Interval Metastases After Neoadjuvant Chemoradiotherapy for Patients with Locally Advanced Esophageal Cancer: A Multicenter Observational Cohort Study.

BACKGROUND: Despite trimodality treatment, 10% to 20% of patients with esophageal cancer experience interval metastases after surgery. Restaging may identify patients who should not proceed to surgery, as well as a subgroup with limited metastases for whom long-term disease-control can be obtained. This study aimed to determine the proportion of patients with interval metastases after neoadjuvant chemoradiotherapy (nCRT) and to evaluate treatment and survival. METHODS: Patients who had cT2-4aN0-3M0 esophageal cancer treated with nCRT were identified from a trial database. Metastases detected up to 14 weeks after nCRT on 18F-FDG-PET/CT or during surgery were categorized as oligometastases (≤3 lesions located in one single organ or one extra-regional lymph node station) or as non-oligometastases. The primary outcome was the proportion of patients with metastases after nCRT. The secondary outcomes were overall survival (OS) and the site and treatment of metastases. RESULTS: Between 2013 and 2021, 973 patients received nCRT, and 10.3% had interval metastases. Of 100 patients, 30 (30%) had oligometastases, located mostly in non-regional lymph nodes (33.3%) or bones (26.7%). The median OS of this group was 13.8 months (95% confidence interval [CI] 9.2-27.1 months). Of 30 patients, 12 (40%) with oligometastases underwent potentially curative treatment, with a median OS of 22.8 months (95% CI 10.4-NA). The patients with non-oligometastases underwent mostly systemic therapy or BSC and had a median OS of 9 months (95% CI 7.4-10.9 months). CONCLUSIONS: Interval metastases were detected in about 10% of patients after nCRT, underscoring the importance of re-staging with 18F-FDG-PET/CT for those who proceed to surgery. A favorable survival might be accomplished for a subgroup of patients with oligometastases.

Overall survival after definitive chemoradiotherapy for patients with esophageal cancer: a retrospective cohort study.

Definitive chemoradiotherapy (dCRT) is a potentially curative therapy for esophageal cancer. As indications for dCRT differ widely, it is challenging to draw conclusions on outcomes and survival. The aim of this study was to evaluate overall survival (OS) and recurrence patterns according to indications for treatment. Patients who underwent dCRT (50.4 Gy concomitant with carboplatin/paclitaxel) for esophageal cancer between 2012 and 2022 were identified. Indications for dCRT were: cervical tumor, irresectable disease, unfit for surgery, and patient and/or physician preference. The primary endpoint was OS calculated with the Kaplan-Meier method. Secondary endpoints included the proportion of patients that completed the dCRT regimen, 30- and 90-day mortality, and disease recurrence. One hundred and fifty-seven patients were included (72.6% esophageal squamous cell carcinoma) with a median follow-up of 20 months (IQR 10.0-43.9). The full dCRT regimen was completed by 116 patients (73.9%). Thirty- and 90-day mortality were 2.5% and 8.3%, respectively. Median and 5-year OS for all patients were 22.9 months (95% CI 18.0-27.9) and 31.4%, respectively. The median OS per indication was 23.7 months (95% CI 6.5-40.8) for patients with cervical tumors, 10.9 months (95% 0.0-23.2) for irresectable disease, 28.2 months (95% CI 12.3-44.0) for unfit patients, and 22.9 months (95% CI 15.4-30.5) for patients' preference for dCRT (P = 0.11). Disease recurrence was observed in 74 patients (46%), located locoregionally (46%), distant (19%), or combined (35%). Patients who underwent dCRT had a 5-year OS of 31.4%, but OS differed according to indications for treatment with patients who had irresectable disease having the worst prognosis.

Predictive value of baseline serum carbohydrate antigen 19-9 level on treatment effect of neoadjuvant chemoradiotherapy in patients with resectable and borderline resectable pancreatic cancer in two randomized trials.

