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Purpose The currently used scheme for radioligand therapy (RLT) of patients with metastatic castration-resistant prostate cancer (mCRPC) consists of 4–6 cycles of 6.0–7.4 GBq [177Lu]Lu-PSMA-617 each. This standard treatment scheme has proved safe and effective resulting in objective response in most patients with no significant toxicity. Many patients, however, show high-volume residual tumor burden after the sixth cycle and may benefit from treatment continuation. Extended treatment with additional cycles has been withheld due to concerns on potential increased toxicity. Methods Twenty-six patients with high-volume residual tumor burden (according to CHAARTED) after standard RLT with [177Lu]Lu-PSMA-617 and no alternative treatment option received additional RLT cycles reaching a median of 10 (range 7–16) cycles with a mean activity of 7.4 ± 0.9 GBq per cycle. Response assessment with [68Ga]Ga-PSMA-11 PET/CT was done every 2–3 cycles or if disease progression was clinically suspected or based on change in PSA value (according to the PCWG3 criteria). Toxicity was measured using routine blood work up including blood counts, liver and renal function, and was graded according to CTCAE v5.0 criteria. Survival outcome was calculated based on the Kaplan-Meier method. Results Further PSA decline of 33 ± 28% during the extended treatment was observed in 21/26 (81%) patients, whereas 5/26 (19%) patients showed a PSA increase; correspondingly in 11/21 patients with an initial response (PR or SD) to extended cycles, treatment was discontinued due to progressive disease, whereas six (23%) patients achieved low-volume residual disease. Two (8%) patients died without showing progression, and two (8%) patients are still under therapy. The median progression-free survival was 19 (95% CI: 15–23) months, and the overall survival was 29 (95% CI: 18–40) months. Grade ≥ 3 hematological toxicities occurred in 4/26 (15%) patients during treatment extension, and nephrotoxicity (grade ≥ 3) was observed in 1/26 (4%) patient during the follow-up. Conclusion Extended radioligand therapy is a feasible treatment option in patients with high-volume residual tumor after the completion of standard treatment with six cycles of [177Lu]Lu-PSMA-617. Improved survival and the acceptable safety profile warrant further investigation of the concept of additional cycles in selected patients.

Current risk-stratification systems for prostate cancer (PCa) do not sufficiently reflect the disease heterogeneity. Genomic classifiers (GC) enable improved risk stratification after surgery, but less data exist for patients treated with definitive radiation therapy (RT) or RT in oligo-/metastatic disease stages. To guide future perspectives of GCs for RT, we conducted (1) a systematic review on the evidence of GCs for patients treated with RT and (2) a survey of experts using the Delphi method, addressing the role of GCs in personalized treatments to identify relevant fields of future clinical and translational research. We performed a systematic review and screened ongoing clinical trials on ClinicalTrials.gov. Based on these results, a multidisciplinary international team of experts received an adapted Delphi method survey. Thirty-one and 30 experts answered round 1 and round 2, respectively. Questions with ≥75% agreement were considered relevant and included in the qualitative synthesis. Evidence for GCs as predictive biomarkers is mainly available to the postoperative RT setting. Validation of GCs as prognostic markers in the definitive RT setting is emerging. Experts used GCs in patients with PCa with extensive metastases (30%), in postoperative settings (27%), and in newly diagnosed PCa (23%). Forty-seven percent of experts do not currently use GCs in clinical practice. Expert consensus demonstrates that GCs are promising tools to improve risk-stratification in primary and oligo-/metastatic patients in addition to existing classifications. Experts were convinced that GCs might guide treatment decisions in terms of RT-field definition and intensification/deintensification in various disease stages. This work confirms the value of GCs and the promising evidence of GC utility in the setting of RT. Additional studies of GCs as prognostic biomarkers are anticipated and form the basis for future studies addressing predictive capabilities of GCs to optimize RT and systemic therapy. The expert consensus points out future directions for GC research in the management of PCa. ispartof: Int J Radiat Oncol Biol Phys vol:116 issue:3 pages:503-520 ispartof: location:United States status: published

Epidemiological data indicate that more than 50 % of patients with newly-diagnosed rectal cancer are older than 70 years, with rising numbers expected over the next decades. Treatment decision-making is challenging in elderly and frail patients with rectal cancer, whereas standardized treatment guidelines for this patient cohort are lacking. Elderly and frail rectal cancer patients are often considered by surgeons as unfit to undergo radical surgery as the risk of surgical complications and postoperative mortality rises with increasing age and comorbidity. Furthermore, these patients often receive no treatment at all, resulting in local and/or systemic disease progression with associated symptoms and impaired quality of life (QoL). Recent data from randomized trials in young fit patients with early stage rectal cancer indicate that RT dose escalation can be safely delivered using external beam (chemo)radiotherapy (EBRT) followed by endoluminal radiotherapeutic modalities, such as contact X-ray brachytherapy (CXB) or high-dose rate endorectal brachytherapy (HDR-BT). However, prospective studies testing this therapeutic concept in elderly and frail patients remain limited. Here, we review the current evidence in the epidemiology and the management of elderly and frail patients with rectal cancer. We summarize the potential of RT dose escalation to achieve long-term local control of the primary tumour, prevent disease-related morbidity, improve QoL and even organ preservation. Future perspectives and open questions will be discussed as well.

