High-dose-rate brachytherapy at 3 Gy per fraction for lip carcinoma: Treatment outcomes and toxicity at 5-years.

PURPOSE: Low-dose-rate brachytherapy (LDR-BT) is a well-established treatment for lip cancer. High-dose-rate (HDR)-BT is a promising alternative to LDR-BT, but data are limited. In this context, we retrospectively evaluated treatment outcomes in a series of patients who underwent HDR-BT for lip carcinoma between 2003 and 2021. MATERIALS AND METHODS: A total of 32 patients were included in this study, with a median age of 73.5 years (range, 61 - 88). The indications for HDR-BT were as follows: primary treatment (n = 17), adjuvant treatment (n = 3), and recurrent disease after surgery (n = 12). The prescribed dose was 18 fractions of 3 Gy administered twice daily. RESULTS: At a median followup of 45 months (range, 12 -232), the 5-year local recurrence-free interval was 96.9% (95% CI: 90.9-100%), the disease-free interval was 85% (95% CI: 70.9-99.1), and 5-year overall survival was 64.7% (95% CI: 44.7-84.8). Eleven patients died, all on age related comorbidities. Acute toxicity manifested as G1 dry desquamation in 6 patients (18.8%), G2 erythema in 10 patients (31.2%) and G3 confluent moist desquamation in 16 patients (50%). Late complications included G1 fibrosis (100% of cases). G1 and G2 depigmentation was observed in 8 (25%) and 6 (18%) patients, G1 telangiectasia occurred in 5 patients (16%). CONCLUSIONS: These data support the use of HDR-BT for lip cancer. The dose and fractionation schedule used in this study (18 fractions x 3 Gy twice daily) seems to be effective and safe.

High-Dose-Rate Brachytherapy as an Organ-Sparing Treatment for Early Penile Cancer.

BACKGROUND: Low-dose-rate brachytherapy is an effective organ-sparing treatment for patients with early-stage penile cancer. However, only limited data are available on the role of high-dose-rate brachytherapy (HDR-BT) in this clinical setting. METHODS: Between 2002 and 2020, 31 patients with early penile cancer were treated at our center with interstitial HDR BT at a dose of 18 × 3 Gy twice daily. A breast brachytherapy template was used for the fixation of stainless hollow needles. RESULTS: The median follow-up was 117.5 months (range, 5-210). Eight patients (25.8%) developed a recurrence; of these, seven were salvaged by partial amputation. Six patients died of internal comorbidities or a second cancer. The probability of local control at 5 and 10 years was 80.7% (95% CI: 63.7-97.7%) and 68.3% (95% CI: 44.0-92.6%), respectively. Cause-specific survival was 100%. Only one case of radiation-induced necrosis was observed. The probability of penile sparing at 5 and 10 years was 80.6% (95% CI: 63.45-97.7%) and 62.1% (95% CI: 34.8-89.4%), respectively. CONCLUSIONS: These results show that HDR-BT for penile cancer can achieve results comparable to LDR-BT with organ sparing. Despite the relatively large patient cohort-the second largest reported to date in this clinical setting-prospective data from larger samples are needed to confirm the role of HDR-BT in penile cancer.

Cardiac doses of accelerated partial breast irradiation with perioperative multicatheter interstitial brachytherapy.

PURPOSE: To quantify mean heart dose (MHD) and doses to the left anterior descending artery (LAD) and left ventricle (LV) in a retrospective series of patients who underwent perioperative accelerated partial breast irradiation with multicatheter interstitial brachytherapy (MIB-APBI). METHODS: Sixty-eight patients with low-risk left breast cancer were treated with MIB-APBI at our institution between 2012 and 2017. Interstitial tubes were inserted during the tumorectomy and sentinel node biopsy and APBI was started 6 days later. The prescribed dose was 34 Gy in 10 fractions (twice a day) to the clinical target volume (CTV). The heart, LAD, and LV were contoured and the distance between each structure and the CTV was measured. The MHD, mean and maximum LAD doses (LAD mean/max), and mean LV doses (LV mean) were calculated and corrected to biologically equivalent doses in 2­Gy fractionation (EQD2). We also evaluated the impact of the distance between the cardiac structures and the CTV and of the volume receiving the prescribed dose (V100) and high-dose volume (V150) on heart dosimetry. RESULTS: Mean EQD2 for MHD, LAD mean/max, and mean LV were 0.9 ± 0.4 Gy (range 0.3-2.2), 1.6 ± 1.1 Gy (range, 0.4-5.6), 2.6 ± 1.9 Gy (range, 0.7-9.2), and 1.3 ± 0.6 Gy (range, 0.5-3.4), respectively. MHD, LAD mean/max, and LV mean significantly correlated with the distance between the CTV and these structures, but all doses were below the recommended limits (German Society of Radiation Oncology; DEGRO). The MHD and LV mean were significantly dependent on V100. CONCLUSION: Perioperative MIB-APBI resulted in low cardiac doses in our study. This finding provides further support for the value of this technique in well-selected patients with early-stage left breast cancer.

