Efficacy and safety of second-line fotemustine in elderly patients with recurrent glioblastoma.

Fotemustine (FTM) is a common treatment option for glioblastoma patients refractory to temozolomide (TMZ). Although elderly patients represent a large component of glioblastoma population, the feasibility and the efficacy of second-line FTM are not available in those patients.We retrospectively analyzed the records of glioblastoma patients older than 65 years, receiving FTM at a dose of 70-100 mg/m(2) of FTM every week for 3 consecutive weeks (induction phase) and then every 3 weeks (70-100 mg/m(2)), as second-line treatment.Between January 2004 and December 2011, 65 glioblastoma patients (median age, 70 years; range, 65-79 years) were eligible for this analysis. Sixty-five patients received a total of 364 FTM cycles, with a median of 4 cycles for each patient. After induction, we observed 1 complete response (1.5 %), 12 partial responses (18.5 %), 18 stable diseases (27.7 %), and 34 patients' progressions (47.7 %). Disease control rate was 43.1 %. Median survival from the beginning of FTM therapy was 7.1 months, while the median progression-free survival was 4.2 months, and the 6-months progression free survival rate was 35.4 %. The most relevant grade 3-4 toxicity events were thrombocytopenia (15.3 %) and neutropenia (9.2 %). In the univariate and multivariate analysis, time from radiotherapy to FTM, number of TMZ and FTM cycles and disease control resulted independent prognostic factors.This study showed that FTM is a valuable therapeutic option for elderly glioblastoma patients, with a safe toxicity profile.

A retrospective pooled analysis of response patterns and risk factors in recurrent malignant glioma patients receiving a nitrosourea-based chemotherapy.

BACKGROUND: At recurrence the use of nitrosoureas is widely-used as a therapeutic option for glioblastoma (GBM) patients. The efficacy of fotemustine (FTM) has been demonstrated in phase II clinical trials; however, these papers report a wide range of progression-free-survival (PFS-6 m) rates, ranging from 21% to 52%. We investigated whether FTM could have a different response pattern in respect to time to adjuvant temozolomide failure, or whether specific independent risk factors could be responsible for the wide range of response rates observed. METHODS: Recurrent GBM patients have been treated with fotemustine 75-100 mg/sqm at day 1, 8, 15 and after 4/5 weeks of rest with 100 mg/sqm every 21 days. Patients were stratified in 4 groups according to time to temozolomide failure: before starting (B0), during the first 6 months (B1), after more than 6 months of therapy (B2), and after a treatment-free interval (B3). Primary endpoint was PFS-6 m. A multivariable analysis was performed to identify whether gender, time after radiotherapy, second surgery and number of TMZ cycles could be independent predictors of the clinical benefit to FTM treatment. RESULTS: 163 recurrent GBM patients were included in the analysis. PFS-6 m rates for the B0, B1, B2 and B3 groups were 25%, 28%, 31.1% and 43.8%, respectively. The probability of disease control was higher in patients with a longer time after radiotherapy (p = 0.0161) and in those who had undergone a second surgery (p = 0.0306). CONCLUSIONS: FTM is confirmed as a valuable therapeutic option for patients with recurrent GBM and was active in all study patient groups. Time after the completion of radiotherapy and second surgery are independent treatment-related risk factors that were predictive of clinical benefit.

Radiation Recall Pneumonitis COVID-19 Infection Induced After Adjuvant Breast Cancer Radiotherapy. A Known Phenomenon in an Unknown Pandemic Disease: A Case Report.

The COVID-19 pandemic has opened several new disease scenarios, yielding novel syndromes that have never been seen before and resurrecting old inflammatory phenomena that are no longer recorded, such as radiation recall (RR) syndromes. Radiation recall syndrome is a limited field inflammatory reaction that occurs in a volume that was irradiated several months or years previously before being induced by a triggering factor. The most frequently reported phenomena are skin reactions; however, other organs could be involved, such as the lungs in radiation recall pneumonitis (RRP). It is a well-described inflammatory reaction that occurs within a pulmonary volume that was irradiated several months or years previously via radiotherapy (RT), triggered by factors such as drugs, including chemotherapy agents, immunotherapy, or vaccination. Indeed, during the COVID-19 pandemic, RRP following anti-COVID-19 vaccination or SARS-CoV2 infection was recently reported. ACE receptor-rich tissues such as lung or skin tissues were mainly involved. Herein, we present a case of RRP triggered by COVID-19 pulmonary infection in a woman who previously underwent adjuvant breast cancer radiotherapy. Although symptoms were typical, pulmonary CT findings depicted a unique distribution of ground-glass opacities (GGOs) throughout the previous radiation portals and mirror-like the radiation fields. Anamnesis and radiation plan evaluation were crucial in the diagnosis of RRP.