Purpose High-dose-rate (HDR) brachytherapy (BRT) and stereotactic body radiotherapy (SBRT) are currently the two treatment options for definitive radiotherapy of prostate cancer, employing extreme hypofractionation. There are only very few studies comparing their dosimetry, all using computed tomography for treatment planning. We present here a real-word dosimetric comparison between SBRT and ultrasound-based virtual HDR-BRT, with both imaging modalities coming from the same patient. Methods and Materials Patients with prostate cancer on a prospective trial evaluating the toxicity of robotic-based SBRT were treated to a total dose of 35 Gy in 5 fractions. Fifteen patients were included in this analysis. During ultrasound-based fiducial implantation, a three-dimensional data set as in real HDR-BRT procedure was acquired. Virtual HDR-BRT plans were generated and various organs at risk and prostate dosimetric parameters were evaluated. Results Concerning prostate, SBRT achieved significant higher D98, V35 Gy, and V37.5 Gy coverage, whereas virtual HDR-BRT achieved significant higher intratumoral doses reflected in the V42 Gy and V52.5 Gy. Rectal Dmax, V36 Gy, and V29 Gy were significantly lower for HDR-BRT with no difference as for V18 Gy. SBRT was significantly inferior regarding bladder dosimetry (Dmax, V36 Gy, V18 Gy), whereas urethra Dmax and V44 Gy where significantly higher at the expense of HDR-BRT. Conclusions HDR-BRT is superior regarding rectum and bladder dosimetry, with SBRT being superior relative to urethra dosimetry. A randomized study is warranted to define the best extreme hypofractionated modality.

In order to improve oncologic outcomes in radiotherapy treatments of patients with unresectable pelvic sidewall recurrences of uterine cervical cancer, we combined high-dose-rate interstitial brachytherapy (HDR-ISBT) with newly tested hypoxic radiosensitizer Kochi oxydol-radiation therapy for unresectable carcinomas (KORTUC II), an enzyme-targeting radiosensitization treatment involving intra-tumoral injection of sodium hyaluronate mixed with hydrogen peroxide. We report on a 63-year-old patient referred to our department with an extensive pelvic sidewall recurrence of uterine cervical cancer after initial hysterectomy. The tumor size was 55 × 25 × 80 mm, with a calculated volume of 89.7 cc. Whole pelvic irradiation of 50 Gy in 25 fractions was administered, combined with weekly cisplatin injections. KORTUC II injections were given two times: at day 21 (42 Gy) and at day 24 (48 Gy). After finishing whole pelvic irradiation, HDR-ISBT of 25 Gy in 5 fractions b.i.d. over 3 days was administered. KORTUC II was also injected at the time of implantation. Dose-volume histogram (DVH) values for clinical target volume were D 90 , D 98 , and D 100 of 6.0, 5.0, and 3.5 Gy per fraction, respectively. D2cc values were 2.1, 4.1, 3.2, and 2.0 Gy per fraction for the bladder, rectum, sigmoid colon, and small bowel, respectively. No acute adverse events ≥ grade 3 were observed. Repeated grade 3 pyelonephritis occurred as a late complication at 11, 24, and 26 months after the treatment, and was successfully resolved with antibiotics. Moreover, grade 2 late toxicity was documented, including sciatic neuralgia, lower limb lymphedema, and urinary incontinence. At present, 32 months after HDR-ISBT, the patient remains free of disease, with no toxicity-related deterioration in physical condition.

Die neoadjuvante Strahlentherapie (RT) bzw. Radiochemotherapie (RCT) gilt als Standard in der multimodalen Behandlung des lokal fortgeschrittenen primaren Rektumkarzinoms. Im Fall eines Lokalrezidivs kann sie bei Patienten, bei denen eine kurative radikale Rezidivresektion fraglich erscheint, mit dem Ziel einer verbesserten Resektabilitat erneut eingesetzt werden. Bislang liegen keine prospektiven kontrollierten Phase-III-Studien zur praoperativen Rebestrahlung zur Behandlung des lokal rezidivierten Rektumkarzinoms (LRRK) vor. Konzepte und Ergebnisse der praoperativen Rebestrahlung bei der Behandlung des LRRK werden vorgestellt. Retrospektive Fallserien und prospektive Therapieoptimierungsstudien zur praoperativen Rebestrahlung bei der Behandlung des LRRK werden ausgewertet. Dosiskonzepte in kurativer und palliativer Intention sowie onkologische Ergebnisse werden vorgestellt. Eine Rebestrahlung mit 30–40 Gy als hyperfraktionierte (1,2–1,5 Gy zweimal taglich) oder konventionell fraktionierte (1,8 Gy einmal taglich) RCT mit 5‑FU oder Capecitabin ist bei LRRK mit einem medianen Uberleben von 39–60 Monaten im neoadjuvanten Ansatz bei resezierten Patienten und von 12–16 Monaten im palliativen Konzept assoziiert. Die akute gastrointestinale Toxizitat belauft sich auf 9–20 % bei unzureichender Datenlage zur Spattoxizitat. Eine praoperative RT/RCT des LRRK mit dem Ziel einer kurativen Resektion ist im Sinne einer Rebestrahlung durchfuhrbar. Zur Begrenzung der Toxizitat sollte eine hyperfraktionierte RT/RCT bevorzugt werden. In der palliativen Situation kann die konventionell fraktionierte RCT zu einer guten Symptomkontrolle fuhren.