Accelerated partial breast irradiation with perioperative multicatheter interstitial brachytherapy-A feasibility study.

PURPOSE: To assess the feasibility of high-dose-rate perioperative multicatheter interstitial brachytherapy to deliver accelerated partial breast irradiation (APBI) in selected patients with early breast cancer. METHODS AND MATERIALS: Perioperative multicatheter interstitial brachytherapy for APBI has been used at our department since 2012 for patients with low-risk breast cancer. Interstitial catheters were inserted perioperatively via hollow needles immediately following tumorectomy with sentinel node biopsy. APBI started on Day 6 after surgery. The prescribed dose was 34 Gy (10 fractions of 3.4 Gy bid). Hormonal therapy was prescribed in all cases. RESULTS: Between June 2012 and December 2017, 125 patients were scheduled for APBI. Of these, APBI was not performed in 12 patients (9.6%) due to adverse prognostic factors identified on the definitive biopsy. We observed wound dehiscence in 2/113 cases (1.8%), inflammatory complications requiring antibiotics in 7/113 cases (6.2%), transient Grade I radiodermatitis in 6/113 patients (4.4%), and seroma which resolved spontaneously in 3/113 patients (2.7%). With median followup of 39 months (range 3.3-75.3) no relapses were observed. No late complications in Radiation Therapy Oncology Group Grade 3 or higher were documented. Cosmetic outcome in patients with followup > 2 years was excellent or good in 92%. CONCLUSION: Our preliminary results show that the perioperative multicatheter interstitial high-dose-rate brachytherapy for APBI in selected patients with early breast cancer is feasible. This treatment schedule reduces treatment duration, spares the patients of repeated anesthesia, and enables precise application of the afterloading tubes under direct visual control.

Bone Marrow-sparing Intensity Modulated Radiation Therapy With Concurrent Cisplatin For Stage IB-IVA Cervical Cancer: An International Multicenter Phase II Clinical Trial (INTERTECC-2).

PURPOSE: To test the hypothesis that intensity modulated radiation therapy (IMRT) reduces acute hematologic and gastrointestinal (GI) toxicity for patients with locoregionally advanced cervical cancer. METHODS AND MATERIALS: We enrolled patients with stage IB-IVA cervical carcinoma in a single-arm phase II trial involving 8 centers internationally. All patients received weekly cisplatin concurrently with once-daily IMRT, followed by intracavitary brachytherapy, as indicated. The primary endpoint was the occurrence of either acute grade ≥3 neutropenia or clinically significant GI toxicity within 30 days of completing chemoradiation therapy. A preplanned subgroup analysis tested the hypothesis that positron emission tomography-based image-guided IMRT (IG-IMRT) would lower the risk of acute neutropenia. We also longitudinally assessed patients' changes in quality of life. RESULTS: From October 2011 to April 2015, 83 patients met the eligibility criteria and initiated protocol therapy. The median follow-up was 26.0 months. The incidence of any primary event was 26.5% (95% confidence interval [CI] 18.2%-36.9%), significantly lower than the 40% incidence hypothesized a priori from historical data (P=.012). The incidence of grade ≥3 neutropenia and clinically significant GI toxicity was 19.3% (95% CI 12.2%-29.0%) and 12.0% (95% CI 6.7%-20.8%), respectively. Compared with patients treated without IG-IMRT (n=48), those treated with IG-IMRT (n=35) had a significantly lower incidence of grade ≥3 neutropenia (8.6% vs 27.1%; 2-sided χ2P=.035) and nonsignificantly lower incidence of grade ≥3 leukopenia (25.7% vs 41.7%; P=.13) and any grade ≥3 hematologic toxicity (31.4% vs 43.8%; P=.25). CONCLUSIONS: IMRT reduces acute hematologic and GI toxicity compared with standard treatment, with promising therapeutic outcomes. Positron emission tomography IG-IMRT reduces the incidence of acute neutropenia.