Breast Cancer Adjuvant Radiotherapy in BRCA1/2, TP53, ATM Genes Mutations: Are There Solved Issues?

BRCA1, BRCA2, TP53 and ATM gene mutations are the most studied tumour suppressor genes (TSGs) influencing the loco-regional approach to breast cancer (BC). Due to altered radio sensitivity of mutated cancer cells, mastectomy has always been advised in most patients with BC linked to TSGs mutations in order to avoid or minimize the use of adjuvant radiotherapy (ART). Whether ART is safe or not in these carriers is still debated. As a result, this issue has been widely discussed in the recent ASTRO and ASCO papers, yielding important and useful recommendations on the use of ART according to the mutational status. In this review, we have highlighted the impact of these mutations on local control, toxicities, second tumors, and contralateral breast cancers (CBCs) after ART to solve remaining doubts and encourage the safe use of ART when indicated.

Intensity-modulated radiation therapy with simultaneous integrated boost in unresected left-sided pleural mesothelioma: a case report.

A 77-year-old male patient with unresected malignant pleural mesothelioma, clinical stage T3N0M0 according to the New International Staging System for Diffuse Malignant Pleural Mesothelioma, received intensity-modulated radiotherapy (IMRT) with a simultaneous integrated boost (SIB) after 6 cycles of chemotherapy with cisplatin and pemetrexed. SIB-IMRT delivered 40.5 Gy (1.5 Gy/fraction) to the left pleura and 50 Gy (1.85 Gy/fraction) to the sites of macroscopic disease. Radiotherapy was well tolerated. Two months after the end of radiotherapy the patient showed grade 2 lung toxicity (febrile episodes accompanied by dry cough) that was successfully treated with steroid therapy. Local control lasted for 2 years after SIB-IMRT. Then the tumor recurred marginally to the radiation field and the patient underwent chemotherapy with pemetrexed. Three years from the diagnosis, the patient is alive and in good general condition. He only takes prednisone 5 mg/daily for exertional dyspnea. To the best of our knowledge this is the first reported use of SIB-IMRT in unresected malignant pleural mesothelioma. Considering the dosimetric advantages of SIB-IMRT and the clinical results observed in our patient, additional evaluation of this technique seems justified.

From Anemia to Erythropoietin Resistance in Head and Neck Squamous Cell Carcinoma Treatment: A Carousel Driven by Hypoxia.

Anemia has been identified as a significant negative prognosticator in head and neck squamous cell carcinoma (HNSCC) concurrent chemoradiotherapy (CCRT). Irrespective of the causes, anemia in HNSCC is believed to contribute to intratumoral hypoxia, which reduces the effectiveness of radiotherapy and oxygen-dependent chemotherapy. Correction of anemia with recombinant human erythropoietin (rHu-EPO) has been performed as a surrogate for hypoxia compensation to improve tumor control and survival outcomes. However, the results of the most important EPO clinical trials have been disappointing. Following the recent finding that EPO and its receptor (EPOR) are both expressed in HNSCC specimens, a new hypothesis has been advanced. This postulates that hypoxic signaling might activate EPOR through the hypoxia-inducible factor (HIF) signaling pathway and its downstream effectors, including carbonic anhydrase 9 (CA-9), glucose transporter 1 (GLUT-1), and vascular endothelial growth factor (VEGF), leading to the failure of rHu-EPO treatment, as assessed from the results of the best-known EPO trials. This review addresses the relationship among anemia, hypoxia, and tumoral EPO/EPOR expression in HNSCC treatment in an attempt to elucidate the main mechanisms involved in the resistance to rHu-EPO therapy, as in a carousel.

