Potential anatomical triggers for plan adaptation of cervical cancer external beam radiotherapy.

This study aimed to identify potential anatomical variation triggers using magnetic resonance imaging for plan adaption of cervical cancer patients to ensure dose requirements were met over an external beam radiotherapy course. Magnetic resonance images (MRIs) acquired before and during treatment were rigidly registered to a pre-treatment computerised tomography (CT) image for 11 retrospective cervix cancer datasets. Target volumes (TVs) and organs at risk (OARs) were delineated on both MRIs and propagated onto the CT. Treatment plans were generated based on the pre-treatment contours and applied to the mid-treatment contours. Anatomical and dosimetric changes between each timepoint were assessed. The anatomical changes included the change in centroid position and volume size. Dosimetric changes included the V30Gy and V40Gy for the OARs, and V95%, V100%, D95% and D98% for the TVs. Correlation with dosimetric and anatomical changes were assessed to determine potential replan triggers. Changes in the bowel volume and position in the superior-inferior direction, and the high-risk CTV anterior posterior position were highly correlated with a change in dose to the bowel and target, respectively. Hence changes in bowel and high-risk CTV could be used as a potential replan triggers.

Assessment of intrafraction motion and its dosimetric impact on prostate radiotherapy using an in-house developed position monitoring system.

Purpose: To implement an in-house developed position monitoring software, SeedTracker, for conventional fractionation prostate radiotherapy, and study the effect on dosimetric impact and intrafraction motion. Methods: Thirty definitive prostate radiotherapy patients with implanted fiducial markers were included in the study. All patients were treated with VMAT technique and plans were generated using the Pinnacle planning system using the 6MV beam model for Elekta linear accelerator. The target dose of 60 Gy in 20 fractions was prescribed for 29 of 30 patients, and one patient was treated with the target dose of 78 Gy in 39 fractions. The SeedTracker position monitoring system, which uses the x-ray images acquired during treatment delivery in the Elekta linear accelerator and associated XVI system, was used for online prostate position monitoring. The position tolerance for online verification was progressively reduced from 5 mm, 4 mm, and to 3 mm in 10 patient cohorts to effectively manage the treatment interruptions resulting from intrafraction motion in routine clinical practice. The delivered dose to target volumes and organs at risk in each of the treatment fractions was assessed by incorporating the observed target positions into the original treatment plan. Results: In 27 of 30 patients, at least one gating event was observed, with a total of 177 occurrences of position deviation detected in 146 of 619 treatment fractions. In 5 mm, 4 mm, and 3 mm position tolerance cohorts, the position deviations were observed in 13%, 24%, and 33% of treatment fractions, respectively. Overall, the mean (range) deviation of -0.4 (-7.2 to 5.3) mm, -0.9 (-6.1 to 15.6) mm, and -1.7 (-7.0 to 6.1) mm was observed in Left-Right, Anterior-Posterior, and Superior-Inferior directions, respectively. The prostate CTV D99 would have been reduced by a maximum value of 1.3 Gy compared to the planned dose if position deviations were uncorrected, but with corrections, it was 0.3 Gy. Similarly, PTV D98 would have been reduced by a maximum value of 7.6 Gy uncorrected, with this difference reduced to 2.2 Gy with correction. The V60 to the rectum increased by a maximum of 1.0% uncorrected, which was reduced to 0.5%. Conclusion: Online target position monitoring for conventional fractionation prostate radiotherapy was successfully implemented on a standard Linear accelerator using an in-house developed position monitoring software, with an improvement in resultant dose to prostate target volume.

Reducing the margin in prostate radiotherapy: optimizing radiotherapy with a general-purpose linear accelerator using an in-house position monitoring system.