Bone-seeking 223Radium-dichloride (223Ra) is an established treatment prolonging survival and reducing morbidity in selected patients with metastatic castration-resistant prostate cancer (mCRPC) with skeletal involvement. Radioligand therapy with 177Lutetium-PSMA-617 (177Lu-PSMA-617) has been increasingly implemented in patients with mCRPC failing conventional treatment options. In this study, the safety and efficacy of 177Lu-PSMA-617 in patients with progressive bone involvement under treatment with 223Ra was assessed. Twenty-eight men (median age 73 years, range 63–89 years) with progressive mCRPC, who started 177Lu-PSMA-617 within 8 weeks after the last 223Ra administration, received a median of 4 (IQR 3–6) and a total of 120 cycles of 223Ra and a median of 4 (IQR 2–7) cycles 177Lu-PSMA-617 with a mean treatment activity of 6.5 ± 1.2 GBq per cycle, reaching a mean cumulative activity of 30.7 ± 23.4 GBq. A PSA response (≥50% PSA decline 12 weeks after the first 177Lu-PSMA-617 cycle) was observed in 18/28 (64.3%) patients and imaging-based partial remission (PR) was observed in 11/28 (39.3%) patients. Median imaging-based progression-free survival (PFS) was 10 (95% CI, 6–14) months and median overall survival (OS) was 18 (95% CI, 14–22) months. Patients with low bone tumor burden (2–20 lesions) had a significantly longer OS (28 vs. 14 months, p < 0.045) compared to patients with a high tumor burden (>20 lesions). Grade ≥ 3 hematological toxicity was observed in six patients after their last treatment cycle with anemia, leukopenia and thrombocytopenia in 5/28 (17.9%), 4/28 (14.3%) and 6/28 (21.4%) patients, respectively. In progressive bone-metastatic mCRPC patients, prompt initiation of 177Lu-PSMA-617 after failing 223Ra is effective with an acceptable toxicity profile.

Purpose As the population ages, the incidence of rectal cancer among elderly patients is rising. Due to the risk of perioperative morbidity and mortality, alternative nonoperative treatment options have been explored in elderly and frail patients who are clinically inoperable or refuse surgery. Methods Here we present technical considerations and first clinical experience after treating a cohort of six rectal cancer patients (T1‑3, N0‑1, M0; UICC stage I-IIIB) with definitive external-beam radiation therapy (EBRT) followed by image-guided, endorectal high-dose-rate brachytherapy (HDR-BT). Patients were treated with 10–13 × 3 Gy EBRT followed by HDR-BT delivering 12–18 Gy in two or three fractions. Tumor response was evaluated using endoscopy and magnetic resonance imaging of the pelvis. Results Median age was 84 years. All patients completed EBRT and HDR-BT without any high-grade toxicity (> grade 2). One patient experienced rectal bleeding (grade 2) after 10 weeks. Four patients (67%) demonstrated clinical complete response (cCR) or near cCR, there was one partial response, and one residual tumor and hepatic metastasis 8 weeks after HDR-BT. The median follow-up time for all six patients is 42 weeks (range 8–60 weeks). Sustained cCR without evidence of local regrowth has been achieved in all four patients with initial (n)cCR to date. Conclusion Primary EBRT combined with HDR-BT is feasible and well tolerated with promising response rates in elderly and frail rectal cancer patients. The concept could be an integral part of a highly individualized and selective nonoperative treatment offered to patients who are not suitable for or refuse surgery.

Bone-seeking 223Radium-dichloride (223Ra) is an established treatment prolonging survival and reducing morbidity in selected patients with metastatic castration-resistant prostate cancer (mCRPC) with skeletal involvement. Radioligand therapy with 177Lutetium-PSMA-617 (177Lu-PSMA-617) has been increasingly implemented in patients with mCRPC failing conventional treatment options. In this study, the safety and efficacy of 177Lu-PSMA-617 in patients with progressive bone involvement under treatment with 223Ra was assessed. Twenty-eight men (median age 73 years, range 63–89 years) with progressive mCRPC, who started 177Lu-PSMA-617 within 8 weeks after the last 223Ra administration, received a median of 4 (IQR 3–6) and a total of 120 cycles of 223Ra and a median of 4 (IQR 2–7) cycles 177Lu-PSMA-617 with a mean treatment activity of 6.5 ± 1.2 GBq per cycle, reaching a mean cumulative activity of 30.7 ± 23.4 GBq. A PSA response (≥50% PSA decline 12 weeks after the first 177Lu-PSMA-617 cycle) was observed in 18/28 (64.3%) patients and imaging-based partial remission (PR) was observed in 11/28 (39.3%) patients. Median imaging-based progression-free survival (PFS) was 10 (95% CI, 6–14) months and median overall survival (OS) was 18 (95% CI, 14–22) months. Patients with low bone tumor burden (2–20 lesions) had a significantly longer OS (28 vs. 14 months, p < 0.045) compared to patients with a high tumor burden (>20 lesions). Grade ≥ 3 hematological toxicity was observed in six patients after their last treatment cycle with anemia, leukopenia and thrombocytopenia in 5/28 (17.9%), 4/28 (14.3%) and 6/28 (21.4%) patients, respectively. In progressive bone-metastatic mCRPC patients, prompt initiation of 177Lu-PSMA-617 after failing 223Ra is effective with an acceptable toxicity profile.

