Search

Background: Few data are available regarding the effectiveness of immune checkpoint inhibitors in advanced upper tract urothelial carcinoma (UTUC) patients. Methods: To provide a real-world experience with anti-PD-1/PD-L1-based therapy in UTUC patients, we involved an Italian network in a multicenter retrospective analysis. Results: A total of 78 UTUC patients were enrolled. The median follow-up was 25.1 months. The median progression-free survival (mPFS) was 2.2 months (95% CI 1.8–2.6), and the median OS (mOS) was 6.0 months (95% CI 3.6–8.4). The Sonpavde score (including performance status > 0, hemoglobin

10.3389/fonc.2022.1088962 Abstract: Endometrial cancer (EC) is the most common gynecologic cancer in Europe and its prevalence is increasing. EC includes a biological and clinical heterogeneous group of tumors, usually classified as type I (endometrioid) or type II (non-endometrioid) based on the histopathological characteristics. In 2013, a new molecular classification was proposed by The Cancer Genome Atlas (TCGA) based on the comprehensive molecular profiling of EC. Several molecular somatic alterations have been described in development and progression of EC. Using these molecular features, EC was reclassified into four subgroups: POLE ultra-mutated, MSI hypermutated, copy-number low, and copy-number high that correlate with the prognosis. To this regard, it is widely reported that EC has more frequent mutations in the phosphatidylinositol 3-kinase (PI3K) pathway signaling than any other tumor. PIK3CA is the main significant mutated gene after PTEN alterations. Overall, over 90% of endometrioid tumors have activating PI3K molecular alterations that suggests its critical role in the EC pathogenesis. Thus, the dysregulation of PI3K pathway represents an attractive target in EC treatment. Herein, we report a radiological and clinically meaningful response to a selective PIK3 inhibitor in a patient with extensively pre-treated advanced endometrioid EC harboring a somatic activating PIK3CA hotspot mutation. These evidences provide the rational for translational strategies of the PI3K inhibition and could support the clinical usefulness of PIK3CA genotyping in advanced EC. To our knowledge, this is the first clinical case of PIK3CA-mutated EC successfully treated with alpelisib.

Platinum-based chemotherapy (PBCT) is the standard first-line treatment for advanced urothelial carcinoma (UC). Potential cross-sensitivity can be hypothesized between platinum drugs and poly-ADP ribose-polymerase (PARP) inhibitors.To compare maintenance treatment with the PARP inhibitor niraparib plus best supportive care (BSC) versus BSC alone in patients with advanced UC without disease progression after first-line PBCT.Meet-URO12 is a randomized, multicenter, open-label phase 2 trial. Patients with advanced UC, without disease progression after four to six cycles of PBCT, with Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, were enrolled between August 2019 and March 2021. Randomization was stratified by ECOG performance status (0/1) and response to PBCT (objective response/stable disease).Patients were randomized (2:1) to experimental arm A (niraparib 300 or 200 mg daily according to body weight and baseline platelets, plus BSC) or control arm B (BSC alone).The primary endpoint was progression-free survival (PFS). The analysis was performed on an intention-to-treat basis. The secondary endpoints reported in this primary analysis are progression-free rate at 6 mo and safety (adverse event rate).Fifty-eight patients were randomized (39 in arm A and 19 in arm B). The median age was 69 yr, ECOG performance status was 0 in 66% and 1 in 34%; and the best response with chemotherapy was objective response in 55% and stable disease in 45%. The median PFS was 2.1 mo in arm A and 2.4 mo in arm B (hazard ratio 0.92; 95% confidence interval 0.49-1.75, p = 0.81). The 6-mo progression-free rates were 28.2% and 26.3%, respectively. The most common adverse events with niraparib were anemia (50%, grade [G]3 11%), thrombocytopenia (37%, G3-4 16%), neutropenia (21%, G3 5%), fatigue (32%, G3 16%), constipation (32%, G3 3%), mucositis (13%, G3 3%), and nausea (13%, G3 3%). The main limitation of the study is the small sample size: in March 2021, approval of maintenance avelumab for the same setting rendered randomization of patients in the control arm to BSC alone unethical, and accrual was stopped prematurely.Addition of maintenance niraparib to BSC after first-line PBCT did not demonstrate a significant improvement in PFS in patients with UC. These results do not support the conduction of a phase 3 trial with single agent niraparib in this population.In this trial, we tested the efficacy of niraparib as maintenance treatment in patients affected by advanced urothelial cancer after the completion of first-line chemotherapy. We could not demonstrate a significant improvement in progression-free survival with maintenance niraparib.

