Prospective multicentre analysis of the therapeutic approach and prognostic factors determining overall survival in elderly patients with non-small-cell lung carcinoma treated with curative intent.

Objective: To analyse patterns of treatment with curative intent commonly used in elderly patients with locally advanced non-small-cell lung carcinoma (NSCLC) and predictive factors of overall survival in routine clinical practice. Methods: This multicentre prospective study included consecutive patients aged ≥65 years old diagnosed with NSCLC between February 2014 and January 2018. Inclusion criteria: age ≥65 years, stage IIIA/IIIB NSCLC. Treatment decisions were taken by a multidisciplinary committee. Kaplan-Meier curves and log-rank test were used to identify which clinical/treatment-associated variables, or pre-treatment quality of life (QOL) considering EORTC QLQ-C30 (and LC13 module) were predictive of overall survival. Results: A total of 139 patients were recruited. Median follow-up was 9.9 months (1.18-57.36 months) with a median survival of 14 months (range 11-17 months). In the group>75-year-old patients, the committee recommended chemotherapy and sequential radiotherapy (55.6%) or radiotherapy alone (22.2%), rather than surgery (3.7%) or concomitant radiochemotherapy (16.5%). However, in 65- to 75-year-old patients, surgery and concomitant radiochemotherapy were recommended in half of cases (p=0.003). Regarding multivariate analysis, the risk of death was higher in patients with pre-existing heart disease (p=0.002), low score for physical functioning (p=0.0001), symptoms of dysphagia (p=0,01), chest pain (p=0.001), and those not undergoing surgical treatment (p=0.024). Conclusions: Patients >75 years received more conservative treatments. Surgery improved survival and should be carefully considered, regardless of patient age. Comorbidities and poor baseline QOL are predictive of shorter survival. Advances in knowledge: Measuring these parameters before treatment may help us to define a population of frail patients with a poorer prognosis to facilitate decision making in clinical practice.

Pain response and quality of life assessment in patients with moderate/severe neuropathic pain due to bone metastasis undergoing treatment with palliative radiotherapy and tapentadol: A prospective multicentre pilot study.

INTRODUCTION: To assess pain response rate (RR) and quality of life (QoL), in patients with moderate/severe neuropathic pain (NP) due to bone metastasis (BM) undergoing palliative 3D radiotherapy plus tapentadol. METHODS: We conducted a prospective multicentre pilot study. Patients were assessed before radiotherapy using the validated questionnaire (Douleur Neuropathique en 4 questions). Response to radiotherapy (8 Gy-30 Gy/1-10fr) at one and two months was assessed according the International Bone Metastases Consensus criteria. INCLUSION CRITERIA: radiological evidence of BM, NP according to DN4 (cut-off score ≥ 4), no spinal cord compression, worst pain score ≥ 5/10. Nonparametric Mann-Whitney U test compared changes in QoL among response groups. RESULTS: Seventeen patients (13 men, 4 woman), median age 67 years (42-81), were included. Pre-treatment median pain severity was 7.5 (5-10). Median dose of tapentadol administered before radiotherapy was 100 mg/24 h (100-300 mg). Overall RR 1 month after radiotherapy was 10/16 = 62.5%: 3/16 (18.8%) achieving a complete response (CR) and 7/16 (43.8%) a partial response (PR). Overall RR 2 months after RT was 5/10 (50%): 10% a CR and 40% a PR. ITT RR for this study at 1 and 2 months was 10/17 = 59% and 5/17 = 29%, respectively. Patients responding to radiotherapy had significant improvement in EORTC QLQ-C30 emotional functioning (EF) (p = 0.025) and fatigue symptom scale scores (p = 0.035) one month after radiotherapy. Painful site symptom QLQ-BM22 scores improved 2 months after radiotherapy (p = 0.024). CONCLUSIONS: Palliative radiotherapy plus tapentadol shows an acceptable pain response and QoL improvement especially regarding EF, fatigue and painful site symptom scales in patients with moderate/severe NP due to BM. Therefore, it could be an alternative to manage NP in daily practice.