Baseline uptake on prostate-specific membrane antigen (PSMA)-targeted imaging is a prerequisite for radioligand therapy (RLT) with [177Lu]Lu-PSMA-617. This study aims to quantify lesion-based response to RLT in relation to pretreatment standard molecular imaging metrics derived from [68Ga]Ga-PSMA-11 PET/CT. Sixty-one patients with mCRPC underwent [68Ga]Ga-PSMA-11 PET/CT imaging before and after a median of 4 (IQR 2–6) RLT cycles. Maximum and mean standardized uptake values (SUVmax, SUVmean), as well as tumor-to-liver ratio (TLR), were assessed. A median of 12 (IQR 7–17) lesions was analyzed per patient, resulting in a total of 718 lesions. Lesions with ≥30% SUVmax decline or falling below the blood pool uptake were considered responsive; ≥30% SUVmax increase marked lesion progression. Additionally, 4-point visual scoring was performed according to E-PSMA consensus. In total, 550/718 (76.6%) lesions responded to RLT, including 389/507 (76.7%) bone metastases and 143/181 (79.0%) lymph node metastases. Baseline SUVmax, SUVmean, and TLR values were associated with lesion response by a moderate but significant correlation (rs = 0.33, p < 0.001, rs = 0.32, p < 0.001, and rs = 0.31, p < 0.001, respectively). For the classification of lesion progression based on baseline PSMA uptake, receiver operating characteristics (ROC) found SUVmax, SUVmean, and TLR to have comparable discriminatory value (AUC 0.85, 0.87, and 0.83). Of 42 tumor sites with baseline uptake below the liver (V-score < 2), 19/42 (45.2%) were responsive, 9/42 (21.4%) were stable, and 14/42 (33.3%) showed progression, leaving liver uptake a threshold with low prognostic value for the identification of RLT-refractory lesions (PPV 33%). This was observed accordingly for various liver uptake-based thresholds, including TLR < 1.5

Purpose: Tongue edema is a potential cause of treatment target underdosage in high-dose-rate interstitial brachytherapy (HDR-ISBT) of mobile tongue cancer. To prevent such edema-associated alteration of dosimetry, we developed a special silicon device. In this report we communicate our initial experience with two mobile tongue cancer patients whom we treated using this new device. Material and methods: The device consists of silicone tubes with a fixed width and scalable length depending on tongue size. These tubes are lined and fixed like a palisade, allowing the device to be used also as a template. The device is placed next to the lateral border of the tongue and on the floor of the mouth. In addition, a vinyl template can be placed on the dorsal tongue surface with both devices combined for implantation guidance. Between June and August 2012, two patients with locally confined tongue cancer were treated. Results: Between June and August 2012, two mobile tongue cancer patients classified as cT2N0M0 were treated with HDR-ISBT using the silicone device. They underwent ISBT as monotherapy with fractional doses of 6.0 Gy up to a total physical dose of 54.0 Gy. The D90 (CTV) values of both patients were 6.3 Gy and 6.6 Gy and the D2cc (mandible) values were 3.4 Gy and 2.6 Gy, respectively. At present, both patients remain without local disease recurrence at 60 and 56 months after ISBT, respectively. Conclusions: The described silicone device has the potential to prevent underdosage to the treatment target related to tongue edema. It has been shown to be safe and easy to implement.

Bone-seeking

Simple Summary Despite the implementation of efficient screening and vaccination programs, uterine cervical cancer remains a leading cause of cancer-related mortality in women worldwide. New therapeutic approaches have so far failed to improve treatment response and prognosis significantly, especially in patients with recurrent disease or metastases. Further, robust molecular markers to predict therapy response and survival are scarce and their routine use is limited in clinical practice. Accordingly, there is an urgent need to identify and establish molecular markers to predict therapy response and clinical outcome to improve treatment and survival in cervical cancer. Abstract Uterine cervical cancer is one of the leading causes of cancer-related mortality in women worldwide. Each year, over half a million new cases are estimated, resulting in more than 300,000 deaths. While less-invasive, fertility-preserving surgical procedures can be offered to women in early stages, treatment for locally advanced disease may include radical hysterectomy, primary chemoradiotherapy (CRT) or a combination of these modalities. Concurrent platinum-based chemoradiotherapy regimens remain the first-line treatments for locally advanced cervical cancer. Despite achievements such as the introduction of angiogenesis inhibitors, and more recently immunotherapies, the overall survival of women with persistent, recurrent or metastatic disease has not been extended significantly in the last decades. Furthermore, a broad spectrum of molecular markers to predict therapy response and survival and to identify patients with high- and low-risk constellations is missing. Implementation of these markers, however, may help to further improve treatment and to develop new targeted therapies. This review aims to provide comprehensive insights into the complex mechanisms of cervical cancer pathogenesis within the context of molecular markers for predicting treatment response and prognosis.

Perirectal hyaluronate gel injection (HGI) appears to be a promising technique for healthy tissue dose sparing in pelvic radiotherapy. In this analysis, we report our initial experience of HGI in gynecologic brachytherapy, focusing on its safety and effectiveness for dose reduction to the rectum. Between July 2013 and May 2014, 36 patients received HGI for primary/salvage gynecologic brachytherapy. Dosimetric effect analysis was based on pre- and post-HGI computed tomography dataset registration with corresponding dose–volume histogram evaluation. The maximum dose to the most exposed 0.1 cm3 (D0.1cm3) and 2.0 cm3 (D2.0cm3) were used as index values for rectum and bladder dose evaluation. The dose indexes for target volume (TV) coverage were TV D90/V100. In all cases, HGI was well tolerated, with no acute or late adverse events documented at a median follow-up of 220 days (range, 18–1046 days). Rectum D2.0cm3 and D0.1cm3 were significantly decreased by HGI (P < 0.001 and P = 0.003, respectively), with no significant impact on dosimetric parameters of bladder and TV coverage. Factors correlating negatively with the dosimetric effect of HGI were an increasing number of interstitial catheters (P = 0.003) as well as Lcranial100% (P = 0.014) and Lcranial80% (P = 0.001) [i.e. the length from the anal verge to the most cranial point at which the 100% and 80% isodose lines, respectively, crossed the rectum]. The concept of HGI for gynecologic brachytherapy is plausible, and our initial experience indicates it to be an effective technique for rectal dose reduction in radiotherapy of intrapelvic tumours.

