Focused Ultrasound and RadioTHERapy for non-invasive palliative pain treatment in patients with bone metastasis: a study protocol for the three armed randomized controlled FURTHER trial.

BACKGROUND: Cancer-induced bone pain (CIBP), caused by bone metastases, is a common complication of cancer and strongly impairs quality of life (QoL). External beam radiotherapy (EBRT) is the current standard of care for treatment of CIBP. However, approximately 45% of patients have no adequate pain response after EBRT. Magnetic resonance image-guided high-intensity focused ultrasound (MR-HIFU) may improve pain palliation in this patient population. The main objective of this trial was to compare MR-HIFU, EBRT, and MR-HIFU + EBRT for the palliative treatment of bone metastases. METHODS/DESIGN: The FURTHER trial is an international multicenter, three-armed randomized controlled trial. A total of 216 patients with painful bone metastases will be randomized in a 1:1:1 ratio to receive EBRT only, MR-HIFU only, or combined treatment with EBRT followed by MR-HIFU. During a follow-up period of 6 months, patients will be contacted at eight time points to retrieve information about their level of pain, QoL, and the occurrence of (serious) adverse events. The primary outcome of the trial is pain response at 14 days after start of treatment. Secondary outcomes include pain response at 14 days after trial enrolment, pain scores (daily until the 21st day and at 4, 6, 12 and 24 weeks), toxicity, adverse events, QoL, and survival. Cost-effectiveness and cost-utility analysis will be conducted. DISCUSSION: The FURTHER trial aims to evaluate the effectiveness and cost-effectiveness of MR-HIFU-alone or in combination with EBRT-compared to EBRT to relieve CIBP. The trial will be performed in six hospitals in four European countries, all of which are partners in the FURTHER consortium. TRIAL REGISTRATION: The FURTHER trial is registered under the Netherlands Trials Register number NL71303.041.19 and ClinicalTrials.gov registration number NCT04307914. Date of trial registration is 13-01-2020.

Combining radiotherapy and focused ultrasound for pain palliation of cancer induced bone pain; a stage I/IIa study according to the IDEAL framework.

BACKGROUND: Cancer induced bone pain (CIBP) strongly interferes with patient's quality of life. Currently, the standard of care includes external beam radiotherapy (EBRT), resulting in pain relief in approximately 60% of patients. Magnetic Resonance guided High Intensity Focused Ultrasound (MR-HIFU) is a promising treatment modality for CIBP. METHODS: A single arm, R-IDEAL stage I/IIa study was conducted. Patients presenting at the department of radiation oncology with symptomatic bone metastases in the appendicular skeleton, as well as in the sacrum and sternum were eligible for inclusion. All participants underwent EBRT, followed by MR-HIFU within 4 days. Safety and feasibility were assessed, and pain scores were monitored for 4 weeks after completing the combined treatment. RESULTS: Six patients were enrolled. Median age was 67 years, median lesion diameter was 56,5 mm. In all patients it was logistically possible to plan and perform the MR-HIFU treatment within 4 days after EBRT. All patients tolerated the combined procedure well. Pain response was reported by 5 out of 6 patients at 7 days after completion of the combined treatment, and stabilized on 60% at 4 weeks follow up. No treatment related serious adverse events occurred. CONCLUSION: This is the first study to combine EBRT with MR-HIFU. Our results show that combined EBRT and MR-HIFU in first-line treatment of CIBP is safe and feasible, and is well tolerated by patients. Superiority over standard EBRT, in terms of (time to) pain relief and quality of life need to be evaluated in comparative (randomized) study.

Tumor cavitation in patients with stage III non-small-cell lung cancer undergoing concurrent chemoradiotherapy: incidence and outcomes.