Pattern of relapse and dosimetric analysis of a single dose 19 Gy HDR-brachytherapy phase II trial.

PURPOSE: To report the pattern of relapse within the prostate with reference to the initial site of disease in patients treated with single fraction 19-Gy. METHODS AND MATERIALS: Forty-four patients were treated according to a prospective study of single-fraction HDR-brachytherapy. Treatment was delivered using 192Ir to a dose of 19 Gy prescribed to the prostate. Patients who experienced a biochemical failure underwent a re-staging multiparametric MRI (mpMRI) and MRI-TRUS fusion biopsy to rule-out local recurrence. In patients with visible Dominant intraprostatic lesions (DIL) on pretreatment mpMRI, the site of local relapse was compared with the initial site of disease. The dose received by the site of recurrence was investigated. RESULTS: The median follow-up period was 48 months (range 29-63). The PSA nadir was reached at 24 months follow-up, with a median value of 1.07 ng/mL. To date, 14 patients (32%) have experienced biochemical failure (4 patients low-risk and 10 intermediate-risk; p = 0.013). Re-staging mpMRI was performed in 11/14 patients. Eleven patients underwent MRI-TRUS fusion biopsy confirming local relapse in all patients. The analysis of DVH of all 44 patients revealed that patients with biochemical failure had received significantly lower doses in terms of V100, V125 and D90 (p = 0.032, p = 0.018 and p = 0.018 respectively). In patients with DILs on diagnostic mpMRI, the mean D90 and D98 on DIL were lower for patients with biochemical failure. CONCLUSIONS: This dosimetric analysis demonstrates a dose-response relationship in patients treated with single fraction 19 Gy. Patients with intermediate risk disease, with visible DIL on mpMRI and patients treated with cooler implants have higher incidence of biochemical and local failure.

Late toxicity after single dose HDR prostate brachytherapy and EBRT for localized prostate cancer: Clinical and dosimetric predictors in a prospective cohort study.

PURPOSE: To describe the genitourinary (GU) and gastrointestinal (GI) late toxicity profile and to analyse the clinical and dosimetry outcomes predictors of the combination of EBRT and high-dose-rate (HDR) prostate brachytherapy (BT) for localized prostate cancer. MATERIALS AND METHODS: Between January 2012 and May 2017, 210 patients were included in a prospective protocol. Treatment consisted in HDR-BT (15 Gy single fraction) plus 3DCRT (37.5 Gy/15 fractions). Univariate and multivariate logistic regressions were used to analyse the impact of variables on late toxicity. RESULTS: Median age was 71 (56-82), 12.4% of patients had low, 44.3% intermediate and 41% high-risk prostate cancer. Median prostate volume was 28.4 cc. Median V100, V150, V200 were 98.2%, 27% and 7.4% respectively. Median urethra Dmax, rectum D1cc and D2cc, were 113.5%, 62.2%% and 54.2% respectively. After a median follow-up of 41 months (5-75) late G2 GU and GI late toxicity was observed in 14.8% and 5.2% of patients respectively. Late G3 GU and GI toxicity occurred in 0% and 1% of patients respectively. There were no outcome correlations with late G ≥ 2 GU toxicity on univariate analysis. Previous cardiovascular comorbidity (p = 0.042), and dose to the rectum D2cc (p = 0.016) and D1cc (p = 0.017) were associated with G ≥ 2 GI toxicity. Multivariate analysis showed that rectum D1cc (HR11.56; 95%CI 1.4-92.1; p = 0.021) and prior history of cardiovascular disease (HR3.6; 95%CI 1-12.9; p = 0.045) remained independent predictors of G ≥ 2 GI toxicity. CONCLUSIONS: There is a low incidence of late GU and GI morbidity using single fraction HDR-BT and hypofractionated EBRT. Previous cardiovascular disease and dose to the rectum were observed to correlate with GI toxicity.