Highly Efficient Training, Refinement, and Validation of a Knowledge-based Planning Quality-Control System for Radiation Therapy Clinical Trials.

PURPOSE: To demonstrate an efficient method for training and validation of a knowledge-based planning (KBP) system as a radiation therapy clinical trial plan quality-control system. METHODS AND MATERIALS: We analyzed 86 patients with stage IB through IVA cervical cancer treated with intensity modulated radiation therapy at 2 institutions according to the standards of the INTERTECC (International Evaluation of Radiotherapy Technology Effectiveness in Cervical Cancer, National Clinical Trials Network identifier: 01554397) protocol. The protocol used a planning target volume and 2 primary organs at risk: pelvic bone marrow (PBM) and bowel. Secondary organs at risk were rectum and bladder. Initial unfiltered dose-volume histogram (DVH) estimation models were trained using all 86 plans. Refined training sets were created by removing sub-optimal plans from the unfiltered sample, and DVH estimation models… and DVH estimation models were constructed by identifying 30 of 86 plans emphasizing PBM sparing (comparing protocol-specified dosimetric cutpoints V10 (percentage volume of PBM receiving at least 10 Gy dose) and V20 (percentage volume of PBM receiving at least 20 Gy dose) with unfiltered predictions) and another 30 of 86 plans emphasizing bowel sparing (comparing V40 (absolute volume of bowel receiving at least 40 Gy dose) and V45 (absolute volume of bowel receiving at least 45 Gy dose), 9 in common with the PBM set). To obtain deliverable KBP plans, refined models must inform patient-specific optimization objectives and/or priorities (an auto-planning "routine"). Four candidate routines emphasizing different tradeoffs were composed, and a script was developed to automatically re-plan multiple patients with each routine. After selection of the routine that best met protocol objectives in the 51-patient training sample (KBPFINAL), protocol-specific DVH metrics and normal tissue complication probability were compared for original versus KBPFINAL plans across the 35-patient validation set. Paired t tests were used to test differences between planning sets. RESULTS: KBPFINAL plans outperformed manual planning across the validation set in all protocol-specific DVH cutpoints. The mean normal tissue complication probability for gastrointestinal toxicity was lower for KBPFINAL versus validation-set plans (48.7% vs 53.8%, P<.001). Similarly, the estimated mean white blood cell count nadir was higher (2.77 vs 2.49 k/mL, P<.001) with KBPFINAL plans, indicating lowered probability of hematologic toxicity. CONCLUSIONS: This work demonstrates that a KBP system can be efficiently trained and refined for use in radiation therapy clinical trials with minimal effort. This patient-specific plan quality control resulted in improvements on protocol-specific dosimetric endpoints.

High-dose-rate brachytherapy in early oral cancer with close or positive margins.

PURPOSE: Retrospective evaluation of high-dose-rate brachytherapy (HDR BT) in early oral cancer and factors influencing tumor control. METHODS AND MATERIALS: A total of 30 patients with T1-T3N0 tongue and floor of mouth cancer were treated with tumor excision±elective neck dissection and HDR BT 18×3 Gy b.i.d. The Kaplan-Meier model was used for survival analyses, and the log-rank test and Cox regression analyses were used to evaluate the influence of T-stage, histologic grade, resection margin, depth of invasion, and vascular endothelial growth factor (VEGF) intensity on local control (LC), nodal control (NC), disease-free survival (DFS), and overall survival (OS). Median followup was 40 months (6-145). RESULTS: Actuarial 3-year LC, NC, DFS, DFS after salvage treatment, and OS were 85.4%, 69.2%, 65.4%, 75.6%, and 73.0%, respectively. The log-rank test and univariate Cox regression analysis revealed the following correlations, namely tumor grade correlated with LC, DFS, and OS; T-stage with NC and DFS; depth of invasion and VEGF intensity with NC, DFS, and OS. Associations detected on the multivariate analysis were as follows: tumor grade with LC, depth of invasion with NC, depth of invasion and tumor grade with DFS, and VEGF intensity with DFS after salvage treatment. Only one case of osteoradionecrosis and two cases of soft tissue necrosis occurred. CONSLUSION: The HDR BT 18×3 Gy b.i.d. is a safe treatment of early oral cancer with a good LC. The T-stage, tumor grade, depth of invasion, and intensity of VEGF were significant predictors of locoregional control.