Are there overlapping clinical features between thoracic radiotherapy side effects and covid-19 pneumonia? Radiation pneumonitis outside the radiation ports: Three case reports.

Respiratory involvement of COVID-19 infection, with presentations ranging from a mild flu-like illness to potentially lethal acute respiratory distress syndrome, is the main clinical manifestation in adults. Chest imaging shows a pictorial fashion of images due to the severity and stage of the disease, starting from focal nodular or mass-like opacities with air bronchogram to areas of ground glass consolidation or whited out lung. However, during the COVID-19 pandemic, CT findings could yield confounding reporting in the case of cancer patients previously treated with thoracic radiotherapy (tRT) due to atypical radiation pneumonitis occurring outside the radiation ports. Hypersensitivity pneumonitis and radiation-induced bronchiolitis obliterans organizing pneumonitis (RT-BOOP) are accounted for in this report.

A multidisciplinary expert opinion on CINV and RINV, unmet needs and practical real-life approaches.

Introduction: A range of combination chemotherapy regimens are currently used in clinical practice. However, international antiemetic guidelines often only categorize the emetogenic potential of single agents rather than the emetogenicity of combination chemotherapy regimens. To manage the nausea and vomiting induced by antineoplastic combinations, guidelines suggest antiemetics that are appropriate for the component drug with the highest emetogenic potential. Furthermore, antiemetic guidelines generally do not consider the influence of other factors, including individual patient characteristics, on the emetic effects of cancer treatments. Similarly, the emetogenic potential of radiotherapy is stratified only according to the site of radiation, while other factors contributing to emetic risk are overlooked.Areas covered: An Expert Panel was convened to examine unresolved issues and summarize the current clinical research on managing nausea and vomiting associated with combination chemotherapy and radiotherapy.Expert opinion: The panel identified the incidence of nausea and vomiting induced by multi-drug combination therapies currently used to treat cancer at different anatomic sites and by radiotherapy in the presence of other risk factors. Based on these data and the clinical experience of panel members, several suggestions are made for a practical approach to prevent or manage nausea and vomiting due to chemotherapy regimens and radiation therapy.

Competing Morbidities In Advanced Head And Neck Squamous Cell Carcinoma Concurrent Chemoradiotherapy: A Strong Implication Of A Multidisciplinary Team Approach.

Concurrent chemoradiotherapy (CCRT) is the standard approach for the treatment of locally advanced head and neck squamous cell carcinoma. Despite its undisputed advantages, CCRT is associated with acute and late toxicities, leading to unfavorable implications (eg, unplanned interruptions and noncancer-related mortality). The former prolongs the overall treatment time leading to a detrimental effect on tumor control. The latter consists of several noncancer morbidities arising from treatment-related toxicities, identifying a new pathway in cancer fate. This pathway has been termed noncancer mortality or competing mortality and consists of a series of treatment-competing morbidities, which nullify all therapeutic efforts aimed at curing these patients. The management of patients with head and neck squamous cell carcinoma who experience treatment-related toxicities is complex and requires expertise in oncological treatment as well as supportive care. The optimal management of these patients should start with knowledge regarding the most important competing morbidities developing during all phases of the disease (ie, from diagnosis to follow-up) to minimize treatment interruptions, ensure appropriate psychological support, and achieve the best oncological result. The purpose of the present review is to analyze the most important competing morbidities due to patient's condition at baseline and CCRT, which could result in noncancer mortality. A multidisciplinary team approach is strongly required in the management of this disease.

Radiotherapy in advanced glottic laryngeal carcinoma in a patient with Wegener's granulomatosis: how much radiation dose is needed?