Monoclonal antibodies targeting the checkpoint inhibitors (CPIs), programmed cell death protein-1 or programmed cell death ligand-1, are changing the landscape of urothelial carcinoma therapeutics. Overall, clinical studies in metastatic or advanced urothelial cancer showed that CPIs provided a slight improvement in survival and a relevant advantage in safety, compared with chemotherapy. After reviewing published and ongoing trials, the authors discuss expected answers to unmet needs, with a special attention to the research of biological markers for patients with urothelial cancer eligible for treatment with CPIs in this article.

Advanced, recurrent and metastatic endometrial cancer (EC) has a dismal prognosis due to poor response rates to conventional treatments. In the era of precision medicine, the improved understanding of cancer genetics and molecular biology has led to the development of targeted therapies, such as poly (ADP-ribose) polymerase (PARP) inhibitors. This class of drugs that inhibit PARP enzymes has been investigated in many different types of tumors and its use in the treatment of gynecological malignancies has rapidly increased over the past few years. Data from several clinical trials showed that PARP inhibitors have a beneficial role in cancers with a defect in the homologous DNA recombination system, regardless of the BRCA mutational status. Since EC frequently shows mutations in PTEN and TP53 genes, indirectly involved in the homologous DNA recombination pathway, several in vivo and in vitro studies investigated the efficacy of PARP inhibitors in EC, showing promising results. This review will discuss the use of PARP inhibitors in endometrial cancer, summarizing data from preclinical studies and providing an overview of the ongoing trials, with a special focus on the development of combined treatment strategies with PARP inhibitors and immune checkpoint inhibitors.

469 Background: In the phase 3 JAVELIN Bladder 100 trial (NCT02603432), avelumab (anti–PD-L1) 1LM plus best supportive care (BSC) in patients (pts) with la/mUC whose disease did not progress after 1L platinum-based chemotherapy (PBC) significantly extended overall survival (OS) vs BSC alone, and it is now recommended internationally as standard of care with level 1 evidence. We report real-world descriptive pt characteristics and outcomes data from a large, multicenter, Italian compassionate use program (CUP) assessing avelumab 1LM in pts with la/mUC. Methods: This prospective, noninterventional CUP was initiated on Jan 18, 2021, to provide early access to avelumab before reimbursement by the Italian Medicines Agency for pts with la/mUC. Avelumab was provided upon physician request and after approval by local ethics committees in accordance with the Italian compassionate use regulation. Avelumab 800 mg IV was administered every 2 weeks per local prescribing information to adult pts aged ≥18 years with la/mUC who were progression-free following PBC (4-6 cycles, starting 4-10 weeks after last dose of PBC). Pts who had a relapse within 12 months of prior adjuvant or neoadjuvant systemic therapy, including immune checkpoint inhibitors, were not eligible. Results: As of Aug 16, 2022, 464 pts (78.4% male, 21.6% female) were included from 140 Italian centers from Jan 2021-Mar 2022. Median age at inclusion was 70 years (IQR, 63-76 years). At the start of 1L PBC, 346 pts (73.9%) had metastatic disease and 40 (8.6%) had unresectable locally advanced disease (disease stage not defined [N/D] in 78 pts [16.8%]). ECOG PS was 0 in 321 pts (69.2%), 1 in 140 (30.2%), and N/D in 3 (0.7%). Primary tumor site was upper tract in 148 pts (31.9%) and lower tract in 309 (66.6%) (N/D in 7 [1.5%]). 1L PBC comprised carboplatin + gemcitabine in 241 pts (51.9%), cisplatin + gemcitabine in 214 (46.1%), and other PBC in 9 (1.9%); 225 pts (48.5%) received 4 cycles of PBC, 54 (11.6%) received 5 cycles, and 177 (38.2%) received 6 cycles (other or N/D in 8 [1.7%]). Complete response to 1L PBC was achieved in 51 pts (11.0%), partial response in 266 (57.3%), and stable disease in 147 (31.7%). For 391 pts currently evaluable for OS and progression-free survival (PFS) from the start of avelumab, the 12-month OS rate was 69.1% (95% CI, 64.4%-73.6%), while median OS was not reached. The 12-month PFS rate was 38.9% (95% CI, 34.0%-43.7%) and median PFS was 6.6 months (95% CI, 5.6-8.9 months). Grade 3-4 adverse events occurred in 33 pts (7.1%). Conclusions: This CUP included a large pt population representative of daily clinical practice in 140 Italian oncology centers and the results are consistent with those of previous studies. Overall, these real-world data strengthen the findings of JAVELIN Bladder 100 and provide further support for avelumab 1LM as a standard of care in eligible pts with la/mUC.