Purpose: To study the feasibility of optimizing the Clinical Target Volume to Planning Target Volume (CTV-PTV) margin in prostate radiotherapy(RT) with a general-purpose linear accelerator using an in-house developed position monitoring system, SeedTracker. Methods: A cohort of 30 patients having definitive prostate radiotherapy treated within an ethics-approved prospective trial was considered for this study. The intrafraction prostate motion and the position deviations were measured using SeedTracker system during each treatment fraction. Using this data the CTV-PTV margin required to cover 90% of the patients with a minimum of 95% of the prescription dose to CTV was calculated using van Herk's formula. The margin calculations were performed for treatment scenarios both with and without applying the position corrections for observed position deviations. The feasibility of margin reduction with real-time monitoring was studied by assessing the delivered dose that incorporates the actual target position during treatment delivery and comparing it with the planned dose. This assessment was performed for plans generated with reduced CTV-PTV margin in the range of 7mm-3mm. Results: With real-time monitoring and position corrections applied the margin of 2.0mm, 2.1mm and 2.1mm in LR, AP and SI directions were required to meet the criteria of 90% population to receive 95% of the dose prescription to CTV. Without position corrections applied for observed position deviations a margin of 3.1mm, 4.0mm and 3.0mm was required in LR, AP and SI directions to meet the same criteria. A mean ± SD reduction of 0.5 ± 1.8% and 3 ± 7% of V60 for the rectum and bladder can be achieved for every 1mm reduction of PTV margin. With position corrections applied, the CTV D99 can be delivered within -0.2 ± 0.3 Gy of the planned dose for plans with a 3mm margin. Without applying corrections for position deviations the CTV D99 was reduced by a maximum of 1.1 ± 1.1 Gy for the 3mm margin plan and there was a statistically significant difference between planned and delivered dose for 3mm and 4mm margin plans. Conclusion: This study demonstrates the feasibility of reducing the margin in prostate radiotherapy with SeedTracker system without compromising the dose delivery accuracy to CTV while reducing dose to critical structures.

Treatment of Pyogenic Flexor Tenosynovitis in the Emergency Department Setting With WALANT Technique.

BACKGROUND: The standard of care for treatment of pyogenic flexor tenosynovitis (PFT) involves antibiotic therapy and prompt irrigation of the flexor tendon sheath, traditionally performed in the operating room. With the acceptance of wide-awake local anesthesia no tourniquet (WALANT) hand surgery and its potential ability to minimize time to flexor tendon sheath irrigation, we sought to determine whether closed irrigation of the flexor tendon sheath could be safely and effectively performed in the emergency department setting with WALANT technique. METHODS: A retrospective review was conducted of the senior author's hand surgery consultations over a 12-month period. Six patients were identified who were diagnosed with PFT and subsequently underwent irrigation of the flexor tendon sheath using WALANT technique. Patient outcomes such as length of hospital stay, need for reoperation, infectious etiology, perioperative complications, and postprocedure range of motion (ROM) were identified. RESULTS: Six patients with diagnosis of PFT underwent irrigation of the flexor tendon sheath in the emergency department with local anesthesia only. The irrigation procedures were all well-tolerated. One patient required reoperation due to lack of appropriate clinical improvement following initial irrigation. Four of 6 patients regained their preinjury ROM while the remaining 2 patients had mild proximal interphalangeal joint extension lag. There were no complications associated with the procedures. CONCLUSIONS: Surgical treatment of PFT with closed irrigation of the flexor tendon sheath in the emergency department utilizing WALANT technique was safe, effective, and well-tolerated. Local anesthesia alone can be used effectively for irrigation procedures of the flexor tendon sheath.

Rates of MRI simulator utilisation in a tertiary cancer therapy centre.

Magnetic resonance imaging (MRI) is increasingly being integrated into the radiation oncology workflow, due to its improved soft tissue contrast without additional exposure to ionising radiation. A review of MRI utilisation according to evidence based departmental guidelines was performed. Guideline utilisation rates were calculated to be 50% (true utilisation rate was 46%) of all new cancer patients treated with adjuvant or curative intent, excluding simple skin and breast cancer patients. Guideline utilisation rates were highest in the lower gastrointestinal and gynaecological subsites, with the lowest being in the upper gastrointestinal and thorax subsites. Head and neck (38% vs 45%) and CNS (46% vs 67%) cancers had the largest discrepancy between true and guideline utilisation rates due to unnamed reasons and non-contemporaneous diagnostic imaging respectively. This report outlines approximate MRI utilisation rates in a tertiary radiation oncology service and may help guide planning for future departments contemplating installation of an MRI simulator.

Radiation Therapy Techniques and Treatment-Related Toxicity in the PORTEC-3 Trial: Comparison of 3-Dimensional Conformal Radiation Therapy Versus Intensity-Modulated Radiation Therapy.