Intraoperative radiotherapy with the Intrabeam® device for the treatment of resectable pancreatic adenocarcinoma. / Radioterapia intraoperatoria con Intrabeam® para el tratamiento del adenocarcinoma de páncreas resecable.

INTRODUCTION: The application of intraoperative radiation therapy to the tumor bed after resection of pancreatic cancer has been shown to be beneficial in the local control of the disease. The objective of this study was to evaluate the preliminary outcomes after the application of a single intraoperative dose to the tumor bed with a new intraoperative radiotherapy device (Intrabeam®) in terms of viability, safety and short-term results. METHODS: We studied 5 patients who underwent pancreaticoduodenectomy for resectable pancreatic cancer in which a radiotherapy boost (5Gy) was intraoperatively applied to the tumoral bed using the portable Intrabeam® device, a low-energy point-source X-ray. Postoperative complications, hospital stay and mortality, recurrences and short-term survival were analyzed. RESULTS: Mean patient age was 68 years. All patients had a T3-stage tumor and one of them N1. In 3 patients, R0 resection was performed, while R1 resection was conducted in 2. Perioperative mortality was 0%. The only complications included delayed gastric emptying and postoperative hemorrhage. There were no pancreatic fistulas. During follow-up (mean: 11.2 months), there was a relapse in the patient who had undergone R1 resection. CONCLUSIONS: The application of radiotherapy with the Intrabeam® device in selected patients has not resulted in increased perioperative morbidity or mortality; therefore, this is a safe procedure for the treatment of resectable cancer.

Review of the treatment of Graves' ophthalmopathy: The role of the new radiation techniques.

Graves ophthalmopathy (GO) is an autoimmune disorder and the most frequent extrathyroidal manifestation of Graves' disease. GO is an inflammatory process leading to an increased volume of the extraocular muscles and orbital connective and adipose tissues associated with multiple histopathological changes. Despite recent progress in the understanding of its pathogenesis, GO often remains a major diagnostic and therapeutic challenge. It has become increasingly important to classify patients into categories based on disease severity and activity. Low doses of radiotherapy (RT) have demonstrated a benefit in the treatment of moderate-to-severe GO with very few side effects. New RT techniques deliver a more conformal dose distribution to the target and decrease the dose to normal healthy tissue minimizing the risk of side effects. In this review we briefly analyzed the pathogenesis of GO and discussed the most relevant therapeutic approaches, with particular emphasis in the new RT technics. Appropriately designed and powered clinical studies are necessary to determine the most effective treatment with the lowest risk of side effects.

Volumetric Modulated Arc Therapy (VMAT) make a difference in retro-orbital irradiation treatment of patients with bilateral Graves' ophthalmopathy. Comparative analysis of dosimetric parameters from different radiation techniques.

BACKGROUND: Graves' ophthalmopathy is the commonest extrathyroidal manifestation of Graves' disease. Treatment options include steroid therapy, corrective/decompressive surgery, radiation therapy or combination of these approaches. AIM: Our purpose was to investigate if retro-orbital irradiation with Volumetric Modulated Arc Therapy (VMAT) yielded better target coverage and dose sparing to adjacent normal structures compared to 3-Dimensional Conformal Radiotherapy (3DCRT) and Lateral Opposing Conformed Fields (LOCF). METHODS: Fourteen consecutive patients diagnosed with bilateral Graves' ophthalmopathy were prospectively recruited into this study from August 2012 until August 2014. An individual VMAT, 3DCRT and LOF plan was created for each patient. Conformity Index (CI), Homogeneity Index (HI) and other dosimetric parameters of the targets and organs-at-risk (OAR) were analyzed in all 28 orbits compared between the different techniques. RESULTS: CI generated by VMAT was superior to that produced by 3DCRT(p < .001) and LOF (p < .001). As expected, 3DCRT was also superior to LOF (p = .007). Regarding the OARs sparing dose (lens, globes, retina and lacrimal glands), VMAT showed a significant benefit when compared with 3DCRT and LOCF, with no differences between the two latter techniques. CONCLUSIONS: VMAT should be preferred over 3DCRT and LOF for bilateral Graves' ophthalmopathy treatment.

