Pancreatic cancer outcome-local treatment with radiation using MRI-LINAC.

Introduction: Stereotactic MR-guided on-table adaptive radiotherapy (SMART) allows the precise delivery of high-dose radiation to tumors in great proximity to radiation-sensitive organs. The aim of this study is to evaluate the toxicity and clinical outcome in locally advanced or recurrent pancreatic tumors, with or without prior irradiation, treated with SMART. Methods: Patients were treated for pancreatic cancer (PC) using SMART technology to a prescribed dose of 50 Gy (BED10, 100 Gy) in five fractions, with daily on-table adaptation of treatment plan. Endpoints were acute and late toxicities, local control, local disease-free period, and overall survival. Results: A total of 54 PC patients were treated between August 2019 and September 2022, with a median follow-up of 8.9 months from SMART. The median age was 70.4 (45.2-86.9) years. A total of 40 patients had upfront inoperable PC (55% were locally advanced and 45% metastatic), and 14 had local recurrence following prior pancreatectomy (six patients also had prior adjuvant RT). Of the patients, 87% received at least one chemotherapy regimen (Oxaliplatin based, 72.2%), and 25.9% received ≥2 regimens. Except from lower CA 19-9 serum level at the time of diagnosis and 6 weeks prior to SMART in previously operated patients, there were no significant differences in baseline parameters between prior pancreatectomy and the inoperable group. On-table adaptive replanning was performed for 100% of the fractions. No patient reported grade ≥2 acute GI toxicity. All previously irradiated patients reported only low-grade toxicities during RT. A total of 48 patients (88.9%) were available for evaluation. Complete local control was achieved in 21.7% (10 patients) for a median of 9 months (2.8-28.8); three had later local progression. Eight patients had regional or marginal recurrence. Six- and 12-month OS were 75.0% and 52.1%, respectively. Apart from mild diarrhea 1-3 months after SMART and general fatigue, there were no significant differences in toxicity and outcomes between post-pancreatectomy and inoperable groups. Conclusion: SMART allows safe delivery of an ablative dose of radiotherapy, with minimal treatment-related toxicity, even in previously resected or irradiated patients. In this real-world cohort, local control with complete response was achieved by 20% of the patients. Further studies are needed to evaluate long-term outcome and late toxicity.

Comparison of intravenous 5-Fluorouracil with Oral Capecitabine in the Treatment of Anal Squamous Cell Carcinoma Using Modern Radiation Techniques.

BACKGROUND: Anal squamous cell carcinoma (ASqCC) is a rare malignancy, traditionally treated with combined chemoradiation, with a continuous infusion of 5-fluorouracil (5-FU) and mitomycin C (MMC). Replacing intravenous (IV) 5-FU with oral capecitabine (oral fluoropyrimidine) has been reported as a non-inferior treatment option. However, these data are scarce, with variable results. OBJECTIVES: To examine the outcome of patients with ASqCC treated with either IV 5-FU or capecitabine concomitantly with radiation therapy. To compare treatment side effects, local recurrence, and general outcome. METHODS: We reviewed charts of patients who were diagnosed with stage I-III ASqCC. All participating patients received chemoradiation at the Assuta Medical Center between 2011 and 2019. RESULTS: In this study, 43 patients with ASqCC were eligible; 14 received 5-FU and 29 were treated with capecitabine. Basic characteristics were similar between the two groups, with longer follow-up for the 5-FU group. Six months following treatment, 100% (13/13 with adequate follow-up) of the 5-FU group had complete clinical response, compared to 84% in the capecitabine group (21/24), P = 0.143. The local recurrence incidence was higher in the 5-FU group at 23% (7, 10, 26 months following therapy, and none in the capecitabine group (P = 0.088). Although local and hematological toxicities were similar between groups, one patient receiving capecitabine died during chemoradiotherapy. CONCLUSIONS: Oral capecitabine demonstrated non-inferior disease control in ASqCC treated with chemoradiotherapy. We recommend oral capecitabine over continuous IV 5-FU in locally and locally advanced ASqCC. Close monitoring of side effects is required to reduce major toxicity.

Prophylactic breast irradiation reduces background parenchymal enhancement (BPE) on MRI: A secondary analysis.

PURPOSE: We recently showed that prophylactic breast irradiation (PBI) reduces the risk of contralateral breast cancer in BRCA mutation carriers undergoing treatment for early breast cancer. It has been suggested that Background Parenchymal Enhancement (BPE) may be a biomarker for increased risk of breast cancer. METHODS: For participants in the trial we reviewed the MRI prior to enrollment and following radiation treatment and scored the contralateral breast for BPE and density. RESULTS: Significant reduction of BPE was more commonly noted following PBI (p = 0.011) compared to the control group. CONCLUSION: Reduction of BPE by PBI may contribute to its prophylactic effect.