BACKGROUND: Guidelines suggest that the serum carbohydrate antigen (CA19-9) level should be used when deciding on neoadjuvant treatment in patients with resectable and borderline resectable pancreatic ductal adenocarcinoma (hereafter referred to as pancreatic cancer). In patients with resectable pancreatic cancer, neoadjuvant therapy is advised when the CA19-9 level is 'markedly elevated'. This study investigated the impact of baseline CA19-9 concentration on the treatment effect of neoadjuvant chemoradiotherapy (CRT) in patients with resectable and borderline resectable pancreatic cancers. METHODS: In this post hoc analysis, data were obtained from two RCTs that compared neoadjuvant CRT with upfront surgery in patients with resectable and borderline resectable pancreatic cancers. The effect of neoadjuvant treatment on overall survival was compared between patients with a serum CA19-9 level above or below 500 units/ml using the interaction test. RESULTS: Of 296 patients, 179 were eligible for analysis, 90 in the neoadjuvant CRT group and 89 in the upfront surgery group. Neoadjuvant CRT was associated with superior overall survival (HR 0.67, 95 per cent c.i. 0.48 to 0.94; P = 0.019). Among 127 patients (70, 9 per cent) with a low CA19-9 level, median overall survival was 23.5 months with neoadjuvant CRT and 16.3 months with upfront surgery (HR 0.63, 0.42 to 0.93). For 52 patients (29 per cent) with a high CA19-9 level, median overall survival was 15.5 months with neoadjuvant CRT and 12.9 months with upfront surgery (HR 0.82, 0.45 to 1.49). The interaction test for CA19-9 level exceeding 500 units/ml on the treatment effect of neoadjuvant CRT was not significant (P = 0.501). CONCLUSION: Baseline serum CA19-9 level defined as either high or low has prognostic value, but was not associated with the treatment effect of neoadjuvant CRT in patients with resectable and borderline resectable pancreatic cancers, in contrast with current guideline advice.

A prospective cohort study on active surveillance after neoadjuvant chemoradiotherapy for esophageal cancer: protocol of Surgery As Needed for Oesophageal cancer-2.

BACKGROUND: Neoadjuvant chemoradiotherapy (nCRT) followed by esophagectomy is a standard treatment for potentially curable esophageal cancer. Active surveillance in patients with a clinically complete response (cCR) 12 weeks after nCRT is regarded as possible alternative to standard surgery. The aim of this study is to monitor the safety, adherence and effectiveness of active surveillance in patients outside a randomized trial. METHODS: This nationwide prospective cohort study aims to accrue operable patients with non-metastatic histologically proven adenocarcinoma or squamous cell carcinoma of the esophagus or esophagogastric junction. Patients receive nCRT and response evaluation consists of upper endoscopy with bite-on-bite biopsies, endoscopic ultrasonography plus fine-needle aspiration of suspicious lymph nodes and 18F-fluorodeoxyglucose positron emission tomography/computed tomography scan. When residue or regrowth of tumor in the absence of distant metastases is detected, surgical resection is advised. Patients with cCR after nCRT are suitable to undergo active surveillance. Patients can consult an independent physician or psychologist to support decision-making. Primary endpoint is the number and severity of adverse events in patients with cCR undergoing active surveillance, defined as complications from response evaluations, delayed surgery and the development of distant metastases. Secondary endpoints include timing and quality of diagnostic modalities, overall survival, progression-free survival, fear of cancer recurrence and decisional regret. DISCUSSION: Active surveillance after nCRT may be an alternative to standard surgery in patients with esophageal cancer. Similar to organ-sparing approaches applied in other cancer types, the safety and efficacy of active surveillance needs monitoring before data from randomized trials are available. TRIAL REGISTRATION: The SANO-2 study has been registered at ClinicalTrials.gov as NCT04886635 (May 14, 2021) - Retrospectively registered.

Is stereotactic body radiotherapy an effective treatment in metastatic lung cancer with oligoprogressive disease?

BACKGROUND: Oligoprogression (OPD) is defined as a condition where limited progression (1-3 metastases) is observed in patients undergoing systemic cancer treatment. In this study we investigated the impact of stereotactic body radiotherapy (SBRT) in patients with OPD from metastatic lung cancer. MATERIAL AND METHODS: Data from a cohort of consecutive patients with SBRT treated between June 2015 and August 2021 were collected. All extracranial metastatic sites of OPD from lung cancer were included. Dose regimens consisted of mainly 24 in 2 fractions, 30-51 Gy in 3 fractions, 30-55 Gy in 5 fractions, 52.5 Gy in 7 fractions and 44-56 Gy in 8 fractions. Kaplan-Meier method was used to calculate Overall Survival (OS), Local Control (LC), and Disease-Free Survival (DFS) from the start date of SBRT to the event. RESULTS: Sixty-three patients, 34 female and 29 males were included. Median age was 75 years (range 25-83). All patients received concurrent systemic treatment before the start of the SBRT: 19 chemotherapy (CT), 26 CT plus immunotherapy (IT) or Tyrosin kinase inhibitors (TKI) and 18 IT/TKI. SBRT was delivered to the lung (n = 29), mediastinal node (n = 9), bone (n = 7), adrenal gland (n = 19), other visceral metastases (1) and other node metastases (n = 4). After a median follow-up of 17 months, median OS was 23 months. LC was 93% at 1 year and 87% at 2 years. DFS was 7 months. According to our results, there was no statistically significant correlation between prognostic factors and OS after SBRT in OPD patients. CONCLUSIONS: Median DFS was 7 months, translating into the continuation of effective systemic treatment as other metastases grow slowly. In patients with oligoprogression disease, SBRT is a valid and efficient treatment that may enable postponing the switch of systemic line.