Is argon plasma coagulation an effective and safe treatment option for patients with chronic radiation proctitis after high doses of radiotherapy?

INTRODUCTION: In severe cases refractory to medical treatment, APC appears to be the preferred alternative to control persistent rectal bleeding of patients with chronic radiation proctitis. Although successful outcomes have been demonstrated in patients previously treated with moderate doses of radiotherapy, there is reluctance towards its indication due to the concern of severe adverse events in patients treated with high doses of radiation. OBJECTIVES: The aim of this study was to assess the efficacy and toxicity of APC in the management of bleeding radiationinduced proctitis in patients treated with high doses of radiation for prostate cancer. METHODS AND MATERIALS: Data from 30 patients were treated with APC due to chronic radiation proctitis, were reviewed retrospectively. All cases had prostate cancer and 9 of them (30 %) underwent previous radical prostatectomy. The median dose of conformal 3D External Beam Radiotherapy (EBRT) delivered was 74 Gy (range 46-76). Median rectal D1cc and D2cc was 72.5 and 72.4 Gy respectively. Median rectal V70, V60 and V40 was 12, 39.5 and 80 %. Cardiovascular and digestive disease, diabetes, smoking behaviour, lowest haemoglobin and transfusion requirements were recorded. Indications for treatment with APC were anemia and persistent bleeding despite medical treatment. Argon gas flow was set at 1.8 l/min with an electrical power setting of 50 W. RESULTS: Median age of all patients was 69.6 years. The median lowest haemoglobin level was 9.6 g/dL. Median time between completion of radiotherapy and first session of APC was 13 months. Ninety-four therapeutic sessions were performed (median 3 sessions). Median time follow-up was 14.5 months (range 2-61). Complete response with resolved rectal bleeding was achieved in 23 patients (77 %), partial response in 5 (16 %) and no control in 2 (6 %). No patients required transfusion following therapy. Two patients developed long-term (> 6 weeks) grade 2 rectal ulceration and grade 2 rectal incontinence, respectively. CONCLUSIONS: The argon plasma coagulation is an effective and safe management option in patients with medically refractory rectal bleeding after high doses of radiation for prostate cancer.

Pathological vertebral fracture after stereotactic body radiation therapy for lung metastases. Case report and literature review.

BACKGROUND: Stereotactic body radiation therapy (SBRT) is a radiation technique used in patients with oligometastatic lung disease. Lung and chest wall toxicities have been described in the patients but pathological vertebral fracture is an adverse effect no reported in patients treated with SBRT for lung metastases. CASE PRESENTATION: A 68-year-old woman with the diagnosis of a recurrence of a single lung metastatic nodule of urothelial carcinoma after third line of chemotherapy. The patient received a hypo-fractionated course of SBRT.A 3D-conformal multifield technique was used with six coplanar and one non-coplanar statics beams. A total dose of 48 Gy in three fractions over six days was prescribed to the 95% of the CTV. Ten months after the SBRT procedure, a CT scan showed complete response of the metastatic disease without signs of radiation pneumonitis. However, rib and vertebral bone toxicities were observed with the fracture-collapse of the 7th and 8th vertebral bodies and a fracture of the 7th and 8th left ribs. We report a unique case of pathological vertebral fracture appearing ten months after SBRT for an asymptomatic growing lung metastases of urothelial carcinoma. CONCLUSION: Though SBRT allows for minimization of normal tissue exposure to high radiation doses SBRT tolerance for vertebral bone tissue has been poorly evaluated in patients with lung tumors. Oncologists should be alert to the potential risk of fatal bone toxicity caused by this novel treatment. We recommend BMD testing in all woman over 65 years old with clinical risk factors that could contribute to low BMD. If low BMD is demonstrated, we should carefully restrict the maximum radiation dose in the vertebral body in order to avoid intermediate or low radiation dose to the whole vertebral body.