Utilization of cone beam CT for reconstruction of dose distribution delivered in image-guided radiotherapy of prostate carcinoma - bony landmark setup compared to fiducial markers setup.

The purpose of this study was to compare two different styles of prostate IGRT: bony landmark (BL) setup vs. fiducial markers (FM) setup. Twenty-nine prostate patients were treated with daily BL setup and 30 patients with daily FM setup. Delivered dose distribution was reconstructed on cone-beam CT (CBCT) acquired once a week immediately after the alignment. Target dose coverage was evaluated by the proportion of the CTV encompassed by the 95% isodose. Original plans employed 1 cm safety margin. Alternative plans assuming smaller 7 mm margin between CTV and PTV were evaluated in the same way. Rectal and bladder volumes were compared with initial ones. While the margin reduction in case of BL setup makes the prostate coverage significantly worse (p = 0.0003, McNemar's test), in case of FM setup with the reduced 7 mm margin, the prostate coverage is even better compared to BL setup with 10 mm margin (p = 0.049, Fisher's exact test). Moreover, partial volumes of organs at risk irradiated with a specific dose can be significantly lowered (p < 0.0001, unpaired t-test). Reducing of safety margin is not acceptable in case of BL setup, while the margin can be lowered from 10 mm to 7 mm in case of FM setup.

Predicting factors for locoregional failure of high-dose-rate brachytherapy for early-stage oral cancer.

AIM: Brachytherapy is an alternative to surgery in the treatment of the early stages of oral tongue cancer. The aim of this retrospective study was to analyze the clinical risk factors and possible candidate biomarkers of local and regional tumor control. PATIENTS & METHODS: Twenty-four patients were treated between the years 2001 and 2010. Median follow-up was 37.4 months. Correlation between disease-free survival and clinical stage, tumor grade, resection margin, depth of invasion, and p16, EGF receptor, NF-κB, HIF-1α, HER2, Ku-80, COX-2 and VEGF expression was evaluated. RESULTS: The estimated 5-year local control was 81% and locoregional control was 62%. Depth of tumor invasion (p = 0.018) and higher VEGF expression (p = 0.016) were significantly predictive for worse disease-free survival in Cox multivariate analysis. CONCLUSION: Intensity of VEGF expression and depth of tumor invasion may be significantly negative predictors of disease-free survival in tongue cancer patients treated by brachytherapy alone. Predictive value of VEGF deserves evaluation in larger studies.

Utilization of cone-beam CT for offline evaluation of target volume coverage during prostate image-guided radiotherapy based on bony anatomy alignment.

AIM: To assess target volume coverage during prostate image-guided radiotherapy based on bony anatomy alignment and to assess possibility of safety margin reduction. BACKGROUND: Implementation of IGRT should influence safety margins. Utilization of cone-beam CT provides current 3D anatomic information directly in irradiation position. Such information enables reconstruction of the actual dose distribution. MATERIALS AND METHODS: Seventeen prostate patients were treated with daily bony anatomy image-guidance. Cone-beam CT (CBCT) scans were acquired once a week immediately after bony anatomy alignment. After the prostate, seminal vesicles, rectum and bladder were contoured, the delivered dose distribution was reconstructed. Target dose coverage was evaluated by the proportion of the CTV encompassed by the 95% isodose. Original plans employed a 1 cm safety margin. Alternative plans assuming a smaller 7 mm margin between CTV and PTV were evaluated in the same way. Rectal and bladder volumes were compared with the initial ones. Rectal and bladder volumes irradiated with doses higher than 75 Gy, 70 Gy, 60 Gy, 50 Gy and 40 Gy were analyzed. RESULTS: In 12% of reconstructed plans the prostate coverage was not sufficient. The prostate underdosage was observed in 5 patients. Coverage of seminal vesicles was not satisfactory in 3% of plans. Most of the target underdosage corresponded to excessive rectal or bladder filling. Evaluation of alternative plans assuming a smaller 7 mm margin revealed 22% and 11% of plans where prostate and seminal vesicles coverage, respectively, was compromised. These were distributed over 8 and 7 patients, respectively. CONCLUSION: Sufficient dose coverage of target volumes was not achieved for all patients. Reducing of safety margin is not acceptable. Initial rectal and bladder volumes cannot be considered representative for subsequent treatment.