Added Value of Radiotherapy Following Neoadjuvant FOLFIRINOX for Resectable and Borderline Resectable Pancreatic Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: The added value of radiotherapy following neoadjuvant FOLFIRINOX chemotherapy in patients with resectable or borderline resectable pancreatic cancer ((B)RPC) is unclear. The objective of this meta-analysis was to compare outcomes of patients who received neoadjuvant FOLFIRINOX alone or combined with radiotherapy. METHODS: A systematic literature search was performed in Embase, Medline (ovidSP), Web of Science, Scopus, Cochrane, and Google Scholar. The primary endpoint was pooled median overall survival (OS). Secondary endpoints included resection rate, R0 resection rate, and other pathologic outcomes. RESULTS: We included 512 patients with (B)RPC from 15 studies, of which 7 were prospective nonrandomized studies. In total, 351 patients (68.6%) were treated with FOLFIRINOX alone (8 studies) and 161 patients (31.4%) were treated with FOLFIRINOX and radiotherapy (7 studies). The pooled estimated median OS was 21.6 months (range 18.4-34.0 months) for FOLFIRINOX alone and 22.4 months (range 11.0-37.7 months) for FOLFIRINOX with radiotherapy. The pooled resection rate was similar (71.9% vs. 63.1%, p = 0.43) and the pooled R0 resection rate was higher for FOLFIRINOX with radiotherapy (88.0% vs. 97.6%, p = 0.045). Other pathological outcomes (ypN0, pathologic complete response, perineural invasion) were comparable. CONCLUSIONS: In this meta-analysis, radiotherapy following neoadjuvant FOLFIRINOX was associated with an improved R0 resection rate as compared with neoadjuvant FOLFIRINOX alone, but a difference in survival could not be demonstrated. Randomized trials are needed to determine the added value of radiotherapy following neoadjuvant FOLFIRINOX in patients with (B)PRC.

Largely reduced OAR doses, and planning and delivery times for challenging robotic SBRT cases, obtained with a novel optimizer.

Recently, VOLO™ was introduced as a new optimizer for CyberKnife® planning. In this study, we investigated possibilities to improve treatment plans for MLC-based prostate SBRT with enhanced peripheral zone dose while sparing the urethra, and central lung tumors, compared to existing Sequential Optimization (SO). The primary focus was on reducing OAR doses. For 25 prostate and 25 lung patients treated with SO plans, replanning with VOLO™ was performed with the same planning constraints. For equal PTV coverage, almost all OAR plan parameters were improved with VOLO™. For prostate patients, mean rectum and bladder doses were reduced by 34.2% (P < 0.001) and 23.5% (P < 0.001), with reductions in D0.03cc of 3.9%, 11.0% and 3.1% for rectum, mucosa and bladder (all P ≤ 0.01). Urethra D5% and D10% were 3.8% and 3.0% lower (P ≤ 0.002). For lung patients, esophagus, main bronchus, trachea, and spinal cord D0.03cc was reduced by 18.9%, 11.1%, 16.1%, and 13.2%, respectively (all P ≤ 0.01). Apart from the dosimetric advantages of VOLO™ planning, average reductions in MU, numbers of beams and nodes for prostate/lung were 48.7/32.8%, 26.5/7.9% and 13.4/7.9%, respectively (P ≤ 0.003). VOLO™ also resulted in reduced delivery times with mean/max reductions of: 27/43% (prostate) and 15/41% (lung), P  < 0.001. Planning times reduced from 6 h to 1.1 h and from 3 h to 1.7 h for prostate and lung, respectively. The new VOLO™ planning was highly superior to SO planning in terms of dosimetric plan quality, and planning and delivery times.

Safety and Feasibility of Additional Tumor Debulking to First-Line Palliative Combination Chemotherapy for Patients with Multiorgan Metastatic Colorectal Cancer.