PURPOSE: Radiation therapy techniques have developed from 3-dimensional conformal radiation therapy (3DCRT) to intensity modulated radiation therapy (IMRT), with better sparing of the surrounding normal tissues. The current analysis aimed to investigate whether IMRT, compared to 3DCRT, resulted in fewer adverse events (AEs) and patient-reported symptoms in the randomized PORTEC-3 trial for high-risk endometrial cancer. METHODS AND MATERIALS: Data on AEs and patient-reported quality of life (QoL) of the PORTEC-3 trial were available for analysis. Physician-reported AEs were graded using Common Terminology Criteria for Adverse Events v3.0. QoL was assessed by the European Organisation for Research and Treatment of Cancer QLQC30, CX24, and OV28 questionnaires. Data were compared between 3DCRT and IMRT. A P value of ≤ .01 was considered statistically significant due to the risk of multiple testing. For QoL, combined scores 1 to 2 ("not at all" and "a little") versus 3 to 4 ("quite a bit" and "very much") were compared between the techniques. RESULTS: Of 658 evaluable patients, 559 received 3DCRT and 99 IMRT. Median follow-up was 74.6 months. During treatment no significant differences were observed, with a trend for more grade ≥3 AEs, mostly hematologic and gastrointestinal, after 3DCRT (37.7% vs 26.3%, P = .03). During follow-up, 15.4% (vs 4%) had grade ≥2 diarrhea, and 26.1% (vs 13.1%) had grade ≥2 hematologic AEs after 3DCRT (vs IMRT) (both P < .01). Among 574 (87%) patients evaluable for QoL, 494 received 3DCRT and 80 IMRT. During treatment, 37.5% (vs 28.6%) reported diarrhea after 3DCRT (vs IMRT) (P = .125); 22.1% (versus 10.0%) bowel urgency (P = 0039), and 18.2% and 8.6% abdominal cramps (P = .058). Other QoL scores showed no differences. CONCLUSIONS: IMRT resulted in fewer grade ≥3 AEs during treatment and significantly lower rates of grade ≥2 diarrhea and hematologic AEs during follow-up. Trends toward fewer patient-reported bowel urgency and abdominal cramps were observed after IMRT compared to 3DCRT.

Two new glycosides, farnesyl pentaglycoside and oleanane triglycoside from Lepisanthes rubiginosa, a mangrove plant collected from Thua Thien-Hue province, Vietnam.

Phytochemical investigation of the leaves of Lepisanthes rubiginosa led to the isolation of two new glycosides, lepisantheside A (1) and lepisantheside B (2), together with two known compounds acutoside A (3) and 3-O-[ß-D-xylopyranosyl-(1→3)-ß-D-glucopyranosyl-]-oleanolic acid (4). Their structures were elucidated by means of spectroscopic methods (HR-ESI-MS, 1D and 2D NMR), and by comparison with the reported data. The cytotoxicity of compounds 1-4 against four human cancer cell lines (KB, HepG2, SK-LU-1 and MCF7) was evaluated. Compound 4 exhibited significant activity with IC50 values of 9.57, 6.66, 6.97 and 18.32 µM, respectively, in comparison with the postive control ellipticine.

Feasibility of bone marrow sparing volumetric modulated arc therapy to spare active bone marrow in cervical and vaginal cancer patients: a retrospective dosimetric analysis.

INTRODUCTION: Chemoradiotherapy (CRT) is the standard treatment for locally advanced cervical and vaginal cancer. It is associated with high haematological toxicity (HT) that can lead to treatment interruptions and cancelled chemotherapy cycles, reducing the potential effectiveness of this regimen. Bone marrow sparing (BMS) utilising volumetric modulated arc therapy (VMAT) is one method to reduce dose to the active bone marrow (ABM) so that HT rates are reduced. The aim of this paper was to assess whether BMS-VMAT can effectively spare the ABM whilst maintaining clinically acceptable target and organ-at-risk (OAR) doses. METHODS: Twenty gynaecological cancer patients treated with definitive CRT at the Liverpool/Macarthur Cancer Therapy centres between 2015 and 2020 were retrospectively included. ABM was delineated based on fluorodeoxyglucose positron emission tomography (FDG-PET) imaging. Weekly blood tests and ABM dose parameters at the V10Gy, V20Gy, V30Gy, V40Gy and Dmean were assessed on original plans for any potential correlation with grade 2+ HT. Replanned with VMAT for BMS, various dose parameters were compared with the original plan to assess for any significant differences. RESULTS: Active bone marrow doses were significantly reduced (P < 0.001 for all parameters) in BMS-VMAT plans, and significant improvements in target and OAR coverage were found compared with the original plans. Compared with VMAT only, target and OARs were comparable. No significant correlations between HT and ABM doses were found. CONCLUSION: Bone marrow sparing volumetric modulated arc therapy can significantly reduce dose to the active bone marrow whilst maintaining acceptable target and OAR doses. Future prospective trials are needed to evaluate the clinical impact of BMS on toxicity and compliance.

Are NCCN Resource-Stratified Guidelines for Breast Cancer Systemic Therapy Achievable? A Population-Based Study of Global Need and Economic Impact.