Oligometastatic prostate cancer is an intermediate state between localized disease and widespread metastasis. Its biological and clinical peculiarities are still to be elucidated. New imaging techniques contribute to the detection of patients with oligometastatic disease. PET/CT scanning with prostate-specific membrane antigen can improve the selection of men with true early, low-volume oligometastatic disease, who are candidates for metastasis-directed therapy. Clinical studies demonstrated that androgen deprivation therapy can be delayed in oligometastatic patients with a low tumor burden, although no survival benefit has been demonstrated at present. This article presents available evidence on the treatment strategies for oligometastatic prostate cancer.

In a recent phase 3 randomized trial of 700 patients with advanced urothelial cancer (JAVELIN Bladder 100; NCT02603432), avelumab/best supportive care (BSC) significantly prolonged overall survival relative to BSC alone as maintenance therapy after first-line chemotherapy. Exploratory biomarker analyses were performed to identify biological pathways that might affect survival benefit. Tumor molecular profiling by immunohistochemistry, whole-exome sequencing and whole-transcriptome sequencing revealed that avelumab survival benefit was positively associated with PD-L1 expression by tumor cells, tumor mutational burden, APOBEC mutation signatures, expression of genes underlying innate and adaptive immune activity and the number of alleles encoding high-affinity variants of activating Fc gamma receptors. Pathways connected to tissue growth and angiogenesis might have been associated with reduced survival benefit. Individual biomarkers did not comprehensively identify patients who could benefit from therapy; however, multi-parameter models incorporating genomic alteration, immune responses and tumor growth showed promising predictive utility. These results characterize the complex biologic pathways underlying survival benefit from immune checkpoint inhibition in advanced urothelial cancer and suggest that multiple biomarkers might be needed to identify patients who would benefit from treatment.

Background: Survival outcomes are poor for patients with metastatic urothelial carcinoma who receive standard, first-line, platinum-based chemotherapy. We assessed the overall survival of patients who received durvalumab (a PD-L1 inhibitor), with or without tremelimumab (a CTLA-4 inhibitor), as a first-line treatment for metastatic urothelial carcinoma.Methods: DANUBE is an open-label, randomised, controlled, phase 3 trial in patients with untreated, unresectable, locally advanced or metastatic urothelial carcinoma, conducted at 224 academic research centres, hospitals, and oncology clinics in 23 countries. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1. We randomly assigned patients (1:1:1) to receive durvalumab monotherapy (1500 mg) administered intravenously every 4 weeks; durvalumab (1500 mg) plus tremelimumab (75 mg) administered intravenously every 4 weeks for up to four doses, followed by durvalumab maintenance (1500 mg) every 4 weeks; or standard-of-care chemotherapy (gemcitabine plus cisplatin or gemcitabine plus carboplatin, depending on cisplatin eligibility) administered intravenously for up to six cycles. Randomisation was done through an interactive voice–web response system, with stratification by cisplatin eligibility, PD-L1 status, and presence or absence of liver metastases, lung metastases, or both. The coprimary endpoints were overall survival compared between the durvalumab monotherapy versus chemotherapy groups in the population of patients with high PD-L1 expression (the high PD-L1 population) and between the durvalumab plus tremelimumab versus chemotherapy groups in the intention-to-treat population (all randomly assigned patients). The study has completed enrolment and the final analysis of overall survival is reported. The trial is registered with ClinicalTrials.gov, NCT02516241, and the EU Clinical Trials Register, EudraCT number 2015-001633-24.Findings: Between Nov 24, 2015, and March 21, 2017, we randomly assigned 1032 patients to receive durvalumab (n=346), durvalumab plus tremelimumab (n=342), or chemotherapy (n=344). At data cutoff (Jan 27, 2020), median follow-up for survival was 41·2 months (IQR 37·9–43·2) for all patients. In the high PD-L1 population, median overall survival was 14·4 months (95% CI 10·4–17·3) in the durvalumab monotherapy group (n=209) versus 12·1 months (10·4–15·0) in the chemotherapy group (n=207; hazard ratio 0·89, 95% CI 0·71–1·11; p=0·30). In the intention-to-treat population, median overall survival was 15·1 months (13·1–18·0) in the durvalumab plus tremelimumab group versus 12·1 months (10·9–14·0) in the chemotherapy group (0·85, 95% CI 0·72–1·02; p=0·075). In the safety population, grade 3 or 4 treatment-related adverse events occurred in 47 (14%) of 345 patients in the durvalumab group, 93 (27%) of 340 patients in the durvalumab plus tremelimumab group, and in 188 (60%) of 313 patients in the chemotherapy group. The most common grade 3 or 4 treatment-related adverse event was increased lipase in the durvalumab group (seven [2%] of 345 patients) and in the durvalumab plus tremelimumab group (16 [5%] of 340 patients), and neutropenia in the chemotherapy group (66 [21%] of 313 patients). Serious treatment-related adverse events occurred in 30 (9%) of 345 patients in the durvalumab group, 78 (23%) of 340 patients in the durvalumab plus tremelimumab group, and 50 (16%) of 313 patients in the chemotherapy group. Deaths due to study drug toxicity were reported in two (1%) patients in the durvalumab group (acute hepatic failure and hepatitis), two (1%) patients in the durvalumab plus tremelimumab group (septic shock and pneumonitis), and one (Interpretation: This study did not meet either of its coprimary endpoints. Further research to identify the patients with previously untreated metastatic urothelial carcinoma who benefit from treatment with immune checkpoint inhibitors, either alone or in combination regimens, is warranted.Funding: AstraZeneca.