Wegener's granulomatosis (WG) is an autoimmune disorder characterized by necrotizing granulomas involving mainly the upper-lower respiratory and renal tracts, albeit a potentially life-threatening involvement of other body parts is not rare. Furthermore, there are several reports accounting for an increased risk of solid malignancies due to the autoimmune disease per se, or the immunosuppressive therapies. Among treatments, radiotherapy could be a therapeutic option as proven by its use in typical WG lesions such as solitary granulomas or subglottic stenosis, successfully treated with low radiation dose. Herein, we report a case of squamous cell carcinoma of the glottis-subglottic larynx, T3 N0 M0 stage, occurring in a patient with a long-standing WG, heavily treated in the past with cyclophosphamide and rituximab, who achieved a complete response of the tumor using a low-dose radiation therapy and no concurrent chemotherapy. The hypothesis is that this cancer probably arose from a subglottic stenosis as a late manifestation of WG and exhibited more radiosensitivity than a naïve tumor. If so, solid tumors occurring on granulomas within an autoimmune disease course should be treated with a lower radiation dose.

Lower cranial nerve palsy during radiotherapy for glottic cancer in a patient with Wegener's granulomatosis: An interesting case report.

The aim of the present study was to report an unusual case of multiple lower cranial nerve palsies in a patient with Wegener's granulomatosis (WG) during radiotherapy for glottic cancer. WG is an autoimmune disease characterized by necrotizing granulomas mainly in the upper and lower respiratory tract or kidneys; however, the involvement of cranial nerves is not uncommon. Prior to the use of cyclophosphamide (CYC) the 1-year mortality rate was ~82%; the introduction of rituximab (RTX) has revolutionized the course of the WG, with remission rates comparable to those of CYC and superior effectiveness in relapsing patients. Hypogammaglobulinemia and B-cell depletion are the best known monitored side effects affecting survival due to secondary infections. Immunodepression and relapse with lower cranial nerve palsy have a negative impact on prognosis. We herein present the case of a heavily pre-treated GPA patient with secondary immunosuppression, who underwent radiotherapy for glottic cancer and developed multiple low cranial nerve palsies during treatment, which was interrupted at 60 Gy. The possible related causes and the association between previous immunosuppressive treatments and radiotherapy were also analyzed to elucidate the cause of this complication.

Acute and fatal diarrhoea after erlotinib plus abdominal palliative hypofractionated radiotherapy in a metastatic non-small cell lung cancer patient: a case report.

The management of advanced non-small cell lung cancer (NSCLC) has progressed over the last 3 decades due to advances in chemotherapeutic drugs and targeted agents improving survival and quality of life. In particular erlotinib, an orally available human epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor advancing through clinical trials for the treatment of various human malignancies in a large placebo-controlled phase III study, has shown a significantly better OS vs. placebo suggesting its potential benefits in third line and possibly in second line treatments. The association of erlotinib with ionizing radiation has been recently published showing an enhancing antitumor activity and good tolerance. No information are available on side effects when erlotinib is associated with abdominal hypofractionated radiotherapy although diarrhoea is the most known side effect dose-limiting toxicity when the abdomen is treated. Here we report a fatal acute diarrhoea in a metastatic NSCLC patient taking erlotinib during abdominal hypofractionated radiotherapy for metastatic spinal cord compression (MSCC).

Effective nivolumab sequential thoracic radiotherapy in elderly patients with advanced squamous cell lung cancer: did radiation therapy play a role? A case report.

Advanced squamous cell lung carcinoma in elderly patients has a limited chance of cure with first, second line chemotherapy and radiotherapy. Radiotherapy in advanced non-small-cell lung cancer can be used with curative intent for localized or oligometastatic disease using standard or altered fractionations. Current evidence indicates that radiotherapy via diverse cascade mechanisms is able to invoke both local and systemic immunoresponses promoting tumor cell death through an in situ vaccination effect. Moreover, the advancement in immunotherapies is changing the scenario. The combination of radiotherapy and immunotherapy could be a crucial strategy to overcome cancer immunoresistance and improve patient survival, as we found in this case report of an elderly, refractory advanced lung cancer patient who has achieved complete remission after this therapeutic combination.

Single nucleotide polymorphisms and unacceptable late toxicity in breast cancer adjuvant radiotherapy: a case report.