Intensity-modulated radiotherapy in the treatment of subhepatic carcinomas.

BACKGROUND/AIMS: The aim of our study was to evaluate preliminary results of intensity modulated radiotherapy (IMRT) in patients with inoperable subhepatic tumors. METHODOLOGY: Thirteen patients with inoperable cholangiocarcinoma or gall bladder carcinoma were treated by biliary drainage and intensity modulated radiotherapy. In patients with tumors limited to the biliary duct only tumor stenosis was irradiated to the dose of 50-60 Gy. In patients with bulky extraductal tumors the dose was 50 Gy/25 fractions to the whole tumor and an integrated boost was used to raise the dose to the malignant stenosis to 60 Gy/25 fractions. RESULTS: Doses to organs at risk (duodenum, small intestine, liver) were in tolerable limits. In four patients transient fever occurred; one patient had duodenal bleeding that resolved after conservative treatment. Recurrent dilatation of the biliary tract was observed in 4 patients and was managed by exchange of the internal biliary drainage. Median survival was 10.4 months, 5 patients survived for more than one year following diagnosis. CONCLUSIONS: IMRT of inoperable extrahepatic biliary tract tumors allows application of high doses of radiation to the tumor with effective sparing of healthy tissues. The control of jaundice is good. In selected cases IMRT may prolong overall survival.

High-dose rate brachytherapy in the treatment of penile carcinoma--first experience.

PURPOSE: Interstitial low-dose rate brachytherapy (BRT) allows a conservative treatment of T1-T2 penile carcinoma. High-dose rate (HDR) BRT is often considered as a dangerous method for interstitial implants because of higher risk of complications. However, numerous reports suggest that results of HDR-BRT may be comparable to low-dose rate BRT. There are no data available in the literature regarding HDR interstitial BRT for carcinoma of the penis. METHODS AND MATERIALS: Ten patients with early penile carcinoma were treated by interstitial hyperfractionated HDR-BRT at the dose of 18 times 3Gy twice daily between years 2002 and 2009. Breast interstitial BRT template was used for fixation and precise geometry reconstruction of stainless hollow needles. RESULTS: Median followup was 20 months. Our BRT technique and fractionation schedule was well tolerated by all patients. Acute reaction consisted predominantly of penis edema and Grade 2 radiation mucositis that dissolved during 8 weeks after the treatment. We neither observed any postradiation necrosis nor urethral stenosis. The worst late side effects recorded were mild telanagiectasias in the treatment region. At the last followup, all patients were alive without evidence of the tumor and with fully functional organ. CONCLUSIONS: Hyperfractionated interstitial HDR-BRT with 18 times 3 Gy per fraction twice daily is a promising method in selected patients of penile carcinoma and deserves further evaluation in a larger prospective study.

Daily prostate volume and position monitoring using implanted gold markers and on-board imaging during radiotherapy.

PURPOSE: This study aimed to evaluate prostate volume changes and prostate motions during radiotherapy. METHODS: In 2010, twenty-five patients were treated for prostate cancer by external beam radiotherapy with implanted fiducial markers. Coordinates of three gold markers on kilovoltage images were calculated daily. Volume changes in target structure were observed through changes in intermarker distances. Differences in patient position between laser-tattoo alignment and gold marker localization were evaluated. Intrafraction motion was assessed by measuring marker displacement on kilovoltage images acquired before and after fraction delivery. RESULTS: Prostate shrinkage was observed in 60% of patients. The average shrinkage was 7% of the prostate's initial volume. Corrections after laser-tattoo alignment remained mostly below 1 cm. The difference between marker centroid position on the actual images and the planning images was 2 +/- 1 mm on average. The extension of intrafraction movements was 7.6 +/- 0.2 mm on average. CONCLUSIONS: In our retrospective study, the possibility for prostate volume changes during radiotherapy was revealed. Intrafraction movements turned out to be the limiting factor in safety margin reduction.