INTRODUCTION: Local treatment of metastases is frequently performed in patients with multiorgan metastatic colorectal carcinoma (mCRC) analogous to selected patients with oligometastatic disease for whom this is standard of care. The ORCHESTRA trial (NCT01792934) was designed to prospectively evaluate overall survival benefit from tumor debulking in addition to chemotherapy in patients with multiorgan mCRC. Here, we report the preplanned safety and feasibility evaluation after inclusion of the first 100 patients. METHODS: Patients were eligible if at least 80% tumor debulking was deemed feasible by resection, radiotherapy and/or thermal ablative therapy. In case of clinical benefit after three or four cycles of respectively 5-fluorouracil/leucovorin or capecitabine and oxaliplatin ± bevacizumab patients were randomized to tumor debulking followed by chemotherapy in the intervention arm, or standard treatment with chemotherapy. RESULTS: Twelve patients dropped out prior to randomization for various reasons. Eighty-eight patients were randomized to the standard (n = 43) or intervention arm (n = 45). No patients withdrew after randomization. Debulking was performed in 82% (n = 37). Two patients had no lesions left to treat, five had progressive disease, and one patient died prior to local treatment. In 15 patients (40%) 21 serious adverse events related to debulking were reported. Postoperative mortality was 2.7% (n = 1). After debulking chemotherapy was resumed in 89% of patients. CONCLUSION: Tumor debulking is feasible and does not prohibit administration of palliative chemotherapy in the majority of patients with multiorgan mCRC, despite the occurrence of serious adverse events related to local treatment. IMPLICATIONS FOR PRACTICE: This first prospective randomized trial on tumor debulking in addition to chemotherapy shows that local treatment of metastases is feasible in patients with multiorgan metastatic colorectal cancer and does not prohibit administration of palliative systemic therapy, despite the occurrence of serious adverse events related to local treatment. The trial continues accrual, and overall survival (OS) data and quality of life assessment are collected to determine whether the primary aim of >6 months OS benefit with preserved quality of life will be met. This will support evidence-based decision making in multidisciplinary colorectal cancer care and can be readily implemented in daily practice.

The yield of chest computed tomography in patients with locally advanced pancreatic cancer.

OBJECTIVE: To evaluate the incidence of pulmonary metastases on chest computed tomography (CT) in patients with locally advanced pancreatic cancer (LAPC). METHODS: All patients diagnosed with LAPC in a single tertiary center (Erasmus MC) between October 2011 and December 2017 were reviewed. The staging chest CT scan and follow-up chest CT scans were evaluated. Pulmonary nodules were divided into three categories: apparent benign, too small to characterize, and apparent malignant. RESULTS: In 124 consecutive patients diagnosed with LAPC, 119 (96%) patients underwent a staging chest CT scan at the initial presentation. In 88 (74%) patients no pulmonary nodules were found; in 16 (13%) patients an apparent benign pulmonary nodule was found, and in 15 (13%) patients a pulmonary nodule too small to characterize was found. Follow-up chest CT scan(s) were performed in 111 (93%) patients. In one patient with either no pulmonary nodule or an apparent benign pulmonary nodule at initial staging, an apparent malignant pulmonary nodule was found on a follow-up chest CT scan. However, a biopsy of the nodule was inconclusive. Of 15 patients in whom a pulmonary nodule too small to characterize was found at staging, 12 (80%) patients underwent a follow-up CT scan; in 4 (33%) of these patients, an apparent malignant pulmonary nodule was found. CONCLUSION: In patients with LAPC in whom at diagnosis a chest CT scan revealed either no pulmonary nodules or apparent benign pulmonary nodules, routine follow-up chest CT scans is not recommended. Patients with pulmonary nodules too small to characterize are at risk to develop apparent malignant pulmonary nodules during follow-up.

Prognostic factors of local control and disease free survival in centrally located non-small cell lung cancer treated with stereotactic body radiation therapy.

Background: Stereotactic body radiation therapy (SBRT) results in high local control (LC) rates in patients with non-small cell lung cancer (NSCLC). For central lung tumors, risk-adapted fractionation schedules are used and underdosage to the Planned Target Volume (PTV) is often accepted to respect the dose constraints of the organs at risk in order to avoid high rates of toxicity. The purpose of this study was to analyze the effect of PTV underdosage and other possible prognostic factors on local- and disease control after SBRT in patients with central lung tumors.Material and Methods: Patients with centrally located NSCLC treated with SBRT were included. The doses were converted into biologically equivalent dose using α/ß-value of 10 Gy (BED10). Underdosage to the PTV was defined as the (percentage of) PTV receiving less than 100 Gy BED10; (%)PTV < 100 BED10. Potential prognostic factors for LC and Disease Free Survival (DFS) were evaluated using Cox regression analysis.Results: Two hundred and twenty patients received ≤12 fractions of SBRT. LC-rates were 88% at 2 years and 81% at 3 years. Twenty-seven patients developed a local recurrence. Both the PTV < 100 BED10 and %PTV < 100 BED10 were not prognostic for LC. Tumor size and forced expiratory volume in 1 second (FEV1) were independently prognostic for LC. Disease progression was reported in 75 patients with DFS-rates of 66% at 2 years and 56% at 3 years. Disease recurrence was independent significantly associated with larger tumor diameter, lower lobe tumor location and decreased FEV1. Grade 4-5 toxicity was reported in 10 patients (8 with ultra-central tumors) and was fatal in at least 3 patients.Conclusion: Decrease in tumor coverage was not correlated with the local recurrence probability. The LC and DFS were promising after SBRT of centrally located NSCLC with tumor size, FEV1 and tumor location (for DFS only) as prognostic factors.