BACKGROUND: There has recently been a strong interest in the inter-individual variation in normal tissue and tumor response to radiotherapy (RT), because tissue radiosensitivity seems to be under genetic control. Evidence is accumulating on the role of polymorphic genetic variants, such as single nucleotide polymorphisms (SNPs) that could influence normal tissue response after radiation. The most studied SNPs include those in genes involved in DNA repair (single- and double-strand breaks, and base excision) and those active in the response to oxidative stress. CASE REPORT: We present the case report of a 60-year-old woman with early breast cancer who underwent adjuvant hormone therapy and conventional radiotherapy, and subsequently developed unacceptable cosmetic toxicities of the irradiated breast requiring a genetic test of genes involved in DNA repair mechanisms. The patient was found to be heterozygous for G28152A (T/C) and C18067T (A/G) mutations in X-ray repair cross-complementing group 1 (XRCC1) and 3 (XRCC3), respectively, homozygous for A313G (G/G) mutation in glutathione S transferase Pi 1 (GSTP1), and wild-type for A4541G (A/A) in XRCC3 and G135C (G/G) in RAD51 recombinase. CONCLUSION: The role of SNPs should be taken into account when a severe phenomenon appears in normal tissues after radiation treatment, because understanding the molecular basis of individual radiosensitivity may be useful for identifying moderately or extremely radiosensitive patients who may need tailored therapeutic strategies.

Predictive parameters in hypofractionated whole-breast 3D conformal radiotherapy according to the Ontario Canadian trial.

AIM: To evaluate the possible role of dosimetric parameters according Normal Tissue Complication Probability (NTCP) model as predictive of late toxicity and cosmesis in hypofractionated whole-breast three-dimensional conformal radiotherapy. PATIENTS AND METHODS: A retrospective analysis on 215 consecutive early breast cancer patients treated with breast conserving surgery and adjuvant hypofractionated whole-breast radiotherapy (according the Ontario Canadian trial), with a 6 years median follow-up was conducted. To assess the impact of 10%-20% dose hotspots on different percent values of planning target volume (PTV) of the breast, we retrospectively employed the NTCP model of Lyman. PTV breast (PTVbr), V110 were identified. For statistical analysis the χ2 and paired t-test were used to find a correlation between late skin and subcutaneous toxicity and cosmetic outcome with dosimetrical parameters Multivariate analysis was performed with the aim to assess independently the impact of dosimetric and clinical parameters on late toxicity and cosmesis using Pearson's covariance. RESULTS: Late skin toxicity was recorded in 47/215 (22%); and G3 toxicity occurred in 11 patients (5%). Cosmesis with excellent-good score was found in 172 patients (80%) while fair-poor score was found in 43 patients (20%). In univariate χ2 analysis the V110 >10% of the PTV breast significantly correlated with higher toxicity (P<0.005, OR 9.60 [CI 3.89-23.72]). Cosmesis related to V110 >10% and PTV breast volume over 1,300 cc was significant at multivariate analysis (P<0.005, OR 6.07 [CI 2.36-15.59]). CONCLUSION: To safely use one of the most important whole-breast hypofractionated radiotherapy schedules, we found some predictive paramaters on the basis of NTCP model by Lyman. These parameters may be useful in selection of elegible patients.

Oral vinorelbine: a feasible and safe partner for radiotherapy in the treatment of locally advanced non-small cell lung cancer.

BACKGROUND: Concurrent chemoradiotherapy (CCRT) using cisplatin-based doublets represents the standard of care for locally advanced non-small cell lung cancer (NSCLC), having shown good efficacy and activity in clinical trials. Locally advanced NSCLC occurs frequently in the elderly population, which is often excluded by platinum-based CCRT administration, due to severe associated toxicities. This limitation has been overcome using new-generation drugs such as gemcitabine, docetaxel, paclitaxel, and vinorelbine, which have shown not only to be efficacious but also to have a favorable toxicity spectrum, both in association with cisplatin and as single agents. Vinorelbine is a vinca alkaloid that binds to tubulin, thus inhibiting mitotic microtubule polymerization. Previous studies have clearly demonstrated that vinorelbine acts as a radiosensitizing agent when administered intravenously or orally. Moreover, oral administration of vinorelbine has shown a good clinical safety profile in both elderly and younger patients. METHODS: A comprehensive review of the literature data regarding use of oral vinorelbine concurrently with radiotherapy in NSCLC was done. CONCLUSION: Single-agent oral vinorelbine may represent an effective therapy option for elderly patients with locally advanced lung cancer. This review has described the use of oral vinorelbine both as a monochemotherapy and in combination with cisplatin in the context of CCRT.

