Phase 1 Study of Low-Dose Fractionated Whole Abdominal Radiation Therapy in Combination With Weekly Paclitaxel for Platinum-Resistant Ovarian Cancer (GCGS-01).

PURPOSE: Low-dose fractionated whole abdominal radiation therapy (LDFWART) has synergistic activity with paclitaxel in preclinical models. The aim of this phase 1 trial was to determine the recommended phase 2 dose and preliminary activity of weekly paclitaxel (wP) concurrent with LDFWART in patients with platinum-resistant ovarian cancer (PROC). METHODS AND MATERIALS: Patients were enrolled at de-escalating dose levels of wP (part A), starting at 80 mg/m2, concurrent with fixed-dose LDFWART delivered in 60 cGy fractions twice-daily, 2 days per week, for 6 continuous weeks. After completing the 6-week course of wP + LDFWART, patients received wP until disease progression. Dose-limiting toxicity was evaluated during the first 3 weeks of wP + LDFWART. At wP (80 mg/m2) + LDFWART, no dose-limiting toxicities were observed; this was the established maximum tolerated dose. The trial was expanded (part B) with 7 additional patients with platinum-resistant, high-grade serous ovarian cancer to confirm toxicity and activity. RESULTS: A total of 10 heavily pretreated patients were recruited (3 patients to part A, 7 patients to part B). They had received a median of 5 prior lines of therapy, and 70% of patients had received prior wP; 60% of patients completed 6 weeks of wP + LDFWART. Common related grade ≥3 adverse events were neutropenia (60%) and anemia (30%). Median progression-free survival was 3.2 months, and overall survival was 13.5 months. Of patients evaluable for response, 33% (3 of 9) achieved confirmed biochemical response (CA125 decrease >50% from baseline), 11% (1) achieved a partial response, and 5 patients had stable disease, giving a disease control rate of 66.7% (6 of 9). Four patients had durable disease control of ≥12 weeks, completing 12 to 21 weeks of wP. CONCLUSIONS: The recommended phase 2 dose of wP + LDFWART for 6 weeks is 80 mg/m2. Encouraging efficacy in heavily pretreated PROC patients was observed, suggesting that further development of this therapeutic strategy in PROC should be considered.

Dosimetric evaluation and systematic review of radiation therapy techniques for early stage node-negative breast cancer treatment.

Radiation therapy (RT) is essential in treating women with early stage breast cancer. Early stage node-negative breast cancer (ESNNBC) offers a good prognosis; hence, late effects of breast RT becomes increasingly important. Recent literature suggests a potential for an increase in cardiac and pulmonary events after RT. However, these studies have not taken into account the impact of newer and current RT techniques that are now available. Hence, this review aimed to evaluate the clinical evidence for each technique and determine the optimal radiation technique for ESNNBC treatment. Currently, six RT techniques are consistently used and studied: 1) prone positioning, 2) proton beam RT, 3) intensity-modulated RT, 4) breath-hold, 5) partial breast irradiation, and 6) intraoperative RT. These techniques show dosimetric promise. However, limited data on late cardiac and pulmonary events exist due to challenges in long-term follow-up. Moving forward, future studies are needed to validate the efficacy and clinical outcomes of these current techniques.

Automatic quantification of calcifications in the coronary arteries and thoracic aorta on radiotherapy planning CT scans of Western and Asian breast cancer patients.

PURPOSE: This study automatically quantified calcifications in coronary arteries (CAC) and thoracic aorta (TAC) on breast planning computed tomography (CT) scans and assessed its reproducibility compared to manual scoring. MATERIAL AND METHODS: Dutch (n = 1199) and Singaporean (n = 1090) breast cancer patients with radiotherapy planning CT scan were included. CAC and TAC were automatically scored using deep learning algorithm. CVD risk categories were based on Agatson CAC: 0, 1-10, 11-100, 101-400 and >400. Reliability between automatic and manual scoring was assessed in 120 randomly selected CT scans from each population, with linearly weighted kappa for CAC categories and intraclass correlation coefficient for TAC. RESULTS: Median age was higher in Dutch patients than Singaporean patients: 57 versus 52 years. CAC and TAC increased with age and were more present in Dutch patients than Singaporean patients: 24.2% versus 17.3% and 73.0% versus 62.2%, respectively. Reliability of CAC categories and TAC was excellent in the Netherlands (0.85 (95% confidence interval (CI) = 0.77-0.93) and 0.98 (95% CI = 0.96-0.98) respectively) and Singapore (0.90 (95% CI = 0.84-0.96) and 0.99 (95% CI = 0.98-0.99) respectively). CONCLUSIONS: CAC and TAC prevalence was considerable and increased with age. Deep learning software is a reliable method to automatically measure CAC and TAC on radiotherapy breast CT scans.