Endovascular Coils as Lung Tumor Fiducial Markers for Real-Time Tumor Tracking in Stereotactic Body Radiotherapy: Comparison of Complication Rates with Transthoracic Fiducial Marker Placement.

PURPOSE: To evaluate safety of endovascular coil fiducial placement and compare complication rates with transthoracic fiducial placement in patients with peripheral early-stage lung cancer receiving fiducial markers for stereotactic body radiotherapy (SBRT). MATERIALS AND METHODS: This retrospective study included consecutive patients who received endovascular coils (n = 416 patients, n = 1,335 coils) or transthoracic fiducials (n = 30 patients, n = 80 fiducials) for SBRT between August 2005 and January 2017. During the first 3 years of the study period, patients preferentially received cylindrical platinum fiducial markers by percutaneous transthoracic placement; only patients with contraindications received endovascular coils. Thereafter, patients received endovascular fiducials as the first-line procedure. Endovascular embolization coils were placed via the femoral vein into subsegmental pulmonary artery branches near the tumor. Complications were scored by SIR criteria. RESULTS: The success rate of endovascular coil placement was 99.8%. One patient developed grade 2 hemoptysis requiring procedure discontinuation. Following placement, 1 patient (0.2%) developed grade 3 cardiac arrhythmia. A total of 36 patients (9%) developed grade 1 complications: mild hemoptysis (n = 4; 1%), small asymptomatic pulmonary infarction or hemorrhage (n = 30; 7%), hypoglycemia (n = 1; 0.2%), and vasovagal episode (n = 1; 0.2%). Following transthoracic marker placement, 4 patients (13%) developed a pneumothorax requiring hospital admission and chest tube (grade 2), 6 patients (20%) developed pneumothorax requiring no intervention (grade 1), 2 patients (7%) experienced asymptomatic pulmonary bleeding, and 1 patient (3%) developed persistent pain. CONCLUSIONS: Endovascular coil fiducial placement for lung SBRT is associated with high procedural success rates and lower rates of clinically relevant complications than transthoracic marker placement.

Prediction of early mortality following stereotactic body radiotherapy for peripheral early-stage lung cancer.

BACKGROUND/PURPOSE: To investigate prognostic factors for death within 6 months of stereotactic body radiotherapy (SBRT) for patients with peripheral early-stage non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: This analysis included 586 NSCLC patients with peripheral tumors treated with SBRT. Potential patient and tumor prognostic factors, including the Charlson Comorbidity Index (CCI) and Cumulative Illness Rating Scale (CIRS), were analyzed by logistic regression analysis for association with early mortality (death <6 months after SBRT). Additionally, CCI and CIRS were compared with respect to their predictive ability for early mortality by comparing multivariate models with each comorbidity index, and assessing their respective discriminatory abilities (C-index). RESULTS: A total of 36 patients (6.1%) died within 6 months of the start of SBRT. With a median follow-up of 25 months, 3-year overall survival was 54%. CIRS and tumor diameter were significant predictors of early mortality on multivariate analysis (p = .001). Patients with a CIRS score of 8 or higher and a tumor diameter over 3 cm had a 6-month survival of 70% versus 97% for those lacking these two features (p < .001). CCI was not predictive for early mortality on univariate nor multivariate analysis; the model containing CCI had a C-index of 0.65 versus 0.70 for the model containing CIRS. CONCLUSION: CIRS and tumor diameter predict for early-mortality in peripheral early-stage NSCLC treated with SBRT. CIRS may be a more useful comorbidity index than CCI in this population when assessing short-term life expectancy.

Survival and prognostic factors of pulmonary oligometastases treated with stereotactic body radiotherapy.