BackgroundChemotherapy with carboplatin, paclitaxel, and bevacizumab is the standard therapy for patients with advanced stage ovarian cancer wild-type BRCA after primary surgery. The most frequent side effects of bevacizumab in this setting are hypertension, thrombosis, hemorrhage, and proteinuria, while arthralgia has been poorly described.ObjectiveTo examine the incidence, duration, and reversibility of arthralgia.Patients and methodsA retrospective analysis was performed to describe the occurrence and outcome of arthralgia in 114 patients with advanced ovarian cancer, given first-line treatment with a combination of carboplatin, paclitaxel, and bevacizumab. Statistical analysis was performed to investigate a possible prognostic role of arthralgia, with progression-free survival as endpoint.Results47 of 114 patients (41%) developed arthralgia during therapy. All patients had grade 1 or grade 2 arthralgia. Toxicity persisted after the end of bevacizumab in 17/47 patients (36%). Median progression-free survival for patients without arthralgia was 18 months (95% CI 14 to 24) compared with 29 months (95% CI 21 to not reached) for patients experiencing arthralgia (p=0.03). In order to avoid possible biases related to treatment duration, a multivariable Cox proportional hazards model including toxicity as a time dependent variable and age, stage, and residual disease after primary surgery was performed. In this model no variable showed a statistically significant association with progression-free survival.ConclusionA high incidence of arthralgia (41%) was found and although rogression-free survival was worse for those patients who developed arthralgia, this was not maintained on multivariate analysis. Guidelines for treatment of this adverse event are needed.

The majority of patients with advanced ovarian cancer progress after first-line therapy and require further treatment. Tumor biology, prior chemotherapy, responses to previous therapy, performance status, and toxicity are the characteristics that influence treatment choice. These criteria have been linked to the time between relapse and last platinum therapy: the platinum-free interval. Today, patients are classified as either those who are eligible for a new platinum-based therapy or those for whom platinum is not an option. A nonplatinum regimen should be administered to patients who are not candidates for platinum re-treatment. This group includes patients with early relapse after, or progression during, previous platinum-based chemotherapy and patients with platinum intolerability. A single agent such as weekly paclitaxel, pegylated liposomal doxorubicin (PLD), gemcitabine, or topotecan represents the standard. For patients not treated with bevacizumab in the first line, this drug should be added to chemotherapy. For patients for whom platinum rechallenge is an option (because they are potentially platinum-responsive), different strategies are available with the incorporation of biological drugs targeting angiogenesis or the mechanisms of DNA repair. A BRCA mutation status predicts a better response to platinum and poly(adenosine diphosphate-ribose) polymerase (PARP) inhibition. PARP inhibitors and antiangiogenic drugs have proven efficacy as maintenance therapy after chemotherapy and concurrently with chemotherapy, respectively. These agents have changed current practice, although few biomarkers are available to guide decisions. Patients potentially responsive to platinum who cannot receive the drug again can be treated with a combination of trabectedin and PLD, the most active nonplatinum therapy in this setting.