Intensity-modulated radiation therapy for early-stage breast cancer: is it ready for prime time?

Whole breast external beam radiotherapy (WBEBRT) is commonly used as an essential arm in the treatment management of women with early-stage breast cancer. Dosimetry planning for conventional WBEBRT typically involves a pair of tangential fields. Advancement in radiation technology and techniques has the potential to improve treatment outcomes with clinically meaningful long-term benefits. However, this advancement must be balanced with safety and improved efficacy. Intensity-modulated radiation therapy (IMRT) is an advanced technique that shows promise in improving the planning process and radiation delivery. Early data on utilizing IMRT for WBEBRT demonstrate more homogenous dose distribution with reduction in organs at risk doses. This translates to toxicities reduction. The two common descriptors for IMRT are forward-planning "fields in field" and inverse planning. Unlike IMRT for other organs, the aim of IMRT for breast planning is to achieve dose homogeneity and not organ conformality. The aim of this paper was to evaluate whether IMRT is ready for prime time based on these three points: 1) workload impact, 2) the clinical impact on the patient's quality of life, and 3) the appropriateness and applicability to clinical practice.

Novel anesthetic technique for combined intracavitary and interstitial brachytherapy for cervix cancer in an outpatient setting.

PURPOSE: To determine the feasibility and safety of outpatient combined intracavitary and interstitial brachytherapy for cervix cancer with sedation and local anesthesia. MATERIAL AND METHODS: We included patients diagnosed with non-metastatic cervix cancer and have completed brachytherapy between December 2015 and December 2016. Moderate to deep sedation was achieved using intravenous midazolam, propofol, fentanyl, and oxycodone. Local anesthesia was achieved with 2% lignocaine gel and a paracervical block containing a mixture of 1% ropivacaine, 2% lignocaine, and 1 : 1,000 adrenaline. Ceftriaxone and ondansetron were given prophylactically. Physiologic monitoring was performed throughout and pain scores were recorded using the Numeric Rating Scale. Follow-up was conducted at 8 weeks from the last fraction of brachytherapy. The feasibility and safety endpoints were a post-anesthesia discharge score (PADS) of 9 or above, and no grade 3 or above adverse events, respectively. RESULTS: A total of thirty-five brachytherapy insertions were carried out on nine patients. The median age of the patients was 56 years (range, 40-65). Eight patients had American Society of Anesthesiologists' physical status of I or II, and one had a status of III. The mean duration of the insertion was 39 minutes (standard deviation [SD] = 14), during which no adverse events occurred. There was no significant nausea or vomiting post-sedation. The median pain scores post-insertion and during recovery were 0 (range, 0-6) and 0 (range, 0-7), respectively. At discharge, all patients had pain scores of 0 and maximum PADS of 10. The mean time to discharge was 4.1 hours (SD = 0.95). There were no brachytherapy-related admissions or complications. CONCLUSIONS: Outpatient combined intracavitary and interstitial brachytherapy for cervix cancer with sedation and local anesthesia is feasible and safe. This could potentially lead to significant cost savings.

A prospective dose escalation trial of high-dose-rate brachytherapy boost for prostate cancer: Evidence of hypofractionation efficacy?