BACKGROUND: Stereotactic body radiotherapy (SBRT) for pulmonary oligometastatic disease achieves excellent treatment outcomes in terms of local control and toxicity. Patients treated with SBRT are often elderly and have multiple co-morbidities. This subset of patients may experience different survival as compared to young and fit patients subjected to radical metastasectomies. The purpose of this retrospective study was to evaluate OS and identify factors associated with OS for inoperable pulmonary oligometastases treated with SBRT. MATERIAL AND METHODS: Criteria used for selection of patients with oligometastases included: metastases limited to ≤2 organs and in total ≤5 metastases at the time of treatment. Peripheral tumors were treated with 51 Gy to 60 Gy in three fractions or a single fraction of 30 Gy. Central tumors received a dose of 45-60 Gy in 5-8 fractions. Survival probabilities were estimated by means of Kaplan-Meier method and the relation between potential prognostic factors and OS was studied by means of Cox regression analyses. RESULTS: In this study, 327 inoperable pulmonary oligometastases in 206 patients were treated with SBRT from the year 2005 to 2015. Primary sites of pulmonary oligometastases included colorectal carcinoma (n = 118), lung carcinoma (n = 36), melanoma (n = 11), sarcoma (n = 10), breast carcinoma (n = 7), and other tumors sites (n = 24). Median follow-up was 26 months. Median survival was 33 months. The 2-year and 5-year OS rates were 63% and 30%, respectively. On univariate analysis synchronous oligometastases (HR 0.59) and colorectal primary (HR 0.64) were associated with improved OS. On multivariable analysis synchronous oligometastases (HR 0.56), colorectal primary (HR 0.62) and tumor size <3 cm (HR 0.68) were independently associated with OS. CONCLUSIONS: SBRT to pulmonary oligometastases was associated with a 2-year OS of 63%. Tumor size <3 cm and colorectal primary tumors experienced improved OS compared to tumors >3 cm and non-colorectal primary tumors.

Long-term outcomes following stereotactic body radiotherapy boost for oropharyngeal squamous cell carcinoma.

Background/purpose: To determine the efficacy and toxicity profile of a stereotactic body radiotherapy (SBRT) boost as a first line treatment in patients with oropharyngeal squamous cell carcinoma (OPSCC). Materials and methods: We performed a retrospective cohort study in 195 consecutive OPSCC patients with T1-small T3 disease, treated at Erasmus MC between 2009 and 2016 with a SBRT (3 × 5.5 Gy) boost after 46 Gy IMRT. Primary endpoints were disease-specific survival (DSS) and Grade ≥3 toxicity (Common Terminology Criteria). The Kaplan-Meier method and Cox regression model were applied to determine rates and risk factors. Results: The median follow-up was 4.3 years. Treatment compliance was high (100%). Rates of 5-year DSS and late grade ≥3 toxicity were 85% and 28%, respectively. Five-year overall survival was 67%. The most frequently observed toxicities were mucosal ulceration or soft tissue necrosis (n = 30, 5 year 18%), dysphagia or weight loss (n = 18, 5 year 12%) and osteoradionecrosis (n = 11, 5 year 9%). Current smoker status (hazard ratio [HR] = 2.9, p = .001) and Charlson Comorbidity Index ≥2 (HR = 1.9, p = .03) were was associated with increased toxicity risk. Tooth extraction prior to RT was associated with increased osteoradionecrosis risk (HR = 6.4, p = .006). Conclusion: We reported on outcomes in the largest patient series to date treated with a hypofractionated boost for OPSCC. Efficacy was good with survival rates comparable to conventionally fractionated (chemo)radiotherapy. Grade ≥3 toxicity profiles showed high rates of soft tissue necrosis and osteoradionecrosis. Strategies to mitigate severe toxicity risks are under investigation to improve the tolerability of the SBRT boost.

FOLFIRINOX and radiotherapy for locally advanced pancreatic cancer: A cohort study.

INTRODUCTION: One-third of the patients with pancreatic cancer present with locally advanced unresectable pancreatic cancer (LAPC). Our aim was to determine survival outcomes and toxicity after FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin) followed by radiotherapy (RT) in biopsy-proven patients with LAPC. METHODS: We analysed a cohort of biopsy-proven patients with LAPC, who were eligible for induction FOLFIRINOX (eight cycles) and subsequent RT (30 fractions, 60 Gy). Eligible patients underwent a staging laparoscopy to detect occult metastasis before the treatment. The primary outcome was overall survival (OS), and secondary outcomes were progression-free survival (PFS), treatment-related toxicity, and resection rate. RESULTS: Forty-four patients were diagnosed with biopsy-proven LAPC. Twenty-five patients were eligible and all underwent staging laparoscopy before the treatment. In three (12%) patients occult metastases were found. Twenty-two patients started induction FOLFIRINOX, 17 (77%) completed all cycles. Seventeen (77%) patients were treated with subsequent RT, with 16 (94%) receiving the full dosage. Three (14%) patients underwent a radical resection after the treatment. Median OS was 15.4 months (95% confidence interval [CI], 10.0-20.7), median PFS was 11 months (95% CI, 7.7-14.4). CONCLUSIONS: Median OS after FOLFIRINOX and RT was 15 months in patients with LAPC. Toxicity remains severe, however, most patients completed all eight scheduled cycles of FOLFIRINOX and RT.