PURPOSE: Resource-stratified guidelines (RSG) for cancer provide a hierarchy of interventions, based on resource availability. We quantify treatment need and cost if National Comprehensive Cancer Network (NCCN) RSGs for breast cancer (BC) are adopted globally. METHODS: We developed decision trees for first-course systemic therapy, merged with SEER and Global Cancer Observatory 2018 incidence data to estimate treatment need and cost if NCCN RSG are implemented globally based on country-level income. Simulations were used to quantify need and cost of globally scaling up services to Maximal. RESULTS: Based on NCCN RSG, first-course chemotherapy is indicated in 0% (Basic), 87% (Core), and 86% (Enhanced) but declined to 50% (Maximal) because of incorporation of genomic profiling. First-course endocrine therapy (ET) is indicated in 80% in all settings. In 2018, treatment need was 1.4 million people for chemotherapy, 183,943 for human epidermal growth factor receptor 2 (HER2) therapies and 1.6 million for ET. The cost per person for chemotherapy or HER2 or immunotherapy increased by 17-fold from Core to Maximal ($1,278-$22,313 Australian dollars [AUD]). The cost of ET per person rose eight-fold from Basic to Maximal ($1,236-$9,809 AUD). If all patients with BC globally were treated with Maximal resources, the need for chemotherapy would decline by 28%, whereas cost of first-course treatment would rise by 1.8-fold ($21-$37 billion AUD) because of more costly therapies. CONCLUSION: NCCN RSGs for BC could result in chemotherapy overtreatment in Core and Enhanced settings. The absence of chemotherapy in Basic settings should be reconsidered, and future iterations of RSG should perform cross-tumor comparisons to ensure equitable resource distribution and maximize population-level outcomes. Our model is flexible and can be tailored to the costs, population attributes, and resource availability of any institution or country for health-services planning.

A single-institution review of image-guided brachytherapy for vaginal malignancies using customized molded applicators and interstitial needles.

PURPOSE: To review a single-institution's pattern of practice, dosimetry results, and clinical outcomes for patients with unresectable malignancies of vagina, vulva, or urethra, receiving brachytherapy using customized vaginal moulds with or without interstitial needles. MATERIAL AND METHODS: Twenty-one consecutive patients were reviewed. Patients were treated using customized moulds with or without interstitial needles, implanted with a free-hand technique. Technical implementation, such as type of implant and imaging used were recorded. D90 and D98 of clinical target volume (CTV), D0.1cc of urethra, and D2cc and D0.1cc of bladder and rectum were analyzed. Any adverse clinical outcomes were reported. RESULTS: Eleven patients experienced endometrial cancer recurrences, one a cervical cancer recurrence and nine vaginal or peri-urethral primary disease. After a median follow-up of 3.5 years, local control was achieved in 14 patients (67%). Median D98 and D90 to CTV was 73.7 Gy and 78.3 Gy, respectively. One patient died from disease progression, one developed distant metastasis, and seven failed locally. Median D2cc to bladder was 64.8 Gy, with low-grade toxicity reported. Median D2cc to rectum was 62.9 Gy, with low-grade toxicity and one case of rectal proctitis was observed. Median urethral D0.1cc was 66 Gy, with no toxicity reported. One patient suffered from a sacral insufficiency fracture. It was presumed that vaginal mucosa proximal to CTV received the total dose, with two patients developing vaginal ulcers, which both resolved; 10 patients reported mild telangiectasia, fibrosis, or stenosis. CONCLUSIONS: A review of patients treated with a customized vaginal mould and interstitial needles showed acceptable doses to CTV, with local control achieved in 67% of patients, and reasonable doses to organs at risk (OARs) and acceptable toxicity.

Long-Term Toxicity and Health-Related Quality of Life After Adjuvant Chemoradiation Therapy or Radiation Therapy Alone for High-Risk Endometrial Cancer in the Randomized PORTEC-3 Trial.

