Cocktail without hangover: in search for the optimal chemotherapy in the combined management of non-operable esophageal carcinomas.

BACKGROUND: The worldwide incidence of esophageal cancer has greatly increased over the past few decades making it the sixth deadliest cancer. The disease is often detected in advanced stages when surgery is no longer an option. The standard treatment in these situations is combined chemoradiotherapy, by employing drug cocktails that lead to optimal treatment outcomes both from the perspective of tumor control and normal tissue toxicity. METHODS: The aim of this work was to collate the existing trials and clinical studies reported on non-operable esophageal cancer and to analyze the results based on treatment outcomes after various drug combinations. RESULTS: Of all drug combinations, cisplatin/5-FU is the most well established chemotherapy regimen for esophageal cancer as both neoadjuvant therapy, an alternative option to surgery, and for palliative purposes. Although this regimen is associated with the most toxicity, it also appears to have the best survival benefit and relief of symptoms. CONCLUSIONS: More research is warranted to further increase the therapeutic ratio in non-operable esophageal cancers.

Phase I study evaluating the safety and efficacy of oral panobinostat in combination with radiotherapy or chemoradiotherapy in patients with inoperable stage III non-small-cell lung cancer.

Panobinostat is a radiosensitizing agent and targets the epigenetics of malignancy. This phase I study evaluated the safety and efficacy of combining oral panobinostat with radiotherapy (RT) or chemoradiotherapy (CRT) in patients with inoperable stage III non-small-cell lung cancer. This study had a parallel dose-escalating design combining oral panobinostat twice a week (dose escalations 20, 30, 45 mg) with either palliative RT (group A) or radical CRT (group B) using a standard chemotherapy protocol of cisplatin and etoposide. In group A (RT), nine recruited patients received treatment with oral panobinostat (doses 20, 30, 45 mg) with RT. Two serious adverse events, rapid atrial fibrillation and tracheo-oesophageal fistula, were not attributable to study treatment. The most common grade 3/4 toxicities were thrombocytopenia and lymphopenia, which resolved promptly after cessation of panobinostat. The disease control rate was 66%, the progression-free survival was 3 months and the median overall survival was 9 months. In group B (CRT), panobinostat dose was not escalated beyond 20 mg because of infection-related complications. Serious adverse events included opportunistic infection associated with treatment-related lymphopenia and febrile neutropenia without a source. One patient had cerebral infarct that was not attributed to study treatment. All patients achieved a partial response to treatment. At 33 months of follow-up, all patients were still alive. Panobinostat can be combined with palliative-dose RT at doses up to 45 mg twice a week with tolerable toxicity. Dose-limiting toxicities prevented the dose escalation of the panobinostat with CRT.

A proposed framework for the implementation of head and neck cancer treatment at a new cancer center from a radiation oncology perspective.

BACKGROUND: Establishing a new head and neck cancer (HNC) treatment center requires multidisciplinary team management and expertise. To our knowledge, there are no clear recommendations or guidelines in the literature for the commencement of HNC radiation therapy (RT) at a new cancer center. We propose a novel framework outlining the necessary components required to set-up a new radiation therapy HNC treatment. METHODS: We reviewed the infrastructure and methodology in the commencement of HNC radiation therapy in our cancer care center and invited several external, experienced metropolitan head and neck radiation oncologists to develop a novel consensus guideline that may be used by new RT centers to treat HNC. Recommendations were presented to our internal and external staff specialists using a survey questionnaire with ratings utilized to determine consensus using pre-defined thresholds as per the American Society of Clinical Oncology Guidelines Methodology Manual. CONCLUSION: This consensus recommendation aims to improve RT utilization whilst advocating for optimal patient outcomes by presenting a framework for new radiation therapy centers ready to step up and manage the treatment of head and neck cancer patients. We propose these evidence-based consensus guidelines endorsed by external HNC radiation oncologists.

'Radiation-induced pleomorphic sarcoma with rhabdomyoblastic differentiation of the lower limb following treatment of vaginal squamous cell carcinoma - A case report and review of the literature'.

We present the case of a 59-year-old woman who developed a right thigh pleomorphic sarcoma with rhabdomyoblastic differentiation 6 years following radiotherapy for a vaginal squamous cell carcinoma. The overall 5-year survival for a gynaecological malignancy is more than 80 % and as overall cancer survivorship and life expectancy improves, the incidence of radiation-induced malignancy is increasing (Bjerkehagen et al., 2013). As the prognosis of those malignancies is usually poor, clinicians must have a high index of suspicion to try to detect these cases early.

Quality indicators and technique for analyzing permanent I-125 prostate seed implants: seven years postimplant dosimetry evaluation.

