Phase I trial of hypofractionated chemoradiotherapy in the palliative management of esophageal and gastro-esophageal cancer.

BACKGROUND: Many patients with incurable esophageal cancer (ECa) present with dysphagia as their predominant symptom. Currently there is no consensus on how best to initially manage this scenario with multiple therapeutic options available. We aimed to assess the safety and efficacy of using hypofractionated radiotherapy given over a progressively shorter timeframe with concurrent carboplatin and paclitaxel in the management of patients with ECa and dysphagia. METHODS: In this phase I trial we enrolled patients with histologically proven squamous cell carcinoma or adenocarcinoma of the esophagus or the gastro-esophageal junction with symptomatic dysphagia from local disease and not for curative treatment. Patients needed to be 18 years or older, have an ECOG performance status of 0-2 and be suitable to receive carboplatin and paclitaxel chemotherapy. Patients were placed in four progressively shorter radiation schedules culminating in 30 Gy in 10 fractions in a step wise manner, all with concurrent carboplatin AUC 2 and paclitaxel 50 mg/m2 chemotherapy delivered weekly with the radiation therapy. The primary endpoint was the development of the dose limiting toxicities (DLTs) esophageal perforation or febrile neutropenia. Secondary endpoints were relief of dysphagia, time to improvement of dysphagia, dysphagia progression free survival and overall survival. RESULTS: Eighteen patients were enrolled in the study between October 2014 and March 2019. There were no DLTs experienced during the trial. The most common grade 3 + acute toxicity experienced by patients were nausea and vomiting (both in 4/18 patients). The most common radiation specific acute toxicity experienced was esophagitis with 67% of patients experiencing grade 1-2 symptoms. All patients experienced improvement in dysphagia. The median time to dysphagia improvement was 3 weeks from the start of chemoradiotherapy (CTRT) (range 2-10 weeks). The median dysphagia free survival was 5.8 months with a median overall survival of 8.9 months. CONCLUSION: Hypofractionated palliative CTRT with 30 Gy/10# of radiation therapy with concurrent weekly carboplatin and paclitaxel chemotherapy is well tolerated and provides a good response in improvement of dysphagia. Further studies need to be undertaken which provide both symptomatic improvement in the primary tumor but also control of the metastatic burden in these patients. CLINICAL TRIAL REGISTRATION: This trial was prospectively registered with www.anzctr.org.au Identifier: ACTRN12614000821695.

Challenges in the Management of Childhood Intracranial Germ Cell Tumors in Middle-Income Countries: A 20-Year Retrospective Review From a Single Tertiary Center in Malaysia.

BACKGROUND: A higher incidence of pediatric intracranial germ cell tumors (iGCTs) in Asian countries compared with Western countries has been reported. In Malaysia, the literature regarding pediatric iGCTs have been nonexistent. The aim of this study was to review the management, survival, and long-term outcomes of pediatric iGCTs at a single tertiary center in Malaysia. PATIENTS AND METHODS: We retrospectively reviewed data from patients below 18 years of age with iGCTs treated at the University Malaya Medical Center (UMMC) from 1998 to 2017. RESULTS: Thirty-four patients were identified, with a median follow-up of 3.54 years. Sixteen (47%) patients had pure germinoma tumors (PGs), and the remaining patients had nongerminomatous germ cell tumors (NGGCTs). The median age was 12 years, with a male:female ratio of 4.7:1. Abnormal vision, headache with vomiting, and diabetes insipidus were the commonest presenting symptoms. Twenty-eight patients received initial surgical interventions, 24 were treated with chemotherapy, and 28 received radiotherapy. Eight patients experienced relapses. The 5- and 10-year event-free survival rates were similar at 61.1%±12.6% and 42.9%±12.1% for PG and NGGCT, respectively. The 5- and 10-year overall survival rates were the same at 75.5%±10.8% and 53.3%±12.3% for PG and NGGCT, respectively. Four patients died of treatment-related toxicity. Most of the survivors experienced good quality of life with satisfactory neurologic status. CONCLUSIONS: The survival rate of childhood iGCTs in UMMC was inferior to that reported in developed countries. Late diagnosis, poor adherence to treatment, and treatment-related complications were the contributing factors. Although these results highlight a single institution experience, they most likely reflect similar treatment patterns, outcomes, and challenges in other centers in Malaysia.

Conduct of neuro-oncology multidisciplinary team meetings and closing the "gaps" in the clinical management of childhood central nervous system tumors in a middle-income country.