PURPOSE: The survival results of the PORTEC-3 trial showed a significant improvement in both overall and failure-free survival with chemoradiation therapy versus pelvic radiation therapy alone. The present analysis was performed to compare long-term adverse events (AE) and health-related quality of life (HRQOL). METHODS AND MATERIALS: In the study, 660 women with high-risk endometrial cancer were randomly assigned to receive chemoradiation therapy (2 concurrent cycles of cisplatin followed by 4 cycles of carboplatin/paclitaxel) or radiation therapy alone. Toxicity was graded using Common Terminology Criteria for Adverse Events, version 3.0. HRQOL was measured using EORTC QLQ-C30 and CX24/OV28 subscales and compared with normative data. An as-treated analysis was performed. RESULTS: Median follow-up was 74.6 months; 574 (87%) patients were evaluable for HRQOL. At 5 years, grade ≥2 AE were scored for 78 (38%) patients who had received chemoradiation therapy versus 46 (24%) who had received radiation therapy alone (P = .008). Grade 3 AE did not differ significantly between the groups (8% vs 5%, P = .18) at 5 years, and only one new late grade 4 toxicity had been reported. At 3 and 5 years, sensory neuropathy toxicity grade ≥2 persisted after chemoradiation therapy in 6% (vs 0% after radiation therapy, P < .001) and more patients reported significant tingling or numbness at HRQOL (27% vs 8%, P < .001 at 3 years; 24% vs 9%, P = .002 at 5 years). Up to 3 years, more patients who had chemoradiation therapy reported limb weakness (21% vs 5%, P < .001) and lower physical (79 vs 87, P < .001) and role functioning (78 vs 88, P < .001) scores. Both treatment groups reported similar long-term global health/quality of life scores, which were better than those of the normative population. CONCLUSIONS: This study shows a long-lasting, clinically relevant, negative impact of chemoradiation therapy on toxicity and HRQOL, most importantly persistent peripheral sensory neuropathy. Physical and role functioning impairments were seen until 3 years. These long-term data are essential for patient information and shared decision-making regarding adjuvant chemotherapy for high-risk endometrial cancer.

The value of first-line chemotherapy and targeted therapy in the treatment of breast cancer.

OBJECTIVE: To investigate the value (survival benefit and cost) of first-line chemotherapy and targeted therapy in breast cancer at a population level. METHODS: Based on guideline recommendations, a model of optimal utilisation was constructed for first-line chemotherapy and targeted therapy in breast cancer, calculating the survival benefit and average cost of all regimens recommended for each treatment indication at 5 years and at 10 years. RESULTS: Survival benefits from chemotherapy and targeted therapy differ markedly depending on the treatment indications. The cost per life-year gained at 5 years is $38,044 for stages I and II, $33,749 for stage III and $ 151,668 for patients presenting with stage IV breast cancer. The cost per life-year gained at 10 years is $ 13,587 for early breast cancer. The most expensive chemotherapy indication in breast cancer is the treatment of metastatic HER2-positive breast cancer costing $330,978 per LYG for a survival benefit of 11% at 5 years falling to zero survival benefit at 10 years. CONCLUSION: There are large differences in value between the different indications for first-course chemotherapy and targeted therapy in the treatment of breast cancer that should be considered when pricing cancer drugs.

Adjuvant chemoradiotherapy versus radiotherapy alone in women with high-risk endometrial cancer (PORTEC-3): patterns of recurrence and post-hoc survival analysis of a randomised phase 3 trial.

