Comparative Effectiveness of Chemotherapy Alone Versus Radiotherapy-Based Regimens in Locally Advanced Pancreatic Cancer: A Real-World Multicenter Analysis (PAULA-1).

Different options for locally advanced pancreatic cancer (LAPC) are available based on international guidelines: chemotherapy (CHT), chemoradiation (CRT), and stereotactic body radiotherapy (SBRT). However, the role of radiotherapy is debated in LAPC. We retrospectively compared CHT, CRT, and SBRT ± CHT in a real-world setting in terms of overall survival (OS), local control (LC), and distant metastasis-free survival (DMFS). LAPC patients from a multicentric retrospective database were included (2005-2018). Survival curves were calculated using the Kaplan-Meier method. Multivariable Cox analysis was performed to identify predictors of LC, OS, and DMFS. Of the 419 patients included, 71.1% were treated with CRT, 15.5% with CHT, and 13.4% with SBRT. Multivariable analysis showed higher LC rates for CRT (HR: 0.56, 95%CI 0.34-0.92, p = 0.022) or SBRT (HR: 0.27, 95%CI 0.13-0.54, p < 0.001), compared to CHT. CRT (HR: 0.44, 95%CI 0.28-0.70, p < 0.001) and SBRT (HR: 0.40, 95%CI 0.22-0.74, p = 0.003) were predictors of prolonged OS with respect to CHT. No significant differences were recorded in terms of DMFS. In selected patients, the addition of radiotherapy to CHT is still an option to be considered. In patients referred for radiotherapy, CRT can be replaced by SBRT considering its duration, higher LC rate, and OS rate, which are at least comparable to that of CRT.

Stereotactic body radiotherapy vs conventionally fractionated chemoradiation in locally advanced pancreatic cancer: A multicenter case-control study (PAULA-1).

Conventionally fractionated chemoradiation (CRT) or chemotherapy (CHT) are considered as standard options in locally advanced pancreatic cancer (LAPC) while stereotactic body radiotherapy (SBRT) is an emerging treatment in this setting. The aim of this study was to compare two cohorts of LAPC patients treated with SBRT ± CHT vs CRT ± CHT in terms of local control (LC), distant metastases-free survival (DMFS), progression-free survival (PFS), overall survival (OS), and toxicity. Eighty patients were included. Patients in the two cohorts were matched according to: age ≤/>65 years, tumor diameter (two cut-offs:

Higher Biologically Effective Dose Predicts Survival in SBRT of Pancreatic Cancer: A Multicentric Analysis (PAULA-1).

AIM: The purpose of the present multicentric study was to review stereotactic body radiotherapy (SBRT) with or without chemotherapy (CHT) experience in locally advanced pancreatic cancer (LAPC). Endpoints were overall survival (OS), local control (LC), and distant metastasis-free survival (DMFS). Several parameters' impact on these outcomes was assessed. MATERIALS AND METHODS: Fifty-six patients with LAPC undergoing SBRT+/-CHT were included. SBRT median BEDα/ß10Gy was 48.0 Gy (range=28.0-78.7). Survival curves were calculated by Kaplan-Meier method. A Cox regression model was fitted. RESULTS: At a median follow-up of 15.0 months, 2-year OS, LC, DMFS were: 33.8% 55.4%, and 22.9%, respectively. Patients treated with BEDα/ß10Gy≥48 Gy showed improved OS (p=0.020) and LC (p=0.024). At multivariate analysis, BEDα/ß10Gy≥48 Gy was significantly associated to both higher OS (p=0.042) and LC (p=0.045), while post-SBRT CHT improved DMFS (p=0.003). CONCLUSION: SBRT proved to be tolerable and effective in LAPC. Moreover, BEDα/ß10Gy≥48 Gy was significantly correlated with improved OS and LC.

Integration of stereotactic radiotherapy in the treatment of metastatic colorectal cancer patients: a real practice study with long-term outcome and prognostic factors.

BACKGROUND: There are very few clinical or prognostic studies on the role of SRT (Stereotactic Radiation Therapy) in the continuum of care of metastatic colorectal cancer (mCRC) patients. PATIENTS AND METHODS: Patients affected by oligo-mCRC were treated with SRT before or after front-line standard treatments. SRT was delivered according to a risk-adapted protocol. Total body CT (Computed Tomography) scan was done before therapy and every three months thereafter. The radiologic responses to therapy were evaluated by RECIST (Response Evaluation Criteria In Solid Tumors). FDG-PET (FluoroDeoxyGlucose - Positron Emission Tomography) was done before and after SRT; metabolic responses were evaluated by using the EORTC (European Organization for Research and Treatment of Cancer) criteria. The Kaplan-Meier product limit method was applied to graph Overall Survival (OS) and Progression-Free Survival (PFS). RESULTS: Forty-seven patients were included. Twenty-one patients had disease limited to lungs, 9 to lung and liver, 7 only to liver, 10 to multiple sites. The median prescription SRT dose was 60 Gy per organ in 3 fractions (median biological effective dose of 180 Gy). The reduction of delta SUVmax (maximum Standardized Uptake Value) correlated with the local control (p<0.001) and two-years survival (p=0.003). At univariate analysis, localization of primary tumor, site of metastases, KRAS (Kirsten RAt Sarcoma) oncogene mutational status, response to first-line chemotherapy, response to SRT and number of treated lesions predicted both PFS and OS. DISCUSSION: This real practice experience suggests that further studies are needed to analyze the promising role of SRT in the multidisciplinary management of mCRC.