PURPOSE: The study aimed to evaluate mature outcomes of a Phase I/II high-dose-rate brachytherapy (HDRB) boost protocol. METHODS AND MATERIALS: We analyzed data from 88 patients with T1a-T3a, N0, M0 prostate adenocarcinoma treated on a prospective Phase I/II HDRB boost protocol of 16 (n = 47) or 20 Gy (n = 41) in four fractions, without planned androgen deprivation therapy. HDRB was added to 46 Gy of external beam radiotherapy (EBRT). Outcomes were compared to a contemporaneous retrospective cohort of 104 patients receiving 66 Gy EBRT monotherapy. The primary endpoint was freedom from biochemical failure, defined as a 2 ng/mL rise above the lowest prostate-specific antigen (PSA) (FFbFn2), whereas the American Society of Therapeutic Radiology and Oncology consensus definition (ACD) was used for comparative purposes. RESULTS: For the HDRB cohort, the overall actuarial 5-year FFbFn2 was 67.4% (95% CI: 58.2-75.5%). For the HDRB doses of 16 and 20 Gy, the 5-year FFbFn2 rates were 58.8% (95% CI: 41.9-72.5%) and 77.3% (95% CI: 64.4-88.3%), respectively (log-rank test p = 0.07). Compared to men treated with 66 Gy EBRT, using multivariate analysis, there was no significant benefit to using HDRB with the FFbFn2 outcome (p = 0.52), yet the ACD suggested a significant advantage (hazard ratio 0.50, 95% CI: 0.29-0.86, p = 0.011). There was a trend to better FFbFn2 outcomes with increasing biologically effective doses (p = 0.09), which was significant using the ACD (p = 0.0003). CONCLUSIONS: The data support HDRB boost as a potential means of dose escalation in prostate cancer. Significant findings using the ACD need to be validated with contemporary biochemical failure definitions. Prospective trials to optimize fractionation and evaluate outcomes in comparison to contemporary EBRT techniques are warranted.

Proton therapy for early stage prostate cancer: is there a case?

Proton-beam therapy (PBT) for prostate cancer has been in used for several decades, with its technique evolving significantly over this period. A growing number of centers now routinely utilize pencil-beam scanning as an advanced technique of PBT. Interest and controversy concerning its use have recently come under scrutiny. While the past decade has produced an assemblage of evidence suggesting that PBT is safe and effective for early stage prostate cancer, it is still unknown whether the theoretical dosimetric advantages of PBT translate into meaningful clinical improvements over routine intensity-modulated radiation therapy, which is commonly used for these patients. Outcomes from early trials using whole courses of PBT have shown mixed results when compared with routine intensity-modulated radiation therapy. Therefore, randomized trials comparing these two techniques should be undertaken, as this would help in defining the role of PBT for this patient group. This article aims to describe the basics of PBT, review the reasons for the growing interest in PBT, review the evidence for PBT, review the controversy surrounding PBT, and inquire about PBT's future in the treatment of prostate cancer, with attention to its physical properties, comparative clinical and cost-effectiveness, and advances in its delivery.

Accelerated partial breast irradiation in an Asian population: dosimetric findings and preliminary results of a multicatheter interstitial program.

INTRODUCTION: Accelerated partial breast irradiation (APBI) using the multicatheter method has excellent cosmesis and low rates of long-term toxicity. However, there are few studies looking at the feasibility of this procedure and the outcomes in an Asian population. This study aims to look at outcomes at our hospital. METHODS: We identified 121 patients treated with APBI at our center between 2008 and 2014. The median follow-up for our patient group was 30 months (range 3.7-66.5). The prescribed dose per fraction was 3.4 Gy in 10 fractions. In this study population, 71% of the patients were Chinese while 15% (n=19) were of other Asian ethnicity. RESULTS: In this study, the median breast volume was 850 cc (range 216-2,108) with 59.5% (n=72) patients with a breast volume of <1,000 cc. The average planning target volume was 134 cc (range 28-324). The number of catheters used ranged from 8 to 25 with an average of 18 catheters used per patient. We achieved an average dose homogeneity index of 0.76 in our patients. The average D90(%) was 105% and the average D90(Gy) was 3.6 Gy per fraction. The median volume receiving 100% of the prescribed dose (V100) was 161.7 cc (range 33.9-330.1), 150% of the prescribed dose (V150) and 200% of the prescribed dose (V200) was 39.4 cc (range 14.6-69.6) and 14.72 cc (range 6.48-22.25), respectively. Our dosimetric outcomes were excellent even in patients with breast volume under 1,000 cc. There were no cases of grade 3 skin toxicity or acute pneumonitis. Two patients had a postoperative infection and two patients had fat necrosis postprocedure. CONCLUSION: Multicatheter high dose rate APBI is a safe and feasible procedure that can be carried out with minimal toxicity in Asian patients with breast volumes under 1,000 cc.