Hyperfractionated high-dose rate brachytherapy in the treatment of oral tongue cancer.

BACKGROUND: Low-dose rate brachytherapy is a well established treatment modality of oral cancer. Data about high-dose rate (HDR) brachytherapy are still sparse with various fractionation schedules and heterogeneous results. AIM: The aim of our retrospective study was to evaluate the results of HDR brachytherapy with doses of 3 Gy twice daily. PATIENTS AND METHODS: Twenty patients with squamous cell tongue cancer were treated in the years 2001-2009 by exclusive HDR BT 18 × 3 Gy twice daily. The plastic tube technique was used. Median follow up was 47 months (7.8-118) since brachytherapy. RESULTS: The local and locoregional control was 85% and 68%, respectively. Bone necrosis developed in one case treated without mandibular shielding and soft tissue necrosis in 2 cases. CONCLUSION: It can be concluded that HDR brachytherapy with 18 × 3 Gy twice daily is safe with promising local control. The risk of nodal recurrences is substantial.

Non-closure of peritoneum after abdominal hysterectomy for uterine carcinoma does not increase late intestinal radiation morbidity.

BACKGROUND/AIM: To evaluate whether non-closure of the visceral peritoneum after total abdominal hysterectomy (TAH) and bilateral salpingo-oophorectomy (BSO) in patients with uterine corpus carcinoma influences the volume of the small intestine within the irradiated volume during adjuvant radiotherapy or late radiation intestinal toxicity. MATERIALS AND METHODS: A total of 152 patients after TAH + BSO with adjuvant pelvic radiotherapy were studied. The state of peritonealization was retrospectively evaluated based on surgical protocols. The volume of irradiated bowels was calculated by CT-based delineation in a radiotherapy planning system. The influence of visceral peritonealization upon the volume of the small intestine within the irradiated volume and consequent late morbidity was analyzed. RESULTS: Visceral peritonealization was not performed in 70 (46%) of 152 studied patients. The state of peritonealization did not affect the volume of the irradiated small intestine (p = 0.14). Mean volume of bowels irradiated in patients with peritonealization was 488 cm(3) (range 200-840 cm(3), median 469 cm(3)); mean volume of bowels irradiated in patients without peritonealization was 456 cm(3) (range 254-869 cm(3), median 428 cm(3)). We did not prove any significant difference between both arms. Nor did we observe any influence of non-peritonealization upon late intestinal morbidity (p = 0.34). CONCLUSION: Non-closure of the visceral peritoneum after hysterectomy for uterine corpus carcinoma does not increase the volume of the small intestine within the irradiated volume, with no consequent intestinal morbidity enhancement.

Perioperative hyperfractionated high-dose rate brachytherapy for the treatment of soft tissue sarcomas: multicentric experience.

BACKGROUND: Low-dose rate brachytherapy is a well-established adjuvant treatment for soft tissue sarcomas (STS). The experience with high-dose rate brachytherapy (HDR BT) in this indication is limited. The purpose of our study was to evaluate the viability of perioperative hyperfractionated HDR BT for STS. METHODS: Forty-five patients with primary (17 cases) or recurrent (28 cases) STS were treated with resection and HDR BT between 1998 and 2007. Eleven patients were treated with HDR BT alone (mean dose 40 Gy; 30-54 Gy) and 34 were treated with a combination of HDR BT (mean dose 24 Gy; 15-30 Gy) and external beam radiotherapy (EBRT) (40-50 Gy). Hyperfractionation, 3 Gy twice daily, was used for HDR BT with plastic tubes. Adjuvant chemotherapy was indicated for patients with high risk of dissemination. RESULTS: Local control (LC) was achieved in 17 patients (100%) treated for primary tumor and in 18 of 28 patients (64%) treated for recurrence; this difference was statistically significant (p = 0.004). Distant metastases occurred in seven patients (15.6%). The 5-year overall survival was 70%; the 5-year local control was 74%. LC was significantly better for extremities sarcomas in comparison with trunk tumors, for patients treated with EBRT and BT in comparison with BT alone, and for doses >65 Gy. CONCLUSIONS: Our study suggests that perioperative HDR BT is a promising method for achieving high biological doses with good LC in the postoperative radiotherapy of STS and that combination of BT and EBRT provides better tumor control than BT alone.