Small bowel metastasis from pancreatic cancer in a long-term survival patient with synchronous advanced malignant pleural mesothelioma: A case report and literature review.

Diffuse malignant pleural mesothelioma (MPM) is an aggressive tumor that originates from the surface of the pleura. Approximately 70% of cases are associated with chronic asbestos exposure. MPM is regarded as an incurable disease, with a median survival of ~2 years following intensive multimodality treatment. Pancreatic cancer is a malignancy also associated with a poor prognosis, with only 2% of patients surviving for 5 years. The majority of patients with pancreatic cancer are diagnosed with an advanced stage of disease and experience a poor response to therapy. The development of synchronous MPM and other types of cancer is rare. The present study describes a patient with synchronous, biphasic MPM and pancreatic adenocarcinoma, who was treated with a multimodal therapeutic approach with stereotactic body radiation therapy. Due to a suspected diagnosis of 'acute abdomen', an emergency small intestine resection was performed and a subsequent diagnosis of moderately-differentiated adenocarcinoma was confirmed. During a further immunohistochemical examination, pathologists determined that the small bowel metastasis descended from pancreatic cancer. The onset of bowel metastasis is an event rarely associated with MPM, and has not been previously described in the literature for cases of pancreatic cancer. Therefore, to the best of our knowledge, the present study describes the first case of intestinal metastasis from pancreatic cancer in a long-term survival patient with biphasic MPM.

The current status of novel PET radio-pharmaceuticals in radiotherapy treatment planning of glioma.

Malignant glioma is a primary tumor of the central nervous system, representing a major cause of mortality in a young, productive subset of population. The management of this neoplasm requires aggressive treatments, including radiotherapy. Accurate imaging plays a central role in treatment planning process with curative intent based on radiation therapy. In order to maximize the radiation dose to the tumor and to minimize the damage to the normal surrounding tissue, a reliable identification of viable tumor margins is indeed required. The use of PET in the treatment planning process has become more promising over the years, although many important questions must be addressed. The aim of this article is to critically review the evidence supporting PET in radiotherapy planning, with special emphasis on the role of novel radiopharmaceuticals, comparing its sensitivity and specificity with respect to 18F-FDG and other anatomic imaging modalities.

Sphingosine analog fingolimod (FTY720) increases radiation sensitivity of human breast cancer cells in vitro.

Radiotherapy is one of the most effective therapeutic strategies for breast cancer patients, although its efficacy may be reduced by intrinsic radiation resistance of cancer cells. Recent investigations demonstrate a link between cancer cell radio-resistance and activation of sphingosine kinase (SphK1), which plays a key role in the balance of lipid signaling molecules. Sphingosine kinase (SphK1) activity can alter the sphingosine-1-phosphate (S1P)/ceramide ratio leading to an imbalance in the sphingolipid rheostat. Fingolimod (FTY720) is a novel sphingosine analog and a potent immunosuppressive drug that acts as a SphK1 antagonist, inhibits the growth, and induces apoptosis in different human cancer cell lines. We sought to investigate the in vitro radiosensitizing effects of FTY720 on the MDA-MB-361 breast cancer cell line and to assess the effects elicited by radiation and FTY720 combined treatments. We found that FTY720 significantly increased anti-proliferative and pro-apoptotic effects induced by a single dose of ionizing radiation while causing autophagosome accumulation. At the molecular level, FTY720 significantly potentiated radiation effects on perturbation of signaling pathways involved in regulation of cell cycle and apoptosis, such as PI3K/AKT and MAPK. In conclusion, our data highlight a potent radiosensitizing effect of FTY720 on breast cancer cells and provide the basis of novel therapeutic strategies for breast cancer treatment.

Repeat stereotactic radiosurgery in the management of brain metastases from NSCLC: A case report and review of the literature.

The aims of radiotherapeutic treatment of brain metastases include maintaining neurocognitive function and improvement of survival. Based on these premises, we present a case report in which the role of repeat stereotactic radiosurgery (SRS) was investigated in a patient with a recurrent brain metastasis from non-small cell lung cancer in the same area as previously treated with radiosurgery. A 40-year-old male caucasian patient was diagnosed with brain metastasis from non-small cell lung cancer (NSCLC) and underwent SRS. The patient developed a recurrence of the disease and a second SRS on the same area was performed. After 8 months, tumor restaging demonstrated a lesion compatible with a recurrence and the patient underwent surgery. Histological diagnosis following surgery revealed only the occurrence of radionecrosis. Radiotherapy was well-tolerated and no grade 3/4 neurological toxicity occurred. To date, no consensus exists on the efficacy of retreatment with SRS. Despite the limited number of studies in this field, in the present case report, we outline the outcomes of this unconventional approach.