PURPOSE: Multidisciplinary team meetings (MDTMs) are essential in the clinical management of pediatric central nervous system (CNS) tumors. Evaluations of the impact of MDTMs on childhood CNS tumors and clinicians' perspectives on their effectiveness are scarce. METHODS: We retrospectively reviewed the clinical data of pediatric patients (aged <18 years) with CNS tumors diagnosed and treated in the Pediatric Hematology-Oncology Division at the University Malaya Medical Center from 2008 to 2019. We also conducted a web-based survey of the core members of the multidisciplinary team to evaluate the impact of the MDTMs. RESULTS: During the pre-MDTM era (2008-2012), 29 CNS tumors were diagnosed and treated, and during the MDTM era (2014-2019), 49 CNS tumors were diagnosed and treated. The interval for histologic diagnosis was significantly shorter during the MDTM era (p=0.04), but the interval from diagnosis to chemotherapy or radiotherapy and the 5-year overall survival of the 78 patients did not improve (62.1% ± 9.0% vs. 68.8% ± 9.1%; p=0.184). However, the 5-year overall survival of patients with medulloblastoma or rare tumors significantly improved in the MDTM era (p=0.01). Key factors that contributed to delayed treatment and poor outcomes were postoperative complications, the facility's lack of infrastructure, poor parental education about early treatment, cultural beliefs in alternative medicine, and infection during chemotherapy. Eighteen clinicians responded to the survey; they felt that the MDTMs were beneficial in decision-making and enhanced the continuity of coordinated care. CONCLUSION: MDTMs significantly reduced the diagnostic interval and improved the overall outcomes. However, delayed treatment remains a major challenge that requires further attention.

Medical physics aspects of Intensity-Modulated Radiotherapy practice in Malaysia.

PURPOSE: Intensity Modulated Radiotherapy (IMRT) has changed the practice of radiotherapy since its implementation in the 1990s. The purpose of this study is to review current practice of IMRT in Malaysia. METHODS: A survey on medical physics aspects of IMRT is conducted on radiotherapy departments across Malaysia to assess the usage, experience and QA in IMRT, which is done for the first time in this country. A set of questionnaires was designed and sent to the physicist in charge for their responses. The questionnaire consisted of four sections; (i) Experience and qualification of medical physicists, (ii) CT simulation techniques (iii) Treatment planning and treatment unit, (iv) IMRT process, delivery and QA procedure. RESULTS: A total of 26 responses were collected, representing 26 departments out of 33 radiotherapy departments in operation across Malaysia (79% response rate). Results showed that the medical physics aspects of IMRT practice in Malaysia are homogenous, with some variations in certain areas of practices. Thirteen centres (52%) performed measurement-based QA using 2D array detector and analysed using gamma index criteria of 3%, 3 mm with variation confidence range. In relation to the IMRT delivery, 44% of Malaysia's physicist takes more than 8 h to plan a head and neck case compared to the UK study possibly due to the lack of professional training. CONCLUSIONS: This survey provides a picture of medical physics aspects of IMRT in Malaysia where the results/data can be used by radiotherapy departments to benchmark their local policies and practice.

National survey on image-guided radiotherapy practice in New Zealand.

INTRODUCTION: This survey aimed to assess the use of image-guided radiotherapy (IGRT) within New Zealand (NZ) and evaluate the quality of IGRT delivery. METHOD: All nine centres in NZ were invited to participate in an online survey in November 2015. Questions were asked on type of IGRT technologies available, IGRT use by tumour site and frequency of imaging. In addition, questions were asked in reference to the American Society for Radiation Oncology (ASTRO) White Paper recommendations on safe practice of IGRT. RESULTS: Seven of the nine centres (78%) responded. Kilovoltage cone-beam CT (CBCT), kilovoltage planar imaging and megavoltage electronic portal imaging were the most commonly used IGRT technologies. CBCT was most frequently used in gynaecology (100%), genitourinary (86%) and head and neck (86%) sites. Despite the availability of similar IGRT technologies, there was significant variation in their application between centres. All centres used online IGRT; however, the frequency of imaging varied across the tumour sites and individual centres. Daily online IGRT use ranged from 43% to 86% across the tumour sites. Overall, there was good compliance by the NZ centres to the White Paper recommendations, with at least 71% reached for each element. However, the compliance rates for the individual centres ranged between 50% and 100%. The most commonly identified barrier to IGRT use was lack of guidelines/education (43%). CONCLUSION: Image-guided radiotherapy is widely used in NZ; however, there is a wide variation in its application between centres. Detailed tumour site-specific, imaging modality-specific national guidelines will allow standardization of IGRT practices.

Infections after fiducial marker implantation for prostate radiotherapy: are we underestimating the risks?