Outpatient combined intracavitary and interstitial cervical brachytherapy: barriers and solutions to implementation of a successful programme - a single institutional experience.

Involvement of parametrial disease in locally advanced cervical patients poses a challenge for women undergoing brachytherapy. Current use of the Fletcher suit applicator may not adequately cover the high risk clinical target volume (HR CTV), especially in the parametrial region due to the physical qualities of brachytherapy from the inverse square law and the need to respect organs at risk (OAR) constraints, and leads to lower local control rates. Combined intracavitary and interstitial brachytherapy with the use of 1 or 2 interstitial needles allows adequate coverage of the HR CTV and the clinical evidence have demonstrated a correlation with better clinical results. This procedure is often resource intensive, requiring inpatient stay and magnetic resonance imaging (MRI) planning. In departments where such resources are limited, there is a poor uptake of interstitial brachytherapy. This article discusses the technique of combined intracavitary and interstitial brachytherapy in an outpatient setting, and explores the issues and barriers for implementation and suggestions to overcome such barriers.

Assessing radiation exposure of the left anterior descending artery, heart and lung in patients with left breast cancer: A dosimetric comparison between multicatheter accelerated partial breast irradiation and whole breast external beam radiotherapy.

BACKGROUND AND PURPOSE: This study aims to quantify dosimetric reduction to the left anterior descending (LAD) artery, heart and lung when comparing whole breast external beam radiotherapy (WBEBRT) with multicatheter accelerated partial breast irradiation (MCABPI) for early stage left breast cancer. MATERIALS AND METHODS: Planning CT data sets of 15 patients with left breast cancer receiving multicatheter brachytherapy post breast conserving surgery were used to create two independent treatment plans - WBEBRT prescribed to 50 Gy/25 fractions and MCABPI prescribed to 34 Gy/10 fractions. Dose parameters for (i) LAD artery, (ii) heart, and (iii) ipsilateral lung were calculated and compared between the two treatment modalities. RESULTS: After adjusting for Equivalent Dose in 2 Gy fractions(EQD2), and comparing MCAPBI with WBEBRT, the largest dose reduction was for the LAD artery whose mean dose differed by a factor of 7.7, followed by the ipsilateral lung and heart with a factor of 4.6 and 2.6 respectively. Compared to WBEBRT, the mean MCAPBI LAD was significantly lower compared to WBEBRT (6.0 Gy vs 45.9 Gy; p<0.01). Mean MCAPBI heart D(0.1cc) (representing the dose received by the most highly exposed 0.1 cc of the risk organ, i.e. the dose peak) was significantly lower (16.3 Gy vs 50.6 Gy; p<0.01). Likewise, the mean heart dose (MHD) was significantly lower (2.3 Gy vs 6.0 Gy; p<0.01). Peak dose and mean lung dose (MLD) for ipsilateral lung was also lower for MCAPBI compared to WBEBRT (Peak dose: 22.2 Gy vs 52.0 Gy; p<0.01; MLD: 2.3 Gy vs 10.7 Gy; p<0.01). CONCLUSION: Compared to WBEBRT, MCAPBI showed a significant reduction in radiation dose for the LAD, heart and lung. This may translate into better cardiac and pulmonary toxicities for patients undergoing MCAPBI.

Multi-catheter interstitial accelerated partial breast irradiation - tips and tricks for a good insertion.