Co-application of the GABAB receptor agonist, baclofen, and the mGlu receptor agonist, L-CCG-I, facilitates [(3)H]GABA release from rat cortical nerve endings.

Interaction between different transmitter receptor systems is an emerging feature of neurotransmission at central synapses. G protein-coupled receptors' ability to form dimers or larger hetero-oligomers probably serves to facilitate the integration of diverse signals within the cell. We found that, in nerve terminals isolated from the cerebral cortices of rats, co-application of the GABAB agonist, baclofen, and of the non-selective mGlu agonist, L-CCG-I, potentiates the basal and depolarization-evoked release of [(3)H]GABA via a mechanism that involves mobilization of intracellular Ca(2+) ions. The effect of L-CCG-I + baclofen was abolished by the phospholipase C inhibitor U73122, reduced by Xestospongin C (an IP3 receptor blocker), and blocked by 2-APB, an IP3 receptor antagonist. Pretreatment of the synaptosomes with the lipid-soluble Ca(2+) chelator BAPTA-AM also inhibited the effects of L-CCG-I + baclofen. Subtype-selective non-competitive group I mGlu receptor antagonists, MPEP and CPCCOEt, had no effect on the release enhancement produced by baclofen + L-CCG-I. The enhancement was reversed by the GABAB receptor antagonist, CGP54626, and by the group I/group II mGlu receptor antagonist (R,S)-MCPG. The GABA release-enhancing effects of L-CCG-I + baclofen in our model might reflect the presence on cortical nerve endings of GABAB/group I mGlu receptor heteromers with pharmacological properties distinct from those of the component receptors. Activation of these heteromeric receptors might modify the function of the GABAB receptor in such a way that it facilitates GABAergic transmission, an effect that might be useful under conditions of excessive glutamatergic activity.

Pattern of failures and clinical outcome of patients with locally advanced cervical cancer treated with a tailored integrated therapeutic approach.

AIM: To review a tailored treatment with concurrent chemoradiotherapy (CT/RT) or neoadjuvant chemotherapy (NACT) followed by radical hysterectomy in locally advanced cervical cancer. PATIENTS AND METHODS: One hundred and four patients were treated with a tailored therapeutic approach. CT/RT was the standard treatment for patients with stage Ib2-IIb disease aged more than 70 years, or with high surgical risk, as well as for those with stage III-IV disease. NACT followed by radical hysterectomy was the treatment of choice for patients with stage Ib(2)-IIb disease, maximum age of 70 years and good performance status. RESULTS: For the 61 women who underwent CT/RT, 5-year disease-free (DFS) survival and 5-year overall survival (OS) were 62% and 71%, respectively. Patient outcome was associated with the clinical response to CT/RT (complete responders versus others: 5-year DFS, 81% versus 19%, p<0.001; 5-year OS, 84% versus 37%, p=0.001). For the 43 women who underwent NACT, 5-year DFS and 5-year OS were 66% and 75%, respectively. Patient outcome was associated with the pathological response to chemotherapy (optimal responders versus others: 5-year DFS, 89% versus 62%, p=0.03; 5-year OS, 90% versus 72%, p=0.05). CONCLUSION: Tailored treatments obtained satisfactory clinical outcomes in locally advanced cervical cancer. Optimal pathological response to NACT has been found to be a surrogate endpoint of OS. The identification of biological variables able to predict response to NACT is strongly warranted for an accurate selection of patients who may really benefit from chemosurgical treatment.

A multi-institutional phase II study on second-line Fotemustine chemotherapy in recurrent glioblastoma.

The present study aims to assess the feasibility and the effectiveness of a second-line Fotemustine chemotherapy in patients with recurrent Glioblastoma after standard primary treatment. Between 2005 and 2007, 50 patients with relapsed malignant glioma (median age=56.8 years; median KPS=90) underwent a second-line chemotherapy with Fotemustine. Selected patients were previously treated with a standard 60 Gy Radiotherapy course and Temozolomide Chemotherapy. Patients were stratified into classes according to the prognostic Recursive Partition Analysis. Endpoints of the study were Progression Free Survival at 6 months, duration of Objective Response and Stabilization, Overall Survival and toxicity. At analysis, 36 patients were dead and 14 were alive. Median follow-up from primary diagnosis was 26.6 months. The Efficacy control of the disease was 62%. PFS was 6.1 months; PFS-6 was 52% and median overall survival from primary diagnosis was 24.5 months, with few manageable haematological toxicities. Fotemustine was safe and effective as second-line chemotherapy in recurrent glioblastoma.