Acute toxicity of the bowel after stereotactic robotic radiotherapy for abdominopelvic oligometastases.

AIM: To correlate dose-volume histogram (DVH) parameters with appearance of grade ≥2 acute and late gastrointestinal toxicity of stereotactic body radiotherapy (SBRT) in patients with abdominopelvic solitary or oligometastatic disease outside the liver. MATERIAL AND METHODS: Acute and late bowel toxicity of 84 abdominopelvic oligometastatic patients was registered. A logistic regression was performed between different DVH parameters and presence of grade ≥2 acute and late toxicity. A Normal Tissue Complication Probability (NTCP) model was built with significant parameters to determine complication probabilities (CP). RESULTS: Thirteen (15%) of 84 patients experienced of grade ≥2 acute toxicity, while 8 (10%) reported late toxicity complications. A significant relationship was found for EQD2 (V30Gy, V40Gy, V50Gy and V65Gy) and grade ≥2 acute toxicity. Dmax and D2 were not significant. Late grade ≥2 toxicity was not significantly correlated with any DVH parameter. According to our NTCP model for V40Gy, an irradiated bowel volume of 10 cm3 of V40Gy resulted in CP of grade ≥2 acute toxicity of less than 10%. Local control was 87% at 2 years and 82% at 5 years. Overall survival was 61% at 2 years and 32% at 5 years. CONCLUSIONS: After SBRT for abdominopelvic oligometastases, in general, the presence of acute and late toxicity was low. A significant relationship was found for V30Gy, V40Gy, V50Gy and V65Gy and grade ≥2 acute toxicity. We estimated acute complication probabilities per volume of irradiated bowel by V40Gy and V50Gy.

Factors affecting local control of pulmonary oligometastases treated with stereotactic body radiotherapy.

BACKGROUND: Oligometastases refers to a state of limited metastatic disease. The use of local ablative therapies to patients with oligometastases can result in durable state of remission or long-term cure. Stereotactic body radiotherapy (SBRT) is a highly conformal radiation technique that delivers ablative doses to the target. The study aimed to evaluate local control (LC) and identify factors associated with poor LC in patients with pulmonary oligometastases treated with SBRT. Primary endpoint of the study was to assess LC; secondary endpoint was to determine factors associated with LC. MATERIAL AND METHODS: Criteria used for selection of patients with oligometastases included: metastatic disease limited to a maximum of two organs and no more than five metastatic lesions at time of treatment. Peripheral tumors were treated with 51-60 Gy in three fractions or a single fraction of 30 Gy. Central tumors received a dose of 45-60 Gy in 5-8 fractions. RESULTS: In 206 patients, 327 pulmonary oligometastases were treated with SBRT. Median follow-up was 22 months (range 2-100). LC at 2 and 3 years was 85% and 83%, respectively. On univariate analysis, biological equivalent dose assuming an α/ß ratio of 10 (BED10) < 100 Gy (HR 3.09), single-fraction SBRT (HR 2.83), synchronous metastasis (HR 1.99), and pre-SBRT chemotherapy (HR 2.79) were significantly associated with inferior LC. In the multivariable analysis BED10 <100 Gy (HR 3.59), pre-SBRT chemotherapy (HR 2.61) and presence of synchronous metastasis (HR 2.21) remained independently associated with poor LC. CONCLUSIONS: SBRT achieved an excellent LC of 85% at 2 years. Although retrospective in nature, our study identified three factors associated with inferior LC. These factors may help to refine SBRT practice for pulmonary oligometastases in the future.

Survival after whole brain radiotherapy for brain metastases from lung cancer and breast cancer is poor in 6325 Dutch patients treated between 2000 and 2014.