BACKGROUND: The PORTEC-3 trial investigated the benefit of combined adjuvant chemotherapy and radiotherapy versus pelvic radiotherapy alone for women with high-risk endometrial cancer. We updated the analysis to investigate patterns of recurrence and did a post-hoc survival analysis. METHODS: In the multicentre randomised phase 3 PORTEC-3 trial, women with high-risk endometrial cancer were eligible if they had International Federation of Gynaecology and Obstetrics (FIGO) 2009 stage I, endometrioid grade 3 cancer with deep myometrial invasion or lymphovascular space invasion, or both; stage II or III disease; or stage I-III disease with serous or clear cell histology; were aged 18 years and older; and had a WHO performance status of 0-2. Participants were randomly assigned (1:1) to receive radiotherapy alone (48·6 Gy in 1·8 Gy fractions given on 5 days per week) or chemoradiotherapy (two cycles of cisplatin 50 mg/m2 given intravenously during radiotherapy, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m2 given intravenously), by use of a biased coin minimisation procedure with stratification for participating centre, lymphadenectomy, stage, and histological type. The co-primary endpoints were overall survival and failure-free survival. Secondary endpoints of vaginal, pelvic, and distant recurrence were analysed according to the first site of recurrence. Survival endpoints were analysed by intention-to-treat, and adjusted for stratification factors. Competing risk methods were used for failure-free survival and recurrence. We did a post-hoc analysis to analyse patterns of recurrence with 1 additional year of follow-up. The study was closed on Dec 20, 2013; follow-up is ongoing. This study is registered with ISRCTN, number ISRCTN14387080, and ClinicalTrials.gov, number NCT00411138. FINDINGS: Between Nov 23, 2006, and Dec 20, 2013, 686 women were enrolled, of whom 660 were eligible and evaluable (330 in the chemoradiotherapy group, and 330 in the radiotherapy-alone group). At a median follow-up of 72·6 months (IQR 59·9-85·6), 5-year overall survival was 81·4% (95% CI 77·2-85·8) with chemoradiotherapy versus 76·1% (71·6-80·9) with radiotherapy alone (adjusted hazard ratio [HR] 0·70 [95% CI 0·51-0·97], p=0·034), and 5-year failure-free survival was 76·5% (95% CI 71·5-80·7) versus 69·1% (63·8-73·8; HR 0·70 [0·52-0·94], p=0·016). Distant metastases were the first site of recurrence in most patients with a relapse, occurring in 78 of 330 women (5-year probability 21·4%; 95% CI 17·3-26·3) in the chemoradiotherapy group versus 98 of 330 (5-year probability 29·1%; 24·4-34·3) in the radiotherapy-alone group (HR 0·74 [95% CI 0·55-0·99]; p=0·047). Isolated vaginal recurrence was the first site of recurrence in one patient (0·3%; 95% CI 0·0-2·1) in both groups (HR 0·99 [95% CI 0·06-15·90]; p=0·99), and isolated pelvic recurrence was the first site of recurrence in three women (0·9% [95% CI 0·3-2·8]) in the chemoradiotherapy group versus four (0·9% [95% CI 0·3-2·8]) in the radiotherapy-alone group (HR 0·75 [95% CI 0·17-3·33]; p=0·71). At 5 years, only one grade 4 adverse event (ileus or obstruction) was reported (in the chemoradiotherapy group). At 5 years, reported grade 3 adverse events did not differ significantly between the two groups, occurring in 16 (8%) of 201 women in the chemoradiotherapy group versus ten (5%) of 187 in the radiotherapy-alone group (p=0·24). The most common grade 3 adverse event was hypertension (in four [2%] women in both groups). At 5 years, grade 2 or worse adverse events were reported in 76 (38%) of 201 women in the chemoradiotherapy group versus 43 (23%) of 187 in the radiotherapy-alone group (p=0·002). Sensory neuropathy persisted more often after chemoradiotherapy than after radiotherapy alone, with 5-year rates of grade 2 or worse neuropathy of 6% (13 of 201 women) versus 0% (0 of 187). No treatment-related deaths were reported. INTERPRETATION: This updated analysis shows significantly improved overall survival and failure-free survival with chemoradiotherapy versus radiotherapy alone. This treatment schedule should be discussed and recommended, especially for women with stage III or serous cancers, or both, as part of shared decision making between doctors and patients. Follow-up is ongoing to evaluate long-term survival. FUNDING: Dutch Cancer Society, Cancer Research UK, National Health and Medical Research Council, Project Grant, Cancer Australia Grant, Italian Medicines Agency, and the Canadian Cancer Society Research Institute.

Long-term outcomes in 1121 Australian prostate cancer patients treated with definitive radiotherapy.

INTRODUCTION: Optimal definitive treatment of prostate cancer is controversial, especially in high-risk patients. We report the largest prospective cohort of Australian patients treated with radiotherapy for localised prostate cancer. METHODS: One thousand, one hundred and twenty-one patients with prostate cancer were prospectively registered and treated to a dose of 70-74 Gy. Patients were classified as low, intermediate or high risk based on PSA, clinical staging and Gleason score. Intermediate-risk patients were treated with 0-6 months of hormonal therapy (ADT) and high-risk patients were offered neoadjuvant and adjuvant ADT. Overall survival (OS) and biochemical relapse-free survival (bNED) were calculated using the Kaplan-Meier method. RESULTS: Median follow-up was 92 months. Eight-year OS and bNED were 78.4% and 68.1% respectively in the entire cohort. OS for the low, intermediate and high-risk groups was 84.5%, 78.4% and 68% respectively. For these risk groups, bNED was 80.3%, 65.7% and 53.7% respectively. In the intermediate and high-risk group, OS and bNED decreased with increasing number of risk factors. CONCLUSION: Definitive radiotherapy is an effective treatment for prostate cancer, including in high-risk cases.

Adjuvant chemoradiotherapy versus radiotherapy alone for women with high-risk endometrial cancer (PORTEC-3): final results of an international, open-label, multicentre, randomised, phase 3 trial.