PURPOSE: The roles of postimplant dosimetry (PID) after permanent I-125 implant are to identify and rectify inadequate implants, assess the dosimetric quality indicators, and evaluate dose to the organs at risk. The aim of the current work was to assess the progress of prostate implant quality via postimplant dosimetry over seven years. METHODS: The following factors were investigated to assess the PID results obtained over seven years: the improvement in implant technique, the computed tomography (CT) delineation-based PID versus ultrasound-CT (US-CT) fusion-based PID, and the evolution of parameters such as D90 and NDR (natural dose ratio). The correlation between dosimetric parameters and clinical outcomes were also evaluated. RESULTS: The seven years PID learning curve shows clear changes in dosimetric trend for the 265 patients studied. Manual target contouring on CT was shown to overestimate the prostate volume when compared to ultrasound data, translating to CT-based D90 values being lower than US-CT D90. It was found that NDR does not contribute with additional dosimetric information to postimplant dosimetry evaluation. Patient follow-up data show that 4.7% patients have relapsed, and urinary retention was reported in 2.7% of the patients. CONCLUSIONS: CT-based PID was found less reliable than US-CT fusion-based PID due to target volume overestimation. This result shows the biased interpretation of low D90 values based on CT-based targeting, providing unreliable correlations between D90 and relapse probability. The low urinary retention statistics are in accordance with the PID data for the organ, as only 5.2% of patients had their PID D10 > 218 Gy, i.e., above the recommended GEC-ESTRO guidelines. Besides the "learning" component, the PID D90 curve is influenced by the PID technique.

Carcinosarcomas of the Uterus: Prognostic Factors and Impact of Adjuvant Treatment.

BACKGROUND: Uncertainties remain about the most effective treatment for uterine carcinosarcoma (UCS), a rare but aggressive uterine cancer, due to the limited scope for randomized trials. This study investigates whether nodal excision or adjuvant therapies after hysterectomy offer a survival benefit, using multi-institutional clinical registry data from South Australia. METHODS: Data for all consecutive cases of UCS from 1980 to 2019 were extracted from the Clinical Cancer Registry. Clinical and treatment-related factors associated with disease-specific mortality (DSM) and all-cause mortality (ACM) were determined using multivariable Cox proportional hazards regression, with subgroup analyses by stage. RESULTS: Median follow-up for the 140 eligible cases was 21 months. 94% underwent hysterectomy, and 72% had an additional pelvic lymph node dissection (PLND). Furthermore, 16% received adjuvant chemotherapy; 11% adjuvant radiotherapy and 16% multimodal chemoradiotherapy, with an increase in the latter two modalities over time. DSM was reduced among those who underwent PLND (HR: 0.41; 95%CI: 0.23-0.74), adjuvant chemotherapy (HR: 0.39; 95%CI: 0.18-0.84) or multimodality treatment (HR: 0.11; 95%CI: 0.06-0.30) compared with hysterectomy alone for the whole cohort and for late stage disease (FIGO III/IV) but not for earlier stage disease, except for reduced DSM with multimodal therapy. Findings were similar for ACM. CONCLUSION: Our findings indicate better survival among those who received PLND, chemotherapy and multimodal adjuvant therapy, with the latter applying to early and late stage disease. However, cautious interpretation is warranted, due to potential "indication bias" and limited power. Further research into effective treatment modalities, ideally using prospective study designs, is needed.

Temporal modelling of beryllium oxide ceramics' real-time OSL for dosimetry with a superficial 140 kVp X-ray beam.

A new analysis method for the rtOSL of BeO ceramics is presented, using temporal curve fitting of an expected rtOSL signal to measured rtOSL signals. The presented technique does not require heavy signal averaging to determine the OSL bleaching correction associated with the ΔrtOSL method, reducing uncertainties in the post-correction rtOSL. The corrected rtOSL signal was demonstrated to be linear with dose, and dose-rate independent. The presented technique is expected to be applicable for many other dosimeters capable of the rtOSL technique. The presented technique achieved relative uncertainties in the corrected rtOSL between 3.4% and 6.5%. The initial measurements are promising, but uncertainties are required to be further improved upon before the technique can be used clinically.

Evaluation of a real-time optically stimulated luminescence beryllium oxide (BeO) fibre-coupled dosimetry system with a superficial 140 kVp X-ray beam.