Adjuvant radiotherapy is recommended post breast conserving surgery. Accelerated Partial Breast Irradiation (APBI) offers a more attractive shorter course of treatment over 5 days compared to standard conventional external beam radiotherapy, which is often protracted. Multi-catheter interstitial APBI offers excellent dosimetric coverage. This article describes two insertion techniques for multi-catheter interstitial APBI, the operator dependent freehand technique, and the easier to learn template technique. The indications, benefits, and drawbacks of these two techniques are discussed.

Comparing a volume based template approach and ultrasound guided freehand approach in multicatheter interstitial accelerated partial breast irradiation.

PURPOSE: Currently, there are two described methods of catheter insertion for women undergoing multicatheter interstitial accelerated partial breast irradiation (APBI). These are a volume based template approach (template) and a non-template ultrasound guidance freehand approach (non-template). We aim to compare dosimetric endpoints between the template and non-template approach. MATERIAL AND METHODS: Twenty patients, who received adjuvant multicatheter interstitial APBI between August 2008 to March 2010 formed the study cohort. Dosimetric planning was based on the RTOG 04-13 protocol. For standardization, the planning target volume evaluation (PTV-Eval) and organs at risk were contoured with the assistance of the attending surgeon. Dosimetric endpoints include D90 of the PTV-Eval, Dose Homogeneity Index (DHI), V200, maximum skin dose (MSD), and maximum chest wall dose (MCD). A median of 18 catheters was used per patient. The dose prescribed was 34 Gy in 10 fractions BID over 5 days. RESULTS: The average breast volume was 846 cm(3) (526-1384) for the entire cohort and there was no difference between the two groups (p = 0.6). Insertion time was significantly longer for the non-template approach (mean 150 minutes) compared to the template approach (mean: 90 minutes) (p = 0.02). The planning time was also significantly longer for the non-template approach (mean: 240 minutes) compared to the template approach (mean: 150 minutes) (p < 0.01). The template approach yielded a higher D90 (mean: 95%) compared to the non-template approach (mean: 92%) (p < 0.01). There were no differences in DHI (p = 0.14), V200 (p = 0.21), MSD (p = 0.7), and MCD (p = 0.8). CONCLUSIONS: Compared to the non-template approach, the template approach offered significant shorter insertion and planning times with significantly improved dosimetric PTV-Eval coverage without significantly compromising organs at risk dosimetrically.

Body mass index and patient CT measurements as a predictor of benefit of intensity-modulated radiotherapy to the supraclavicular fossa.

BACKGROUND: Irradiation of the supraclavicular fossa is commonly used as part of adjuvant breast radiotherapy. Intensity-modulated radiotherapy (IMRT) may be used to target this region accurately, and there are subgroups of patients that may benefit more from IMRT than others. We identify the benefit of IMRT over fixed-depth dose prescription to the supraclavicular fossa in patients of different builds in a clinical setting. METHODS: Fifteen patients who received radiotherapy to the left breast and supraclavicular fossa were selected. Computed tomographic planning was used to generate plans for supraclavicular fossa coverage. Dose prescription to 1.5 cm and 3.0 cm depths was compared with IMRT plans. Coverage of the planning target volume and dose to the organs at risk were compared and correlated with patient body mass index (BMI) and computed tomography measurements. RESULTS: Within the IMRT group, increasing depth of the supraclavicular fossa produced significantly better coverage of the planning target volume with IMRT. IMRT resulted in lower mean doses to the brachial plexus (P = 0.00) when compared with 1.5 cm and 3 cm depth dose prescriptions, but higher maximum brachial plexus doses. IMRT was more beneficial in patients with lower BMI because this resulted in a decreased maximum brachial plexus dose (P-values of 0.03 and 0.001 when compared with 1.5 cm and 3.0 cm depth dose prescriptions, respectively). Higher patient BMI resulted in a lower dose contribution of IMRT to the cord (P-values 0.066 and 0.034 when compared with 1.5 cm and 3.0 cm depth dose prescriptions respectively). CONCLUSION: IMRT of the supraclavicular fossa results in lower brachial plexus doses for patients with low BMI while patients with higher BMI benefit from lower mean cord doses. IMRT provides superior coverage of the planning target volume, especially in patients with a deeper supraclavicular fossa.