Low dose rate brachytherapy (LDR-BT) as monotherapy for early stage prostate cancer in Italy: practice and outcome analysis in a series of 2237 patients from 11 institutions.

OBJECTIVE: Low-dose-rate brachytherapy (LDR-BT) in localized prostate cancer is available since 15 years in Italy. We realized the first national multicentre and multidisciplinary data collection to evaluate LDR-BT practice, given as monotherapy, and outcome in terms of biochemical failure. METHODS: Between May 1998 and December 2011, 2237 patients with early-stage prostate cancer from 11 Italian community and academic hospitals were treated with iodine-125 ((125)I) or palladium-103 LDR-BT as monotherapy and followed up for at least 2 years. (125)I seeds were implanted in 97.7% of the patients: the mean dose received by 90% of target volume was 145 Gy; the mean target volume receiving 100% of prescribed dose (V100) was 91.1%. Biochemical failure-free survival (BFFS), disease-specific survival (DSS) and overall survival (OS) were estimated using Kaplan-Meier method. Log-rank test and multivariable Cox regression were used to evaluate the relationship of covariates with outcomes. RESULTS: Median follow-up time was 65 months. 5- and 7-year DSS, OS and BFFS were 99 and 98%, 94 and 89%, and 92 and 88%, respectively. At multivariate analysis, the National Comprehensive Cancer Network score (p < 0.0001) and V100 (p = 0.09) were correlated with BFFS, with V100 effect significantly different between patients at low risk and those at intermediate/high risk (p = 0.04). Short follow-up and lack of toxicity data represent the main limitations for a global evaluation of LDR-BT. CONCLUSION: This first multicentre Italian report confirms LDR-BT as an excellent curative modality for low-/intermediate-risk prostate cancer. ADVANCES IN KNOWLEDGE: Multidisciplinary teams may help to select adequately patients to be treated with brachytherapy, with a direct impact on the implant quality and, possibly, on outcome.

Primary tumor response to preoperative chemoradiation with or without oxaliplatin in locally advanced rectal cancer: pathologic results of the STAR-01 randomized phase III trial.

PURPOSE: To investigate oxaliplatin combined with fluorouracil-based chemoradiotherapy as preoperative treatment for locally advanced rectal cancer. PATIENTS AND METHODS: Seven hundred forty-seven patients with resectable, locally advanced (cT3-4 and/or cN1-2) adenocarcinoma of the mid-low rectum were randomly assigned to receive pelvic radiation (50.4 Gy in 28 daily fractions) and concomitant infused fluorouracil (225 mg/m(2)/d) either alone (arm A, n = 379) or combined with oxaliplatin (60 mg/m(2) weekly × 6; arm B, n = 368). Overall survival is the primary end point. A protocol-planned analysis of response to preoperative treatment is reported here. RESULTS: Grade 3 to 4 adverse events during preoperative treatment were more frequent with oxaliplatin plus fluorouracil and radiation than with radiation and fluorouracil alone (24% v 8% of treated patients; P < .001). In arm B, 83% of the patients treated with oxaliplatin had five or more weekly administrations. Ninety-one percent, compared with 97% in the control arm, received ≥ 45 Gy (P < .001). Ninety-six percent versus 95% of patients underwent surgery with similar rates of abdominoperineal resections (20% v 18%, arm A v arm B). The rate of pathologic complete responses was 16% in both arms (odds ratio = 0.98; 95% CI, 0.66 to 1.44; P = .904). Twenty-six percent versus 29% of patients had pathologically positive lymph nodes (arm A v arm B; P = .447), 46% versus 44% had tumor infiltration beyond the muscularis propria (P = .701), and 7% versus 4% had positive circumferential resection margins (P = .239). Intra-abdominal metastases were found at surgery in 2.9% versus 0.5% of patients (arm A v arm B; P = .014). CONCLUSION: Adding oxaliplatin to fluorouracil-based preoperative chemoradiotherapy significantly increases toxicity without affecting primary tumor response. Longer follow-up is needed to assess the impact on efficacy end points.