BACKGROUND: The use of gold fiducial markers (FM) for prostate image-guided radiotherapy (IGRT) is standard practice. Published literature suggests low rates of serious infection following this procedure of 0-1.3%, but this may be an underestimate. We aim to report on the infection incidence and severity associated with the use of transrectally implanted intraprostatic gold FM. METHODS: Three hundred and fifty-nine patients who underwent transrectal FM insertion between January 2012 and December 2013 were assessed retrospectively via a self-reported questionnaire. All had standard oral fluoroquinolone antibiotic prophylaxis. The patients were asked about infective symptoms and the treatment received including antibiotics and/or related hospital admissions. Potential infective events were confirmed through medical records. RESULTS: 285 patients (79.4%) completed the questionnaire. 77 (27.0%) patients experienced increased urinary frequency and dysuria, and 33 patients (11.6%) reported episodes of chills and fevers after the procedure. 22 patients (7.7%) reported receiving antibiotics for urinary infection and eight patients (2.8%) reported hospital admission for urosepsis related to the procedure. CONCLUSION: The overall rate of symptomatic infection with FM implantation in this study is 7.7%, with one third requiring hospital admission. This exceeds the reported rates in other FM implantation series, but is in keeping with the larger prostate biopsy literature. Given the higher than expected complication rate, a risk-adaptive approach may be helpful. Where higher accuracy is important such as stereotactic prostate radiotherapy, the benefits of FM may still outweigh the risks. For others, a non-invasive approach for prostate IGRT such as cone-beam CT could be considered.

Circulating tumor cell detection in high-risk non-metastatic prostate cancer.

PURPOSE: The detection of circulating tumor cells (CTCs) provides important prognostic information in men with metastatic prostate cancer. We aim to determine the rate of detection of CTCs in patients with high-risk non-metastatic prostate cancer using the CellSearch® method. METHOD: Samples of peripheral blood (7.5 mL) were drawn from 36 men with newly diagnosed high-risk non-metastatic prostate cancer, prior to any initiation of therapy and analyzed for CTCs using the CellSearch® method. RESULTS: The median age was 70 years, median PSA was 14.1, and the median Gleason score was 9. The median 5-year risk of progression of disease using a validated nomogram was 39 %. Five out of 36 patients (14 %, 95 % CI 5-30 %) had CTCs detected in their circulation. Four patients had only 1 CTC per 7.5 mL of blood detected. One patient had 3 CTCs per 7.5 mL of blood detected, which included a circulating tumor microemboli. Both on univariate analysis and multivariate analysis, there were no correlations found between CTC positivity and the classic prognostic factors including PSA, Gleason score, T-stage and age. CONCLUSION: This study demonstrates that patients with high-risk, non-metastatic prostate cancer present infrequently with small number of CTCs in peripheral blood. This finding is consistent with the limited literature available in this setting. Other CTC isolation and detection technologies with improved sensitivity and specificity may enable detection of CTCs with mesenchymal phenotypes, although none as yet have been validated for clinical use. Newer assays are emerging for detection of new putative biomarkers for prostate cancer. Correlation of disease control outcomes with CTC detection will be important.

Extracranial oligometastatic renal cell carcinoma: current management and future directions.

The term 'oligometastases' was formulated to describe an intermediate state between widespread metastases and locally confined disease. The standard of care in metastatic renal cell carcinoma is systemic therapy; however, in patients with solitary or limited metastases, aggressive local therapies may potentially prolong survival. The literature suggests a survival benefit with surgical metastasectomy, with a reported 5-year survival as high as 45% in those who achieve complete resection. More recently, an expanding body of evidence supports the role of stereotactic ablative body radiation therapy for the treatment of oligometastatic renal cell carcinoma and early results demonstrate comparable local control rates with surgery. There is also increasing interest in the abscopal and immunologic effects of localized radiation. With the proliferation of newer targeted agents and immunomodulatory agents, current work is addressing the optimization of patient selection and avenues towards sequencing and combining the various treatment options.

Concordance between thoracic multidisciplinary meeting recommendations for radiation therapy and actual treatment for lung cancer.

INTRODUCTION: There is limited evidence whether decisions of Thoracic Multidisciplinary Meetings (TMDMs) are reflected in the treatment lung cancer patients actually receive. Aims were to determine concordance between TMDM recommendations for radiotherapy (RT) and actual RT administered and to compare cases that received RT that were referred or not referred from TMDMs. METHOD: A retrospective review of demographic and clinical data for all lung cancer cases within the Auckland-Northland region referred for RT from TMDMs (January-June 2009) and all cases that received RT but were not referred from TMDMs (January-August 2009). RESULTS: Of 110 cases referred for RT from TMDMs, 86 (78%) were offered RT (76 with the same treatment intent) and 78 (71%) received RT. Ten (9%) cases were deemed unsuitable for RT; 7 (6%) deteriorated; 4 (4%) declined or did not attend; 3% other. Fifty-one other cases received RT without TMDM presentation. Cases with remote domicile or recurrent disease were significantly less likely to have been presented at TMDMs. TMDM presentation did not significantly increase transit time to RT. The proportion of RT cases referred from TMDMs had increased substantially since 2004. CONCLUSION: The concordance between TMDM recommendations for RT and both the RT administered and the intent of treatment suggests a useful role for TMDMs. Concordance could be increased by improving RT timeliness and improved education of other disciplines and patients regarding the role of RT. Strategies to increase presentation at TMDM include attention to geographically isolated groups.