The purpose of this study was to investigate the potential of real-time optically stimulated luminescence (rtOSL) measurements of a beryllium oxide (BeO) ceramic fibre-coupled luminescence dosimetry system. By pulsing the stimulation laser during the exposure to ionizing radiation, an rtOSL dose-rate measurement can be obtained which could be stem effect free. A portable rtOSL BeO ceramic fibre-coupled dosimetry system is presented and characterized using a constant dose-rate superficial 140 kVp X-ray beam. The rtOSL was measured for dose-rates between 0.29 and 3.88 Gy/min, controlled by varying the source to surface distance. After correcting for OSL decay during the exposure, a linear dose-rate response of the change in rtOSL (ΔrtOSL) was observed. The ΔrtOSL was also observed to be stem effect free.

Stereotactic body radiation therapy for early hepatocellular carcinoma: a retrospective analysis of the South Australian experience.

BACKGROUND: Stereotactic body radiation therapy (SBRT) is an emerging treatment option for liver tumours unsuitable for established curative treatment such as ablation or surgery. The aim of the study is to evaluate the efficacy and safety of SBRT in the treatment of small hepatocellular carcinoma (HCC) in South Australia. METHODS: From 2014 to 2018, 13 HCC patients were treated with SBRT. Eligibility criteria for SBRT included: unsuitable for standard curative therapies (resection or percutaneous ablation), lack of complete response to prior transarterial chemoembolization, Child-Pugh classification ≤B7, tumours ≤5 cm and minimum of up to 6 months follow-up post-SBRT. The prescribed radiation dose was determined by liver function with doses ranging from 40 to 45 Gy in three or five fractions. Records for all patients were reviewed, and treatment response was scored according to the modified response evaluation criteria in solid tumours. Toxicity was graded according to the Common Terminology Criteria for Adverse Events version 4.0. RESULTS: The median follow-up time was 22.7 months, and the median tumour size was 40 mm. The 1 year local control was 92.3%, recurrence-free survival was 67.7% and overall survival was 86.4% at end of study. Three patients underwent liver transplant. No grade ≥3 non-haematological toxicities were observed. One patient experienced acute grade ≥3 haematological toxicity. CONCLUSION: SBRT is a safe, effective and non-invasive alternative treatment option for patients with small HCCs, unsuitable for standard, evidence-based therapies and lacking complete response to transarterial chemoembolization. Randomized controlled trials are required to further investigate the role of SBRT in HCC.

The mutational burden of therapy-related myeloid neoplasms is similar to primary myelodysplastic syndrome but has a distinctive distribution.

Therapy-related myeloid neoplasms (T-MN) are poorly characterized secondary hematological malignancies following chemotherapy/radiotherapy exposure. We compared the clinical and mutational characteristics of T-MN (n = 129) and primary myelodysplastic syndrome (P-MDS, n = 108) patients. Although the somatic mutation frequency was similar between T-MN and P-MDS patients (93% in both groups), the pattern was distinct. TP53 mutations were more frequent in T-MN (29.5 vs. 7%), while spliceosomal complex mutations were more common in P-MDS (56.5 vs. 25.6%). In contrast to P-MDS, the ring sideroblasts (RS) phenotype was not associated with better survival in T-MN, most probably due to genetic association with TP53 mutations. SF3B1 was mutated in 96% of P-MDS with ≥15% RS, but in only 32% T-MN. TP53 mutations were detected in 92% T-MN with ≥15% RS and SF3B1 wild-type cases. Interestingly, T-MN and P-MDS patients with "Very low" or "Low" Revised International Prognostic Scoring System (IPSS-R) showed similar biological and clinical characteristics. In a Cox regression analysis, TP53 mutation was a poor prognostic factor in T-MN, independent of IPSS-R cytogenetics, disease-modifying therapy, and NRAS mutation. Our data have direct implications for T-MN management and provide evidence that, in addition to conventional disease parameters, mutational analysis should be incorporated in T-MN risk stratification.

Oesophageal cancer: Which treatment is the easiest to swallow? A review of combined modality treatments for resectable carcinomas.

Oesophageal cancer is a relatively uncommon malignancy, but with poor prognosis. Despite several treatment options that are available, the 5-year survival rates rarely exceed 40%. This review discusses the main challenges of oesophageal cancer, the available treatment options, and the most effective treatment in terms of overall survival. The outcomes of clinical trials show that neo-adjuvant chemo-radiotherapy using cisplatin and 5-fluorouracil followed by oesophagectomy results in the greatest survival. However, the optimal chemotherapy and radiotherapy schedule remains unclear. There is no satisfactory treatment to date, particularly for patients with co-morbidities or advanced tumours.

Feasibility of spacers to facilitate postoperative radiotherapy for retroperitoneal sarcomas.