Stereotactic Ablative Body Radiation for Stage I Lung Cancer in Israel: A Retrospective Single-Center Report.

BACKGROUND: Stereotactic ablative radiation therapy (SABR) is the application of a very high radiation dose to a small treatment volume. It is the new standard of care in medically inoperable early-stage lung cancer. OBJECTIVES: To report the outcomes of SABR in stage I lung cancer at Sheba Medical Center since its introduction in 2009. METHODS: We conducted a retrospective chart review of patients with stage I lung cancer treated during the period 2009-2015. Survival status was retrieved from the electronic medical records and confirmed with the national registry. Local failure was defined as increased FDG uptake on PETCT scan within a 2 cm radius of the treated region. Toxicity was estimated from medical records and graded according to common toxicity criteria for adverse events (CTCAE) version 4.03. Overall survival and local control were estimated by the Kaplan-Meier method. RESULTS: During the study period 114 patients were treated for 122 stage I lung cancer lesions. Median follow-up time was 27 months (range 8.2-69.5 months), median age was 76 years. Eighty-two percent of the tumors were stage IA (size ≤ 3 cm). Median survival was 46 months; estimated 3 year overall survival was 59% (95%CI 47-69%) and local control was 88% (95%CI 78-94%). Toxicity included chest wall pain in 8.4% of patients, rib fracture in 0.9%, grade 1-2 pneumonitis in 12%, grade 3 in 12% and grade 5 (death) in 0.9%. CONCLUSIONS: SABR has been successfully implemented at Sheba Medical Center for the treatment of stage I lung cancer in inoperable patients. It is associated with excellent local control, minor toxicity and an acceptable overall survival.

Melatonin for Prevention of Breast Radiation Dermatitis: A Phase II, Prospective, Double-Blind Randomized Trial.

BACKGROUND: Radiation-induced dermatitis is commonly seen during radiotherapy for breast cancer. Melatonin-based creams have shown a protective effect against ultraviolet-induced erythema and a radioprotective effect in rats. OBJECTIVES: To evaluate the efficacy of melatonin-containing cream in minimizing acute radiation dermatitis. METHODS: In this phase II, prospective, randomized, placebo-controlled double-blind study, patients who underwent breast-conserving surgery for stage 0-2 breast cancer were randomly allocated to melatonin emulsion (26 women) or placebo (21 women) for twice daily use during radiation treatment and 2 weeks following the end of radiotherapy. All women received 50 Gy whole breast radiation therapy with 2 Gy/fx using computed tomography-based 3D planning. Patients were examined and completed a detailed questionnaire weekly and 2 weeks following the end of treatment. RESULTS: The occurrence of grade 1/2 acute radiation dermatitis was significantly lower (59% vs. 90%, P = 0.038) in the melatonin group. Women older than 50 had significantly less dermatitis than younger patients (56% vs. 100%, P = 0.021). The maximal radiation dermatitis in the study group was grade 2 in 15% of the treated patients. CONCLUSIONS: Patients treated with melatonin-containing emulsion experienced significantly reduced radiation dermatitis compared to patients receiving placebo.

International consensus on use of focused ultrasound for painful bone metastases: Current status and future directions.

Focused ultrasound surgery (FUS), in particular magnetic resonance guided FUS (MRgFUS), is an emerging non-invasive thermal treatment modality in oncology that has recently proven to be effective for the palliation of metastatic bone pain. A consensus panel of internationally recognised experts in focused ultrasound critically reviewed all available data and developed consensus statements to increase awareness, accelerate the development, acceptance and adoption of FUS as a treatment for painful bone metastases and provide guidance towards broader application in oncology. In this review, evidence-based consensus statements are provided for (1) current treatment goals, (2) current indications, (3) technical considerations, (4) future directions including research priorities, and (5) economic and logistical considerations.

Magnetic resonance-guided focused ultrasound for patients with painful bone metastases: phase III trial results.