INTRODUCTION: Commonly reported complications after concurrent chemoradiotherapy (CCRT) in patients with stage III non-small-cell lung cancer (NSCLC) include febrile neutropenia, radiation esophagitis, and pneumonitis. We studied the incidence of tumor cavitation and/or "tumor abscess" after CCRT in a single-institutional cohort. METHODS: Between 2003 and 2010, 87 patients with stage III NSCLC underwent cisplatin-based CCRT and all subsequent follow-up at the VU University Medical Center. Diagnostic and radiotherapy planning computed tomography scans were reviewed for tumor cavitation, which was defined as a nonbronchial air-containing cavity located within the primary tumor. Pulmonary toxicities scored as Common Toxicity Criteria v3.0 of grade III or more, occurring within 90 days after end of radiotherapy, were analyzed. RESULTS: In the entire cohort, tumor cavitation was observed on computed tomography scans of 16 patients (18%). The histology in cavitated tumors was squamous cell (n = 14), large cell (n = 1), or adenocarcinoma (n = 1). Twenty patients (23%) experienced pulmonary toxicity of grade III or more, other than radiation pneumonitis. Eight patients with a tumor cavitation (seven squamous cell carcinoma) developed severe pulmonary complications; tumor abscess (n = 5), fatal hemorrhage (n = 2), and fatal embolism (n = 1). Two patients with a tumor abscess required open-window thoracostomy post-CCRT. The median overall survival for patients with or without tumor cavitation were 9.9 and 16.3 months, respectively (p = 0.09). CONCLUSIONS: With CCRT, acute pulmonary toxicity of grade III or more developed in 50% of patients with stage III NSCLC, who also had radiological features of tumor cavitation. The optimal treatment of patients with this presentation is unclear given the high risk of a tumor abscess.

Nutrition during trimodality treatment in stage III non-small cell lung cancer: not only important for underweight patients.

INTRODUCTION: Trimodality treatment for stage III non-small cell lung cancer (NSCLC), consisting of chemoradiotherapy followed by surgery, is associated with treatment-related toxicity, malnutrition, and postoperative complications. The aim of this retrospective study was to investigate the predictive value of nutritional parameters on postoperative morbidity, mortality, and survival. METHODS: Patients with stage III NSCLC undergoing concurrent chemoradiotherapy followed by surgery in one center between 2003 and 2009 were included. Age, sex, forced expiratory volume in 1 second, body mass index, weight change, and surgical and pathological factors were recorded and related to the occurrence of postoperative complications/mortality, overall survival (OS), and progression-free survival. RESULTS: Of 51 study patients, 17 (33%) had overweight (body mass index ≥ 25) at start of treatment and 20 patients (39%) were malnourished at hospital admission for surgery. Postoperative complications occurred in 25 patients (49%), 6 had major complications, and 2 died within 90 days after surgery, but no significant predictive factors were found. Overall, weight loss ≥5% during induction period was associated with shorter OS (p = 0.03), but especially overweight patients experiencing weight loss ≥5% during induction period (n = 7) had shorter OS (hazard ratio 4.63, p = 0.005; log-rank p = 0.04) and progression-free survival (hazard ratio 6.03, p = 0.007). CONCLUSIONS: This study indicates that malnutrition especially in overweight patients negatively influences survival outcomes of trimodality treatment for stage III NSCLC.

Time and dose-related changes in radiological lung density after concurrent chemoradiotherapy for lung cancer.

Radiation pneumonitis is an important cause of morbidity after concurrent thoracic chemoradiotherapy (CCRT). However, asymptomatic changes in lung density on computed tomography (CT)-scans occur more commonly, and correspond to regions of inflammatory changes. Characterization of dose- and time-related changes in radiological lung density (RLD) may facilitate improved radiation planning, and allow for a more objective measure for assessing damage. We studied changes in RLD following CCRT with cisplatin-etoposide, using deformable registration to co-register follow-up scans. All CT-scans performed for up to 24 months post-treatment were evaluated in 25 patients treated with CCRT for stage III non-small-cell lung cancer. A total of 104 scans (median of 3 per patient) were co-registered with planning scans using a deformable registration tool (VelocityAI, Atlanta, USA). Last follow-up scan was at median 9.4 months (range 3.4-22.6 months). Seven patients developed clinical radiation pneumonitis. RLD changes (in Hounsfield units) were measured in regions receiving 3-66Gy. Linear mixed models were used to study dose-density changes over time. No significant changes in RLD were observed in the first 3 months post-treatment. Increases in RLD were observed at 3-6 months (p<0.0001) and 6-12 months (p=0.006), but stabilized at 1 year. Increases were most evident in regions receiving >30Gy, with only minor density changes at lower dose levels. Planning target volume size was significantly associated with RLD changes (p=0.03). Limiting lung doses to ≤30Gy during CCRT may limit sub-clinical damage, and the time-course of RLD changes may allow for early quantification of pulmonary damage when evaluating novel treatment strategies.