Purpose The purpose of this study was to report our initial experience of hyaluronic acid gel injection (HGI) in the vesicovaginal septum (VVS) for bladder dose reduction in brachytherapy (BT) for uterine cervical carcinoma. Material and methods Between September 2016 and May 2018, 15 uterine cervical cancer patients received HGI in the VVS as a part of their definitive radiotherapy (RT) treatment consisting of external beam radiation therapy (EBRT) with additional BT. Of those, 9 patients received BT both with and without HGI, and remaining 6 patients were excluded because these 6 patients received HGI in the VVS for all BT fractions. All 9 patients received HGI in the rectovaginal septum. For these patients, the dosimetric parameters bladder D2cc, HR-CTV D90, and rectum D2cc were selected, and two groups were generated (BT with vs. without HGI in the VVS) for dosimetric comparison. Results The median cumulative EQD2 for HR-CTV, rectum D2cc, and bladder D2cc for the 9 patients were 73.3, 52.8, and 67.1, respectively. While no statistical difference could be detected for rectal dose reduction, bladder dose was significantly less in the group with HGI in the VVS compared to that without (449 cGy [range, 416-566, 1SD = 66.1] vs. 569 cGy [range, 449-647, 1SD = 59.5], p = 0.033), with no compromising of target coverage. Although it did not reach statistically significance, there was a trend toward better HR-CTV D90 in the group with HGI compared to that without HGI in the VVS (713 cGy vs. 706 cGy, p = 0.085). No severe bleeding, hematuria, bladder wall injury, or urethral injury requiring hospitalization was experienced in association with HGI in the VVS. Conclusions HGI in the VVS can be performed safely and can effectively reduce the bladder dose in BT for uterine cervical cancer patients.

Background Myelosuppression is a potential dose-limiting factor in radioligand therapy (RLT). This study aims to investigate occurrence, severity and reversibility of hematotoxic adverse events in patients undergoing RLT with 177Lu-PSMA-617 for metastatic castration-resistant prostate cancer (mCRPC). The contribution of pretreatment risk factors and cumulative treatment activity is taken into account specifically. Methods RLT was performed in 140 patients receiving a total of 497 cycles. A mean activity of 6.9 \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\pm$$\end{document}± 1.3 GBq 177Lu-PSMA-617 per cycle was administered, and mean cumulative activity was 24.6 \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\pm$$\end{document}± 15.9 GBq. Hematological parameters were measured at baseline, prior to each treatment course, 2 to 4 weeks thereafter and throughout follow-up. Toxicity was graded based on Common Terminology Criteria for Adverse Events v5.0. Results Significant (grade ≥ 3) hematologic adverse events occurred in 13 (9.3%) patients, with anemia in 10 (7.1%), leukopenia in 5 (3.6%) and thrombocytopenia in 6 (4.3%). Hematotoxicity was reversible to grade ≤ 2 through a median follow-up of 8 (IQR 9) months in all but two patients who died from disease progression within less than 3 months after RLT. Myelosuppression was significantly more frequent in patients with pre-existing grade 2 cytopenia (OR: 3.50, 95%CI 1.08–11.32, p = 0.04) or high bone tumor burden (disseminated or diffuse based on PROMISE miTNM, OR: 5.08, 95%CI 1.08–23.86, p = 0.04). Previous taxane-based chemotherapy was associated with an increased incidence of significant hematotoxicity (OR: 4.62, 95%CI 1.23–17.28, p = 0.02), while treatment with 223Ra-dichloride, cumulative RLT treatment activity and activity per cycle were not significantly correlated (p = 0.93, 0.33, 0.29). Conclusion Hematologic adverse events after RLT have an acceptable overall incidence and are frequently reversible. High bone tumor burden, previous taxane-based chemotherapy and pretreatment grade 2 cytopenia may be considered as risk factors for developing clinically relevant myelosuppression, whereas cumulative RLT activity and previous 223Ra-dichloride treatment show no significant contribution to incidence rates. Supplementary Information The online version contains supplementary material available at 10.1186/s13550-021-00805-7.

BACKGROUND Facial skin cancer lesions in close proximity to critical organs require further development of radiotherapeutic techniques for highly conformal treatment, especially when treating elderly frail patients. We report on our treatment technique and first clinical experience for patients with perinasal/periorbital skin cancer treated with individualized epithetic mold high-dose-rate brachytherapy (BRT). METHODS From January 2019, patients with complex shaped or unfavorably located skin cancer not eligible for surgery or external beam radiotherapy (RT) were screened for mold-based BRT. Six patients were identified. Toxicity and clinical response were documented during therapy and posttreatment follow-up. RESULTS Median patient age was 80 years (74-92 years). Median prescription dose was 42 Gy (range, 33-44 Gy) delivered in once-daily fractions of 3 or 4 Gy. Two patients had treatment interruptions caused by acute conjunctivitis grade 2 and a nontreatment-related cardiac event, respectively. At a median follow-up of 335 days (96-628 days), no ≥ grade 2 late toxicity was documented with all patients showing complete clinical response. CONCLUSIONS High-dose-rate BRT with individualized epithetic molds for perinasal/periorbital skin cancer is a well-tolerated and safe treatment option for patients not eligible for primary surgery or definitive external beam RT because of comorbidities or tumor location.