BACKGROUND: Pain due to bone metastases is a common cause of cancer-related morbidity, with few options available for patients refractory to medical therapies and who do not respond to radiation therapy. This study assessed the safety and efficacy of magnetic resonance-guided focused ultrasound surgery (MRgFUS), a noninvasive method of thermal tissue ablation for palliation of pain due to bone metastases. METHODS: Patients with painful bone metastases were randomly assigned 3:1 to receive MRgFUS sonication or placebo. The primary endpoint was improvement in self-reported pain score without increase of pain medication 3 months after treatment and was analyzed by Fisher's exact test. Components of the response composite, Numerical Rating Scale for pain (NRS) and morphine equivalent daily dose intake, were analyzed by t test and Wilcoxon rank-sum test, respectively. Brief Pain Inventory (BPI-QoL), a measure of functional interference of pain on quality of life, was compared between MRgFUS and placebo by t test. Statistical tests were two-sided. RESULTS: One hundred forty-seven subjects were enrolled, with 112 and 35 randomly assigned to MRgFUS and placebo treatments, respectively. Response rate for the primary endpoint was 64.3% in the MRgFUS arm and 20.0% in the placebo arm (P < .001). MRgFUS was also superior to placebo at 3 months on the secondary endpoints assessing worst score NRS (P < .001) and the BPI-QoL (P < .001). The most common treatment-related adverse event (AE) was sonication pain, which occurred in 32.1% of MRgFUS patients. Two patients had pathological fractures, one patient had third-degree skin burn, and one patient suffered from neuropathy. Overall 60.3% of all AEs resolved on the treatment day. CONCLUSIONS: This multicenter phase III trial demonstrated that MRgFUS is a safe and effective, noninvasive treatment for alleviating pain resulting from bone metastases in patients that have failed standard treatments.

Phase II study of concurrent capecitabine and external beam radiotherapy for pain control of bone metastases of breast cancer origin.

BACKGROUND: Pain from bone metastases of breast cancer origin is treated with localized radiation. Modulating doses and schedules has shown little efficacy in improving results. Given the synergistic therapeutic effect reported for combined systemic chemotherapy with local radiation in anal, rectal, and head and neck malignancies, we sought to evaluate the tolerability and efficacy of combined capecitabine and radiation for palliation of pain due to bone metastases from breast cancer. METHODOLOGY/PRINCIPAL FINDINGS: Twenty-nine women with painful bone metastases from breast cancer were treated with external beam radiation in 10 fractions of 3 Gy, 5 fractions a week for 2 consecutive weeks. Oral capecitabine 700 mg/m(2) twice daily was administered throughout radiation therapy. Rates of complete response, defined as a score of 0 on a 10-point pain scale and no increase in analgesic consumption, were 14% at 1 week, 38% at 2 weeks, 52% at 4 weeks, 52% at 8 weeks, and 48% at 12 weeks. Corresponding rates of partial response, defined as a reduction of at least 2 points in pain score without an increase in analgesics consumption, were 31%, 38%, 28%, 34% and 38%. The overall response rate (complete and partial) at 12 weeks was 86%. Side effects were of mild intensity (grade I or II) and included nausea (38% of patients), weakness (24%), diarrhea (24%), mucositis (10%), and hand and foot syndrome (7%). CONCLUSIONS/SIGNIFICANCE: External beam radiation with concurrent capecitabine is safe and tolerable for the treatment of pain from bone metastases of breast cancer origin. The overall and complete response rates in our study are unusually high compared to those reported for radiation alone. Further evaluation of this approach, in a randomized study, is warranted. TRIAL REGISTRATION: ClinicalTrials.gov NCT01784393NCT01784393.

Postoperative chemoradiation for resected gastric cancer--is the Macdonald Regimen Tolerable? a retrospective multi-institutional study.

BACKGROUND: Postoperative chemoradiation as per Intergroup-0116 trial ("Macdonald regimen") is considered standard for completely resected high risk gastric cancer. However, many concerns remain with regards to the toxicity of this regimen. To evaluate the safety and tolerability of this regimen in a routine clinical practice setting, we analyzed our experience with its use. As we did not expect a different toxic profile in patients (pts) with positive margins (R1 resection), these were studied together with pts after complete resection (R0). PATIENTS AND METHODS: Postoperative chemoradiation therapy was given according to the original Intergroup-0116 regimen. Overall survival (OS) and disease free survival (DFS) rates were calculated using the Kaplan-Meier method. Comparison of OS and DFS between R0 and R1 pts was done using the log-rank test. RESULTS: Between 6/2000 and 12/2007, 166 pts after R0 (129 pts) or R1 (37 pts) resection of locally advanced gastric adenocarcinoma received postoperative chemoradiation; 61% were male and the median age was 63 years (range, 23-86); 78% had T ≥ 3 tumors and 81% had N+ disease; 87% of the pts completed radiotherapy and 54% completed the entire chemoradiation plan; 46.4% had grade ≥ 3 toxicity and 32% were hospitalized at least once for toxicity. Three pts (1.8%) died of toxicity: diarrhea (1), neutropenic sepsis (1) and neutropenic sepsis complicated by small bowel gangrene (1). The most common hematological toxicity was neutropenia, grade ≥ 3 in 30% of pts and complicated by fever in 15%. The most common non-hematological toxicities were nausea, vomiting and diarrhea. With a median follow-up of 51 months (range, 2-100), 62% of the R0 patients remain alive and 61% are free of disease. Median DFS and OS for R0 were not reached. R0 pts had a significantly higher 3-year DFS (60% vs. 29%, p = 0.001) and OS (61% vs. 33%, p = 0.01) compared with R1 pts. CONCLUSIONS: In our experience, postoperative chemoradiation as per Intergroup-0116 seems to be substantially toxic, with a mortality rate which seems higher than reported in that trial. Efficacy data appears comparable to the original report. Following postoperative chemoradiation, involvement of surgical margins still has a detrimental impact on patient outcome.