Weekly chemoradiation (docetaxel/cisplatin) followed by surgery in stage III NSCLC; a multicentre phase II study.

BACKGROUND: This prospective study analyzed the feasibility and efficacy of weekly concurrent chemoradiation (docetaxel/cisplatin) followed by surgery. The primary endpoint was radiological response. PATIENTS AND METHODS: Six chemotherapy (docetaxel/cisplatin) cycles were administered on days 1, 8, 15, 22, 29 and 36 with concurrent thoracic radiotherapy in fractions of 1.8 Gy, to a total dose of 45 Gy. Patients underwent surgery depending on results of invasive mediastinal re-staging. RESULTS: Forty-two out of 45 NSCLC stage III patients were evaluable. Nineteen patients showed partial/complete response (46%), 14 stable disease (34%) and eight (20%) progressive disease. Toxicity was mild. The 30-day postoperative mortality was 4.2%. Twenty-four patients (59%) proceeded to surgery and 20 (49%) underwent a complete resection (R0). CONCLUSION: Weekly concurrent chemoradiation (docetaxel/cisplatin) in stage III NSCLC results in a radiological response rate of 46% and mediastinal downstaging in 56%. Complete resection in downstaged patients was achieved in 49% of all patients.

Evaluation of a treatment strategy for optimising preoperative chemoradiotherapy in stage III non-small-cell lung cancer.

OBJECTIVE: Concurrent chemoradiotherapy is standard of care in stage III non-small-cell lung cancer, although surgery may be beneficial in selected patients in whom induction therapy has achieved 'down-staging' of mediastinal nodal disease. Previous studies incorporated treatment 'splits' for re-evaluation, and such gaps lead to poorer survival in patients undergoing chemoradiotherapy. We describe the outcome of a treatment strategy to limit the duration of treatment splits. METHODS: A prospective database (2003-2007) of stage III non-small-cell lung cancer patients treated with concurrent chemoradiotherapy outwith clinical trials at our centre was reviewed. Preoperative chemoradiotherapy consisted of one induction course of cisplatin-gemcitabine, followed by two courses of cisplatin-etoposide with once-daily thoracic radiotherapy using four-dimensional involved-field treatment planning. After a dose of 46-50 Gy, potentially resectable patients without disease progression underwent immediate planned mediastinal re-staging and patients with persistent N2 disease or who were unfit for surgery continued to full-dose radiotherapy. Effort was made to shorten the treatment split by substituting mediastinoscopy for endoscopic procedures (transbronchial and -oesophageal). RESULTS: A total of 34 patients had potentially resectable disease at the start of treatment. Toxicity of chemoradiotherapy was predominantly leucocytopaenia grade III/IV in 38% of courses and grade III oesophagitis in five patients (15%), but was manageable and reversible. After re-staging, 24 patients (71%) proceeded to surgery. A radical resection was achieved in 23 patients; nine had a complete pathological response. Re-staging was accurate with only one false-negative mediastinoscopy. One patient died 10 days after surgery. Median time from end of induction treatment to re-staging or surgery was 12 (range: 0-51 days) and 35 days (range: 18-63 days), respectively. Median survival for resected patients was not reached. Six patients had persisting N2 disease, of which two continued radiotherapy after a split of 3 and 4 days. CONCLUSIONS: Image-guided, involved-field preoperative chemoradiotherapy can be performed with acceptable toxicity, and the present strategy achieves the goal of limiting splits in treatment delivery that may adversely affect survival in patients who do not undergo down-staging with induction therapy.