We aimed to evaluate the factors associated with hemorrhage (HA) of melanoma brain metastases (MBM) after Cyberknife stereotactic radiosurgery (SRS) in the modern era of systemic therapy. A total of 55 patients with 279 MBM were treated in 93 fractions. The median age, SRS dose, radiological follow-up, and time to HA were 60.4 years, 20 Gy, 17.7 months, and 10.7 months, respectively. Radiologically evident HA was documented in 47 (16.8%) metastases. Of the 55 patients, 25 (45.4%) suffered an HA. Among those, HA caused grade 3 toxicity in 10 patients (40%) and grade 1 symptoms in 5 patients (20%). Ten patients (40%) with HA experienced no toxicity. Logistic regression revealed the use of anticoagulants and the administration of systemic therapy within 7/15 days from SRS to be predictive for HA. When considering the HA causing grade 3 symptomatology, only the use of anticoagulants was significant, with the delivery of whole brain radiation therapy (WBRT) before the HA narrowly missing statistical significance. Our retrospective analysis showed that the administration of modern systemic therapy within 7/15 days from SRS may contribute to HA of MBM, though it appears safe, at least concerning grade 3 toxicity. The use of anticoagulants by the time of SRS significantly increased the risk of HA.

To compare dosimetrically the radiation exposure to heart, left ventricle (LV), and left anterior descending artery (LAD) between whole-breast radiotherapy (WBRT) with Active Breathing Coordinator (ABC; ABC-WBRT) and interstitial multicatheter high-dose-rate (HDR) brachytherapy as accelerated partial breast irradiation (ABPI; imHDR-APBI) for left-sided breast cancer (BCA) after breast-conserving surgery (BCS). Between January 2016 and December 2019, 32 and 20 patients were treated with ABC-WBRT (63 Gy/2.25 Gy) and imHDR-APBI (32 Gy/4 Gy), respectively. Among them a matched-pair analysis was performed according to tumor location (clock position) before BCS as well as planning target volume of imHDR-APBI and boost volume of ABC-WBRT. This yielded 17 pairs of patients for whom dosimetric parameters for heart, LV, and LAD were evaluated. The Mann–Whitney test was used for comparison after adjusting for equivalent dose in 2‑Gy fractions (EQD2). In addition, a second analysis of ABC-WBRT to 40.05 Gy in 15 fractions was performed in order to account for the EQD2 difference between the 63-Gy ABC-WBRT and the imHDR-APBI protocol. Tumor location for the 17 pairs of patients relative to breast quadrant was as follows: upper outer 8, lower outer 5, upper inner 3, and lower inner 1. There was no difference regarding mean heart dose (MHD) and V5, whereas D25%, D45%, V10, and V25 significantly favored imHDR-APBI. Likewise, mean dose- and V5-LV did not differ, while Dmax- and V23-LV were significantly higher for ABC-WBRT. For LAD, Dmax, D25%, and V30 significantly favored imHDR-APBI without differences for mean dose and V40. When comparing imHDR-APBI with the 40.05 Gy ABC-WBRT schedule, MHD and mean dose LV were significantly lower in favor of ABC-WBRT. ABC-WBRT and imHDR-APBI yield similar low heart and LV exposure for left-sided BCA after BCS, whereas LAD can be better spared with imHDR-APBI.

This study aimed to determine the efficacy and safety of robotic-based fractionated stereotactic radiotherapy (FSRT) in the treatment of large brainstem metastases (BSMs).Ten BSM were treated in ten patients with FSRT between January 2012 and December 2018. The median age was 61 years (range, 53-74 years) with a median Karnofsky Performance Score of 80 (range, 70-90). Four patients (40%) had received whole-brain radiotherapy prior to FSRT. The median tumor volume was 4.2 cmRobotic-based FSRT for BSM appears to be safe with favorable LC and low toxicity even for large tumors.

An innovative template, based on thoracic cage surface reconstructions for breast interstitial brachytherapy was developed. Hybrid-inverse-planning-optimisation-based implantations and brachytherapy plans, using three custom anthropomorphic breast phantoms, were utilised for its validation. A user independent, inverse planning and inverse implanting technique is proposed.

Purpose To report the clinical outcomes and treatment-related toxicities after combined high-dose-rate (HDR) brachytherapy (BRT) with external beam radiotherapy (EBRT) for patients with clinically localised high-risk prostate cancer. Material and methods Between 2008 and 2012, three hundred and three consecutive patients with organ-confined high-risk prostate cancer were treated with definitive radiotherapy consisting of HDR-BRT followed by supplemental EBRT. The transrectal 3D-ultrasound-based HDR-BRT boost consisted of two single-fraction implants of 10.5 Gy, prescribed to the 90% of the gland (D90), for a total physical dose of 21.0 Gy delivered to the prostatic gland. EBRT was delivered with conventional fractionation, prescribing 45.0 Gy to the prostatic gland and seminal vesicles. Biochemical failure was defined according to the Phoenix Consensus Criteria, genitourinary (GU)/gastrointestinal (GI) toxicity was evaluated using the Common Toxicity Criteria for Adverse Events (version 3.0). Results The median follow-up was 71.6 months. The 7-year overall survival, biochemical control and metastasis-free-survival rates for the entire cohort were 85.7%, 88.3% and 93.8%, respectively. Androgen deprivation therapy was initiated prior to treatment for 92.7% of patients with a median duration of 12 months. Toxicity was scored per event with late Grade 2, 3 and 4 GU adverse events and was found to be 15.3%, 2.2% and 0.3%, respectively. Late Grade 2 GI toxicity accounted for 0.3% with no instances of Grade 3 or higher late adverse events. Conclusion HDR-BRT with supplemental EBRT results in low biochemical relapse-free survival rates associated with a very low incidence of higher-grade late adverse events.