BACKGROUND: Although women with endometrial cancer generally have a favourable prognosis, those with high-risk disease features are at increased risk of recurrence. The PORTEC-3 trial was initiated to investigate the benefit of adjuvant chemotherapy during and after radiotherapy (chemoradiotherapy) versus pelvic radiotherapy alone for women with high-risk endometrial cancer. METHODS: PORTEC-3 was an open-label, international, randomised, phase 3 trial involving 103 centres in six clinical trials collaborating in the Gynaecological Cancer Intergroup. Eligible women had high-risk endometrial cancer with FIGO 2009 stage I, endometrioid-type grade 3 with deep myometrial invasion or lymph-vascular space invasion (or both), endometrioid-type stage II or III, or stage I to III with serous or clear cell histology. Women were randomly assigned (1:1) to receive radiotherapy alone (48·6 Gy in 1·8 Gy fractions given on 5 days per week) or radiotherapy and chemotherapy (consisting of two cycles of cisplatin 50 mg/m2 given during radiotherapy, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m2) using a biased-coin minimisation procedure with stratification for participating centre, lymphadenectomy, stage of cancer, and histological type. The co-primary endpoints were overall survival and failure-free survival. We used the Kaplan-Meier method, log-rank test, and Cox regression analysis for final analysis by intention to treat and adjusted for stratification factors. The study was closed on Dec 20, 2013, after achieving complete accrual; follow-up is ongoing. PORTEC-3 is registered with ISRCTN, number ISRCTN14387080, and ClinicalTrials.gov, number NCT00411138. RESULTS: 686 women were enrolled between Nov 23, 2006, and Dec 20, 2013. 660 eligible patients were included in the final analysis, of whom 330 were assigned to chemoradiotherapy and 330 were assigned to radiotherapy. Median follow-up was 60·2 months (IQR 48·1-73·1). 5-year overall survival was 81·8% (95% CI 77·5-86·2) with chemoradiotherapy versus 76·7% (72·1-81·6) with radiotherapy (adjusted hazard ratio [HR] 0·76, 95% CI 0·54-1·06; p=0·11); 5-year failure-free survival was 75·5% (95% CI 70·3-79·9) versus 68·6% (63·1-73·4; HR 0·71, 95% CI 0·53-0·95; p=0·022). Grade 3 or worse adverse events during treatment occurred in 198 (60%) of 330 who received chemoradiotherapy versus 41 (12%) of 330 patients who received radiotherapy (p<0·0001). Neuropathy (grade 2 or worse) persisted significantly more often after chemoradiotherapy than after radiotherapy (20 [8%] women vs one [1%] at 3 years; p<0·0001). Most deaths were due to endometrial cancer; in four patients (two in each group), the cause of death was uncertain. One death in the radiotherapy group was due to either disease progression or late treatment complications; three deaths (two in the chemoradiotherapy group and one in the radiotherapy group) were due to either intercurrent disease or late treatment-related toxicity. INTERPRETATION: Adjuvant chemotherapy given during and after radiotherapy for high-risk endometrial cancer did not improve 5-year overall survival, although it did increase failure-free survival. Women with high-risk endometrial cancer should be individually counselled about this combined treatment. Continued follow-up is needed to evaluate long-term survival. FUNDING: Dutch Cancer Society, Cancer Research UK, National Health and Medical Research Council Project Grant and Cancer Australia, L'Agenzia Italiana del Farmaco, and Canadian Cancer Society Research Institute.

Effects of siRNA-dependent knock-down of cardiolipin synthase and tafazzin on mitochondria and proliferation of glioma cells.

The mitochondrial phospholipid cardiolipin (CL) has been implicated with mitochondrial morphology, function, and cell proliferation. Changes in CL are often paralleled by changes in the lipid environment of mitochondria that may contribute to mitochondrial function and proliferation. This study aimed to separate the effects of CL content and CL composition from cellular free fatty acid distribution on bioenergetics and proliferation in C6 glioma cells. To this end, cardiolipin synthase and the CL remodelling enzyme, tafazzin, were knocked-down by siRNA in C6 cells. After 72 h of cultivation, we analysed CL composition by means of LC/MS/MS, distribution of cellular fatty acids by means of gas chromatography, and determined oxygen consumption and proliferation. Knock-down of cardiolipin synthase affected the cellular CL content in the presence of linoleic acid (LA) in the culture medium. Knock-down of tafazzin had no consequence with respect to the pattern of cellular fatty acids but caused a decrease in cell proliferation. It significantly changed the distribution of molecular CL species, increased CL content, decreased oxygen consumption, and decreased cell proliferation when cultured in the presence of linoleic acid (LA). The addition of linoleic acid to the culture medium caused significant changes in the pattern of cellular fatty acids and the composition of molecular CL species. These data suggest that tafazzin is required for efficient bioenergetics and for proliferation of glioma cells. Supplementation of fatty acids can be a powerful tool to direct specific changes in these parameters.