CXCL10 promotes invasion-related properties in human colorectal carcinoma cells.

CXCL10 was recently shown to exert antimalignancy functions by influencing the tumor microenvironment. Here, we have taken a different approach, investigating the effects of CXCL10 directly on tumor-promoting functions in colorectal carcinoma (CRC) cells. CXCL10 expression was detected in preferred metastatic sites of CRC (liver, lungs, and lymph nodes), and its CXCR3 receptor was expressed by eight CRC cell lines (detected: reverse transcription-PCR and/or flow cytometry). Detailed analysis was done on two cell lines derived from primary CRC tumors (SW480, KM12C) and their metastatic descendents (SW620 and KM12SM). The three known variants of CXCR3 (CXCR3-A, CXCR3-B, and CXCR3-alt) were detected in all four cell lines. CXCR3 expression was also observed on colorectal tumor cells in biopsies of CRC patients (immunohistochemistry). CXCL10 and CXCR3 expression were potently induced in CRC cells by Interferon gamma and all four CRC cell lines responded to CXCL10 by extracellular signal-regulated kinase 1/2 dephosphorylation. The chemokine did not affect tumor cell growth or angiogenesis-related functions in the tumor cells, such as CXCL8 and vascular endothelial growth factor secretion. Importantly, CXCL10 significantly up-regulated invasion-related properties in CRC cells: It promoted matrix metalloproteinase 9 expression and induced CRC cell migration. Of note, CXCL10-induced migration was detected only in the two metastatic cells and not in their primary counterparts. Also, CXCL10 promoted the adhesion of metastatic cells to laminin. These results suggest that CXCL10 can be exploited by CRC cells toward their progression, thus possibly antagonizing the antimalignancy effects of the chemokine on the tumor microenvironment. Therefore, care should be taken when considering CXCL10 as a therapeutic antitumor modality for CRC treatment.

Children undergoing repeated exposures for radiation therapy do not develop tolerance to propofol: clinical and bispectral index data.

BACKGROUND: The purpose of this study was to apply clinical criteria and Bispectral Index monitor data for evaluating the development of tolerance to propofol in children undergoing repeated drug exposure. METHODS: Children undergoing multiple sessions of radiation therapy during anesthesia for various malignancies were given a predetermined dose of propofol at each session. Heart rate, blood pressure, oxygen saturation, respiratory rate, requirement of additional propofol, and time to emergence and discharge were recorded. The Bispectral Index was monitored continuously, and parameters were extracted and averaged for each week of therapy. RESULTS: Fifteen children (aged 2.5-10 yr) were treated for an average of 5 weeks (24 +/- 6 sessions). There were no significant differences in physiologic parameters or requirements of additional propofol between the weeks of treatment. Bispectral Index data analysis showed that although a nonlinear change with time for each parameter could not be rejected, the differences between the first and last intervals were nonsignificant. CONCLUSIONS: Overall changes with time resulted from random fluctuations without a consistent trend. Combined with clinical data, Bispectral Index parameters showed that tolerance to propofol does not develop in children undergoing repeated exposures to the drug during radiation therapy.

Intractable vomiting from glioblastoma metastatic to the fourth ventricle: three case studies.

Dissemination of malignant glioma to the fourth ventricle with metastatic deposits and intractable vomiting is rare. Leptomeningeal extension of malignant glioma is an uncommon condition that has been reported in patients with end-stage disease and is usually unresponsive to any treatment modality. We describe 3 patients with progressing recurrent glioblastoma multiforme in whom leptomeningeal invasion manifested itself as intractable vomiting due to tumor metastases in the floor of the fourth ventricle. All patients received additional radiation therapy focused to the posterior fossa, with complete resolution of vomiting occurring within 10 days after irradiation. The remission of symptoms in these patients persisted until their death 3-4 months after the repeat radiation therapy. These reports indicate that additional focused radiation should be considered because of its significant therapeutic effect in alleviating intractable nausea and vomiting in patients with glioma metastasized to the posterior fossa.