Purpose The aim of this study was to investigate the efficacy and safety of image-guided high-dose-rate (HDR) interstitial brachytherapy (ISBT) for reirradiation of locally recurrent uterine cervical cancer. Methods and Materials Between 2008 and 2015, patients receiving reirradiation using HDR-ISBT for local gross recurrence of uterine cervical cancer after definitive or postoperative radiotherapy were analyzed retrospectively. The prescription doses per fraction ranged 2.5–6.0 Gy, whereas the cumulative equivalent doses in 2 Gy fractions ranged 48.6–82.5 Gy. The effects of prognostic factors on the local control (LC), progression-free survival, and overall survival were analyzed, and late toxicity data were evaluated. Results Eighteen patients were included in the analysis, with a median followup of 18.1 months. A tumor response was obtained in all patients, with radiological and pathological complete remission seen in 12 (66.7%) patients. The 2-year LC, progression-free survival, and overall survival rates for all patients were 51.3%, 20.0%, and 60.8%, respectively. The hemoglobin level and maximum tumor diameter were shown to be statistically significant prognostic factors for LC (p = 0.028 and 0.009, respectively). Late ≥ Grade 2 adverse events were observed in 5 patients (27.8%). Conclusions Image-guided HDR-ISBT for the reirradiation of locally recurrent uterine cervical cancer may play an important role for local tumor control in a subgroup of patients. However, the treatment indication must be weighed against the risk of higher-grade late toxicity.

Background and purpose To evaluate the oncological outcome of a three-implant high dose rate (HDR) brachytherapy (BRT) protocol as monotherapy for clinically localised prostate cancer. Material and methods Between February 2008 and December 2012, 450 consecutive patients with clinically localised prostate cancer were treated with HDR monotherapy. The cohort comprised of 198 low-, 135 intermediate- and 117 high risk patients being treated with three single-fraction implants of 11.5 Gy delivered to an intraoperative real-time, transrectal ultrasound defined planning treatment volume up to a total physical dose of 34.5 Gy with an interfractional interval of 21 days. Fifty-eight patients (12.8%) received ADT, 32 of whom were high- and 26 intermediate-risk. Biochemical failure was defined according to the Phoenix Consensus Criteria and genitourinary/gastrointestinal toxicity evaluated using the Common Toxicity Criteria for Adverse Events version 3.0. Results The median follow-up time was 56.3 months. The 60-month overall survival, biochemical control and metastasis-free-survival rates were 96.2%, 95.0% and 99.0%, respectively. Toxicity was scored per event with late Grade 2 and 3 genitourinary adverse events of 14.2% and 0.8%, respectively. Late Grade 2 gastrointestinal toxicity amounted 0.4% with no instances of Grade 3 or greater late adverse events to be reported. Conclusions Our results confirm HDR BRT to be a safe and effective monotherapeutic treatment modality for clinically localised prostate cancer.

Purpose: When squamous cell carcinoma of the buccal mucosa (BSCC) extends surrounding anatomical sites such as gingiva, retromolar triangle, or hard palate, it might be challenging to ensure adequate tumor coverage by sole interstitial brachytherapy due to the complexity of catheter implantation. By combining interstitial catheters with an enoral placed, individually assembled “oral spacer plus embedded catheters” device (hybrid of intracavitary-interstitial brachytherapy), it should be easier to deliver the necessary tumoricidal dose to irregular-shaped tumor volumes (clinical target volume – CTV) with improved conformity. The purpose of this analysis was to compare the dose distribution created by the hybrid of intracavitary-interstitial brachytherapy (HBT) with the dose distribution of an interstitial catheter only-approach, based on the interstitial catheters used for HBT (ISBT-only) by evaluating respective treatment plans (HBT plan vs. ISBT-only plan) for the treatment of early stage BSCC. Material and methods: A retrospective analysis was performed for patients with localized BSCC treated between April 2013 and October 2017. All patients received sole HBT without additional external beam radiation therapy or planned neck dissection. Dosimetric parameters taken into account for comparison between actual HBT and virtual ISBT-only were CTV D90, CTV V100, CTV V150, CTV V200, mandible D2cc, and mucosal surface D2cc. Results: Dosimetrically, HBT showed a trend toward better CTV D90 compared to ISBT-only. In addition, HBT demonstrated statistically better CTV V100 coverage compared to ISBT-only. There was no statistically significant difference with respect to CTV V150, CTV V200, and mucosal surface D2cc, while a trend was seen in better mandible D0.1cc between HBT and ISBT-only. Conclusions: The HBT approach appears to enable improved dose coverage of irregular-shaped enoral tumor volumes compared to ISBT-only for patients with early stage BSCC.