Radiation-induced vaginal stenosis: current perspectives.

Treatment of gynecological cancer commonly involves pelvic radiation therapy (RT) and/or brachytherapy. A commonly observed side effect of such treatment is radiation-induced vaginal stenosis (VS). This review analyzed the incidence, pathogenesis, clinical manifestation(s) and assessment and grading of radiation-induced VS. In addition, risk factors, prevention and treatment options and follow-up schedules are also discussed. The limited available literature on many of these aspects suggests that additional studies are required to more precisely determine the best management strategy of this prevalent group after RT.

Incidence of Postsuppression Virologic Rebound in Perinatally HIV-Infected Asian Adolescents on Stable Combination Antiretroviral Therapy.

PURPOSE: To assess the incidence and predictors of postsuppression virologic rebound (VR) among adolescents on stable combination antiretroviral therapy in Asia. METHODS: Perinatally HIV-infected Asian adolescents (10-19 years) with documented virologic suppression (two consecutive viral loads [VLs] <400 copies/mL ≥6 months apart) were included. Baseline was the date of the first VL <400 copies/mL at age ≥10 years or the 10th birthday for those with prior suppression. Cox proportional hazards models were used to identify predictors of postsuppression VR (VL >1,000 copies/mL). RESULTS: Of 1,379 eligible adolescents, 47% were males. At baseline, 22% were receiving protease inhibitor-containing regimens; median CD4 cell count (interquartile range [IQR]) was 685 (448-937) cells/mm3; 2% had preadolescent virologic failure (VF) before subsequent suppression. During adolescence, 180 individuals (13%) experienced postsuppression VR at a rate of 3.4 (95% confidence interval: 2.9-3.9) per 100 person-years, which was consistent over time. Median time to VR during adolescence (IQR) was 3.3 (2.1-4.8) years. Wasting (weight-for-age z-score <-2.5), being raised by grandparents, receiving second-line protease inhibitor-based regimens, starting combination antiretroviral therapy after 2005, and having preadolescent VF were independent predictors of adolescent VR. At VR, median age, CD4 cell count, and VL (IQR) were 14.8 (13.2-16.4) years, 507 (325-723) cells/mm3, and 4.1 (3.5-4.7) log10 copies/mL, respectively. CONCLUSIONS: A modest and consistent incidence of postsuppression VR was documented during adolescence in our cohort. Having poor weight, receiving second-line regimens, and prior VF were associated with an increased VR rate. Adolescents at higher risk of VR may benefit from more intensive VL monitoring to enhance adherence management.

High-risk CTV delineation for cervix brachytherapy: Application of GEC-ESTRO guidelines in Australia and New Zealand.

INTRODUCTION: Image-based brachytherapy for cervical cancer using MRI has been implemented in Australia and New Zealand. The aims of this study were to measure variability in High-risk CTV (HR-CTV) delineation and evaluate dosimetric consequences of this. METHODS: Nine radiation oncologists, one radiation therapist and two radiologists contoured HR-CTV on 3T MRI datasets from ten consecutive patients undergoing cervical brachytherapy at a single institution. Contour comparisons were performed using the Dice Similarity Coefficient (DSC) and Mean Absolute Surface Distance (MASD). Two reference contours were created for brachytherapy planning: a Simultaneous Truth and Performance Level Estimation (STAPLE) and a consensus contour (CONSENSUS). Optimized plans (8 Gy) for both these contours were applied to individual participant's contours to assess D90 and D100 coverage of HR CTV. To compare variability in dosimetry, relative standard deviation (rSD) was calculated. RESULTS: Good concordance (mean DSC≥0.7, MASD≤5 mm) was achieved in 8/10 cases when compared to the STAPLE reference and 6/10 cases when compared to the CONSENSUS reference. Greatest variation was visually seen in the cranio-caudal direction. The average mean rSD across all patients was 27% and 34% for the STAPLE HR-CTV D90 and D100, respectively, and 28% and 35% for the CONSENSUS HR-CTV D90 and D100. Delineation uncertainty resulted in an average dosimetric uncertainty of ±1.5-1.6 Gy per fraction based on an 8 Gy prescribed fraction. CONCLUSIONS: Delineation of HR-CTV for cervical cancer brachytherapy was consistent amongst observers, suggesting similar interpretation of GEC-ESTRO guidelines. Despite the good concordance, there was dosimetric variation noted, which could be clinically significant.