INTRODUCTION: The role and timing of postoperative radiotherapy (PORT) in the management of retroperitoneal sarcoma (RPS) remains controversial. METHOD: This is a retrospective cohort review of patients undergoing curative resection for RPS at a single institution between January 2011 and July 2016. Patient selection was through the South Australian Soft Tissue Tumour Multidisciplinary Group (MDT) based at Royal Adelaide Hospital. An individualised approach, including assessment of resectability, histopathological grade and subtype, and radiotherapy considerations, was taken for each patient. Patients offered preoperative radiotherapy or palliation were excluded. A saline-filled spacer was inserted following operative resection. Radiotherapy commenced postoperatively. Patients underwent laparotomy to remove the device approximately 6 weeks post completion of PORT. Primary endpoints were technical feasibility, perioperative morbidity and radiation toxicity. Secondary endpoints were local recurrence (LR), distant recurrence (DR) and death. RESULTS: During the study period, 40 patients with RPS were managed through the MDT. Twelve patients (ages 33-78) underwent PORT utilising spacers. Radiotherapy toxicity was reported in four patients and extensive adhesions observed in another four patients during spacer removal. Median follow-up was 35 months (range 4-60). Seven patients remain alive and disease free. Four patients developed LR, three developed DR. Three patients died; two with DR and one with LR. Two patients with recurrent/progressive disease are alive; one with DR and one with LR. CONCLUSION: Use of intraoperative spacers to facilitate PORT is feasible, with acceptable toxicity following resection of RPS. Patient selection for this approach remains to be determined.

Patterns of care for patients with advanced soft tissue sarcoma: experience from Australian sarcoma services.

BACKGROUND: There is a paucity of data on the current management of patients with advanced soft tissue sarcoma (STS) in the Australian health care setting. This study utilised the Australian sarcoma database to evaluate the patterns of care delivered to patients with advanced STS at Australian sarcoma services. METHODS: Prospectively collected data from six sarcoma centres in Australia were sourced to identify patients diagnosed with advanced STS between 1 January 2010 and 31 December 2012. Descriptive statistics were analysed for patient demographics, clinicopathological characteristics and treatment patterns. Overall survival was estimated using the Kaplan-Meier product limit method. RESULTS: Of 253 patients with advanced STS, four major STS subtypes were identified: undifferentiated pleomorphic sarcoma (23 %), leiomyosarcoma (17 %), liposarcoma (14 %), and synovial sarcoma (8 %); with the rest grouped as "other STS" (38 %). Approximately one-third of patients received palliative systemic therapy with the most common first-line therapy being doxorubicin alone (50 %). A small percentage of patients participated in clinical trials (20 %). Palliative radiotherapy was utilised mostly for treatment of symptomatic distant metastases and one-third of patients underwent metastasectomy, most commonly for pulmonary metastases. The median overall survival (OS) in this series was 18 months and no significant difference in OS was observed across different STS histological subtypes. CONCLUSIONS: This is the first detailed study outlining patterns of care for Australian patients with advanced STS managed at sarcoma services. These data highlight a particular area of weakness in the lack of clinical trials for sarcoma patients and also serve as an important reference point for understanding how practice may change over time as treatment options evolve.

Comparison of 3 different postimplant dosimetry methods following permanent 125I prostate seed brachytherapy.

Postimplant dosimetry (PID) after Iodine-125 ((125)I) implant of the prostate should offer a reliable qualitative assessment. So far, there is no consensus regarding the optimum PID method, though the latest literature is in favor of magnetic resonance imaging (MRI). This study aims to simultaneously compare 3 PID techniques: (1) MRI-computed tomography (CT) fusion; (2) ultrasound (US)-CT fusion; and (3) manual target delineation on CT. The study comprised 10 patients with prostate cancer. CT/MR scans with urinary catheters in place for PID were done either on day 0 or day 1 postimplantation. The main parameter evaluated and compared among methods was target D90. The results show that CT-based D90s are lower than US-CT D90s (median difference,-6.85%), whereas MR-CT PID gives higher D90 than US-CT PID (median difference, 4.25%). Manual contouring on CT images tends to overestimate the prostate volume compared with transrectal ultrasound (TRUS) (median difference, 23.33%), whereas on US images the target is overestimated compared with MR-based contouring (median difference, 13.25%). Although there are certain differences among the results given by various PID techniques, the differences are statistically insignificant for this small group of patients. Any dosimetric comparison between 2 PID techniques should also account for the limitations of each technique, to allow for an accurate quantification of data. Given that PID after permanent radioactive seed implant is mandatory for quality assurance, any imaging method-based PID (MR-CT, US-CT, and CT) available in a radiotherapy department can be indicative of the quality of the procedure.