The aim of this article is to review and present the published data on high dose rate (HDR) brachytherapy as monotherapy in the treatment of localised prostate cancer. A search and review of the literature was carried out on PubMed and MedLine using the medical subject headings 'high-dose-rate, brachytherapy, prostate cancer, monotherapy' as search terms. The search yielded more than 100 articles and abstracts published between 2000 and 2016. Only original clinical data on HDR monotherapy reporting oncological outcomes were included. When more than one series from the same institution were identified, the most recent one encompassing the largest patient number was considered for analysis. For citation crosscheck, the ISI web of science database was used employing the same search terms. Data tables were generated and summary descriptions created. The main outcome parameters used were biochemical control and toxicity scores. Fifteen articles comprising 3546 patients reported clinical outcome and toxicity, with follow-up ranging from median 1.4 to 8.0 years. A variety of dose and fractionation schedules were described, including 19.0 Gy as a single fraction to 54.0 Gy in nine fractions. Biochemical control rates ranged from 66 to 100% in low-risk, 63 to 98% in intermediate-risk and 81-93% in high-risk patients. Late grade 3 genitourinary and gastrointestinal toxicity was 0-16% and 0-2%, respectively. The reported potency preservation rates ranged from 60 to 90%. In conclusion, high biochemical control and low complication rates are reported with HDR monotherapy. It is a safe and effective local treatment modality for organ-confined prostate cancer with reproducible high-quality dosimetry.

Purpose Intratarget dose escalation with superior conformity is a defining feature of three-dimensional (3D) iridium-192 ( 192 Ir) high-dose-rate (HDR) brachytherapy (BRT). In this study, we analyzed the dosimetric characteristics of interstitial 192 Ir HDR BRT for intrathoracic and cerebral malignancies. We examined the dose gradient sharpness of HDR BRT compared with that of linear accelerator–based stereotactic radiosurgery and stereotactic body radiation therapy, usually called X-Knife, to demonstrate that it may as well be called a Knife. Methods and Materials Treatment plans for 10 patients with recurrent glioblastoma multiforme or intrathoracic malignancies, five of each entity, treated with X-Knife (stereotactic radiosurgery for glioblastoma multiforme and stereotactic body radiation therapy for intrathoracic malignancies) were replanned for simulated HDR BRT. For 3D BRT planning, we used identical structure sets and dose prescription as for the X-Knife planning. The indices for qualitative treatment plan analysis encompassed planning target volume coverage, conformity, dose falloff gradient, and the maximum dose–volume limits to different organs at risk. Results Volume coverage in HDR plans was comparable to that calculated for X-Knife plans with no statistically significant difference in terms of conformity. The dose falloff gradient—sharpness—of the HDR plans was considerably steeper compared with the X-Knife plans. Conclusions Both 3D 192 Ir HDR BRT and X-Knife are effective means for intratarget dose escalation with HDR BRT achieving at least equal conformity and a steeper dose falloff at the target volume margin. In this sense, it can reasonably be argued that 3D 192 Ir HDR BRT deserves also to be called a Knife, namely Iridium-Knife.

To review the current status of interstitial high-dose-rate brachytherapy as a salvage modality (sHDR BRT) for locally recurrent prostate cancer after definitive radiotherapy (RT). A literature search was performed in PubMed using “high-dose-rate, brachytherapy, prostate cancer, salvage” as search terms. In all, 51 search results published between 2000 and 2016 were identified. Data tables were generated and summary descriptions created. The main outcome parameters used were biochemical control (BC) and toxicity scores. Eleven publications reported clinical outcome and toxicity with follow-up ranging from 4–191 months. A variety of dose and fractionation schedules were described, including 19.0 Gy in 2 fractions up to 42.0 Gy in 6 fractions. The 5‑year BC ranged from 18–77%. Late grade 3 genitourinary and gastrointestinal toxicity was 0–32% and 0–5.1%, respectively. sHDR BRT appears as safe and effective salvage modality for the reirradiation of locally recurrent prostate cancer after definitive RT.

Background In recurrent head and neck cancer, therapeutic options are limited and high-quality evidence is rare. The purpose of this report was to present our experience of CT-guided interstitial high-dose rate (HDR) brachytherapy in 4 challenging cases of inoperable recurrent head and neck cancer. Methods A 53-year-old man with mucosal melanoma of the paranasal sinuses, a 61-year-old man with myofibroblastic sarcoma of the nasal cavity, a 51-year-old woman with nasopharyngeal cancer, and a 44-year-old woman with orbital leiomyosarcoma were treated with reirradiation by HDR brachytherapy after previous comprehensive therapy, including full course external radiotherapy (RT). Results All patients showed response to brachytherapy with 1 patient experiencing locoregional failure. The mean lesion-specific disease control was 15 months. Currently, 1 patient is alive and 3 patients died after mean 20 months after treatment. Conclusion In patients with inoperable recurrent head and neck cancer, CT-guided interstitial HDR brachytherapy can play a role in providing palliation and tumor control. © 2017 Wiley Periodicals, Inc. Head Neck 39: E61-E68, 2017.

Background Locally advanced uterine cervical cancer (LAUCC) with lateral tumor extension may not always be covered adequately by conventional intracavitary brachytherapy (ICBT). Hybrid intracavitary and interstitial brachytherapy (HBT) seems to be an effective alternative by improving anatomy-oriented dose optimisation. The purpose of this study was to report initial clinical result for LAUCC treated by HBT. Methods Between January 2012 and November 2015, 42 patients with LAUCC (T1b2-4a) were treated with primary radiation therapy including HBT. Patients with distant metastasis other than para-aortic lymph node spread were excluded from this study. A retrospective analysis was performed for toxicity evaluation and oncological outcome calculation. Results Median follow-up was 23.2 months (range 13.2–71.4). Two-year overall survival, progression free survival, and local control rate were 81.6, 54.4, and 80.2%, respectively. Seven patients experienced local recurrence (16.6%). Of those, five were confined to the uterus and two at the parametria. Late adverse events ≥ grade 3 were seen in 3 patients. Conclusions HBT can generate favorable local control in tumors which cannot be adequately covered by ICBT.