (TARGIT-IORT) during lumpectomy was non-inferior to whole-breast external beam radiotherapy, for local recurrence. In the long-term, no difference was found in any breast cancer outcome, whereas there were fewer deaths from non-breast-cancer causes. TARGIT-IORT should be included in pre-operative consultations with eligible patients. [ABSTRACT FROM AUTHOR]

The term IORT (intraoperative radiotherapy) is currently used for various techniques that show huge differences in dose delivery and coverage of the tissue at risk. The largest evidence for boost IORT preceding whole breast irradiation (WBI) originates from intraoperative electron treatments (IOERT) with single doses around 10 Gy. At median follow-up periods at 6 years, outstandingly low local recurrence rates of less than 1% are observed. Higher local relapse rates were described for G3 tumors and triple negative breast cancers as well as for IORT following primary systemic treatment for locally advanced tumors. Even there, long term (>5y) local tumor control rates mostly beyond 95% were maintained. Compared to other boost methods, an intraoperative treatment has evident advantages in terms of precision (by avoiding a "spatial and/or temporal miss"), cosmetic outcome and patient comfort. Direct visualisation of a tumor bed during surgery guarantees for an accurate dose delivery, which has additionally gained importance in times of primary reconstruction techniques after lumpectomy, since IORT is performed before breast tissue including parts of the tumor bed is mobilized for plastic purposes. As a consequence of direct tissue exposure without distension by hematoma/seroma, IORT allows for small treatment volumes and complete skin sparing, both having a positive effect on late tissue tolerance and, hence, cosmetic appearance. Boost IORT marginally prolongs the surgical procedure, while significantly shortening postoperative radiotherapy. Its combination with external beam radiotherapy to the whole breast (WBI) is currently tested in two multicentric prospective trials: as kV-IORT in the multicentric TARGIT-B (oost) study, and as IOERT in the HIOB trial (3 weeks hypofractionated WBI preceded by IORT electron boost). [ABSTRACT FROM AUTHOR]

Accelerated partial breast irradiation (APBI) has been under clinical investigation for more than 15 years. There are several technical approaches that are clinically established, e.g. brachytherapy, intraoperative radiotherapy (IORT), or external-beam radiotherapy. The understanding of the underlying biology, optimal technical procedures, patient selection criteria, and imaging changes during follow-up has increased enormously. After completion of several phase III trials using brachytherapy or IORT, APBI is currently increasingly used either in phase IV studies, registries, or in selected patients outside of clinical studies. Consensus statements about suitable patients are available from several international and national societies like ASTRO, ESTRO, and DEGRO. One may expect that 15-25% of patients undergoing breast-conserving surgery may qualify for APBI, i.e. patients with small invasive ductal breast cancer without clinical lymph node involvement. [ABSTRACT FROM AUTHOR]