Determinants of toxicity, patterns of failure, and outcome among adult patients with soft tissue sarcomas of the extremity and superficial trunk treated with greater than conventional doses of perioperative high-dose-rate brachytherapy and external beam radiotherapy.

PURPOSE: The present study was undertaken to determine factors predictive of toxicity, patterns of failure, and survival in 60 adult patients with soft tissue sarcomas of the extremity and superficial trunk treated with combined perioperative high-dose-rate brachytherapy and external beam radiotherapy. METHODS AND MATERIALS: The patients were treated with surgical resection and perioperative high-dose-rate brachytherapy (16 or 24 Gy) for negative and close/microscopically positive resection margins, respectively. External beam radiotherapy (45 Gy) was added postoperatively to reach a 2-Gy equivalent dose of 62.9 and 72.3 Gy, respectively. Adjuvant chemotherapy with ifosfamide and doxorubicin was given to patients with advanced high-grade tumors. RESULTS: Grade 3 toxic events were observed in 18 patients (30%) and Grade 4 events in 6 patients (10%). No Grade 5 events were observed. A location in the lower limb was significant for Grade 3 or greater toxic events on multivariate analysis (p = .013), and the tissue volume encompassed by the 150% isodose line showed a trend toward statistical significance (p = .086). The local control, locoregional control, and distant control rate at 9 years was 77.4%, 69.5%, and 63.8%, respectively. On multivariate analysis, microscopically involved margins correlated with local control (p = .036) and locoregional control (p = .007) and tumor size correlated with distant metastases (p = .004). The 9-year disease-free survival and overall survival rate was 47.0% and 61.5%, respectively. Multivariate analysis showed poorer disease-free survival rates for patients with tumors >6 cm (p = .005) and microscopically involved margins (p = .043), and overall survival rates decreased with increasing tumor size (p = .011). CONCLUSIONS: Grade 3 or greater wound complications can probably be decreased using meticulous treatment planning to decrease the tissue volume encompassed by the 150% isodose line, especially in lower limb locations. Microscopically involved margins remain a predictor of local and locoregional failure, despite radiation doses >70 Gy. Patients with tumors ≥6 cm and microscopically involved margins are at high risk of treatment failure and death from the development of distant metastases.

Patterns of response after preoperative treatment in gastric cancer.

PURPOSE: To analyze the rate of pathologic response in patients with locally advanced gastric cancer treated with preoperative chemotherapy with and without chemoradiation at our institution. METHODS AND MATERIALS: From 2000 to 2007 patients were retrospectively identified who received preoperative treatment for gastric cancer (cT3-4/ N+) with induction chemotherapy (Ch) or with Ch followed by concurrent chemoradiotherapy (45 Gy in 5 weeks) (ChRT). Surgery was planned 4-6 weeks after the completion of neoadjuvant treatment. Pathologic assessment was used to investigate the patterns of pathologic response after neoadjuvant treatment. RESULTS: Sixty-one patients were analyzed. Of 61 patients, 58 (95%) underwent surgery. The R0 resection rate was 87%. Pathologic complete response was achieved in 12% of the patients. A major pathologic response (<10% of residual tumor) was observed in 53% of patients, and T downstaging was observed in 75%. Median follow-up was 38.7 months. Median disease-free survival (DFS) was 36.5 months. The only patient-, tumor-, and treatment-related factor associated with pathologic response was the use of preoperative ChRT. Patients achieving major pathologic response had a 3-year actuarial DFS rate of 63%. CONCLUSIONS: The patterns of pathologic response after preoperative ChRT suggest encouraging intervals of DFS. Such a strategy may be of interest to be explored in gastric cancer.