BACKGROUND: Whole brain radiotherapy (WBRT) is considered standard of care for patients with multiple brain metastases or unfit for radical treatment modalities. Recent studies raised discussion about the expected survival after WBRT. Therefore, we analysed survival after WBRT for brain metastases 'in daily practice' in a large nationwide multicentre retrospective cohort. METHODS: Between 2000 and 2014, 6325 patients had WBRT (20 Gy in 4 Gy fractions) for brain metastases from non-small cell lung cancer (NSCLC; 4363 patients) or breast cancer (BC; 1962 patients); patients were treated in 15 out of 21 Dutch radiotherapy centres. Survival was calculated by the Kaplan-Meier method from the first day of WBRT until death as recorded in local hospital data registration or the Dutch Municipal Personal Records Database. FINDINGS: The median survival was 2.7 months for NSCLC and 3.7 months for BC patients (p < .001). For NSCLC patients aged <50, 50-60, 60-70 and >70 years, survival was 4.0, 3.0, 2.8 and 2.1 months, respectively (p < .001). For BC patients, survival was 4.5, 3.8, 3.2 and 2.9 months, respectively (p = .047). In multivariable analyses, higher age was related to poorer survival with hazard ratios (HR) for patients aged 50-60, 60-70 and >70 years being 1.05, 1.19 and 1.34, respectively. Primary BC (HR: 0.83) and female sex (HR: 0.85) were related to better survival (p < .001). INTERPRETATION: The survival of patients after WBRT for brain metastases from NSCLC treated in Dutch 'common radiotherapy practice' is poor, in breast cancer and younger patients it is disappointingly little better. These results are in line with the results presented in the QUARTZ trial and we advocate a much more restrictive use of WBRT. In patients with a more favourable prognosis the optimal treatment strategy remains to be determined. Prospective randomized trials and individualized prognostic models are needed to identify these patients and to tailor treatment.

Pain flare, complexity and analgesia in bone oligometastases treated with stereotactic body radiation therapy.

The aim of our study was to assess the incidence of pain flare and the effectiveness of stereotactic body radiotherapy (SBRT) in pain management of patients with bone oligometastases. We evaluated 48 patients accounting for 54 treatments. The Edmonton Classification System for Cancer Pain (ECS-CP) was applied to identify indicators of treatment-resistant pain, in patients with active pain (NRS ≥ 2) at baseline. Statistical analysis was performed to identify predictors of pain flare and pain control. Pain flare occurred in 38% of treated patients (n = 18/48): No correlation was found between pain flare and patient- or treatment-related variables. In the subset of patients with active pain at baseline (n = 23), pain control was obtained in 62% of patients at 1 year; median time to pain progression after SBRT was 29 months (CI95% 6-52 months). Presence of ≥2ECS-CP features was correlated with earlier pain progression (4 vs. 30 months, p = 0.012). Pain flare occurred in 38% of cases irrespectively of steroid premedication and dose regimen. In patient with baseline active pain, durable pain control was obtained. Presence of ≥2 complexity indicators at the ECS-CP assessment was correlated with impaired pain control and may deserve future investigation in prospective studies.

Stereotactic body radiotherapy for oligometastatic soft tissue sarcoma.

BACKGROUND: Stereotactic body radiotherapy (SBRT) is emerging as a novel treatment option in metastatic soft tissue sarcoma (STS). The aim of our study was to evaluate the effectiveness of exclusive SBRT on disease control and survival in oligometastatic (≤ 3 synchronous lesions) STS. MATERIALS AND METHODS: In total, 16 consecutive patients, accounting for 26 metastases (including 21 lung and 5 lymph node or soft tissue metastases), were treated at our institution with SBRT. Patient- and treatment-related characteristics were collected. Local control (LC), overall survival (OS), distant metastases-free survival (DMFS), and time to initiation of chemotherapy or best supportive care (corrected disease-free survival, cDFS) were assessed. RESULTS: Four-year OS was 54% and median OS was 69 months [95% confidence interval (CI) 20-118 months]. LC of 26 lesions at 4 years was 78%. Median DMFS and cDFS were 17 (95% CI 5-30 months) and 28 months (95% CI 5-52 months), respectively. Disease-free interval < 24 months from primary tumor treatment to first metastasis was the only predictor of reduced LC, cDFS, and OS (p = 0.022, 0.023, and 0.028, respectively). No acute or chronic grade ≥ 3 toxicity was observed. Median follow-up was 36 months (IQR 18-71 months). CONCLUSIONS: In patients with oligometastatic STS, SBRT yields satisfying local control with minimal toxicity. Median OS was 69 months. Repeated SBRT may be considered to extend disease-free and systemic therapy-free interval. Increased time from primary tumor to first metastasis identifies patients with potentially greater benefit from SBRT.