e16013 Background: Several ICI are now approved in different therapeutic settings of metastatic UC. The identification of the optimal therapeutic sequence that includes standard chemotherapy (CT) use is a key objective of further research, mainly in the first-line (1L) setting. In this study, we analyzed the pathways of treatment post-ICI and focused on the effects of CT post-ICI in both 1L and salvage-line (≥2L) therapy of metastatic UC. Methods: Data from 15 Italian centers were collected. Patients (pts) should have received ICI in any line of treatment for metastatic UC and have experienced a disease progression (PD) according to RECIST 1.1. Cox regression analyses were performed within the subgroups, and adjusted Kaplan-Meier curves analyzed the progression-free survival (PFS) and overall survival (OS) post-ICI PD, according to the treatment line. Results: 278 pts (79 in 1L; 199 ≥2L) were analyzed. In total, after ICI, pts were treated with CT (N = 69), ICI beyond PD (N = 20) or no treatment (N = 189). Features associated with no therapy post-ICI were rapid PD on ICI (p < 0.001) and number of metastatic sites (p = 0.002). The objective response (OR) to CT post-ICI was 23.1% in 1L, and 18.5% in ≥2L. Median PFS was 5 months (m) in 1L and 3m ≥2L, median OS on CT was 13m in 1L and 9m ≥2L. Post-ICI CT was not significantly associated with improved OS in 1L on multivariable analyses (MVA): HR: 0.43 (95%CI: 0.15-1.23), but it was significant in MVA in ≥2L pts (HR: 0.22, 95%CI: 0.10-0.48). The type of previous ICI (combination-ICI vs single-agent ICI, p = 0.789), as well as the OR to previous ICI (p = 0.871) had no effect on OS with sequential CT on MVA. In the total population adjusted by line, median OS post-CT was 17m (range 15-NA), and with ICI beyond PD was 8m (6-NA) (p < 0.001). Conclusions: This large multicentric appraisal indicated that CT post-salvage ICI is endowed with similar activity and efficacy compared to ICI-naïve pts. Conversely, CT administered post-ICI in 1L determined less responses and was not significant on MVA. These effects are likely determined by the inability to rescue pts with rapidly aggressive disease. Shifting to salvage CT at the time of PD on ICI remains the preferable option in all suitable pts.

488 Background: UTUC is rarer than bladder UC and typically responds poorly to standard chemotherapy. Analysis of 220 biomarker-evaluable atezo-treated patients (pts) in phase II/III trials suggested worse outcomes in UT vs lower tract UC [Galsky, ESMO 2018]. We explored clinical outcomes in pts with UTUC (renal pelvis or ureter) treated with atezo in the SAUL study. Methods: The single-arm SAUL study (NCT02928406) [Sternberg, Eur Urol 2019] enrolled a broader pt population, including pts with poor clinical characteristics and/or immune-mediated conditions, more representative of real-world practice than typically enrolled in randomized phase III immunotherapy trials. Pts with urinary tract carcinoma received atezo 1200 mg q3w until disease progression/unacceptable toxicity. Baseline characteristics, safety and efficacy were analyzed in subgroups of pts with UTUC (subdivided into renal pelvis or ureter UC) vs bladder UC. Results: Baseline characteristics in the 4 subgroups were generally similar, except for a numerically lower proportion of pts with 0 prior lines of therapy for metastatic disease in the UTUC vs bladder UC subgroup (30% vs 41%). Treatment exposure, safety and efficacy are shown below. Conclusions: These exploratory analyses of SAUL showed very similar efficacy and safety in UT vs bladder UC. This provides reassurance that atezo is active and has an acceptable safety profile in pts with UTUC, who are generally expected to have worse outcomes than bladder UC pts. Clinical trial information: NCT02928406 . [Table: see text]

Objective: The aim of this study was to analyze the long-term toxicity and quality of life (QOL) in patients with locally advanced cervical cancer (LACC) treated with chemoradiation [chemotherapy/radiotherapy (CT/RT)] or neoadjuvant CT (NACT) followed by radical surgery (RS). Methods: Fifty-nine patients with LACC in remission after treatment with NACT + RS (n = 34) or CT/RT (n = 25) were interviewed with an Incontinence Impact Questionnaire (IIQ-7), a Quality of Life Questionnaire (EORTC QLQ-C30), and a Quality of Life Questionnaire for Cervical Cancer (EORTC QLQ-CX24) to compare long-term toxicity and QOL. Results: The mean age was 53 ± 9.8 and 59 ± 11.5 years in the NACT + RS and CT/RT groups, respectively. Overall, diarrhea and constipation were reported in 15 and 68%, respectively, while bladder complaints and a low level of sexual enjoyment were reported in 36 and 47%, respectively. The NACT + RS patients showed a worse sexual activity (74.71 ± 33.57 vs. 92.06 ± 17.96; p = 0.019) and sexual enjoyment (71.21 ± 23.67 vs. 88.88 ± 21.71; p = 0.040) and more frequently complained of constipation (49.01 ± 34.06 vs. 26.66 ± 31.66; p = 0.013), while CT/RT patients more frequently suffered from diarrhea (1.96 ± 7.96 vs. 14.66 ± 28.40; p = 0.017). Conclusions: Many patients treated for LACC have long-term complaints regarding sexual activity and bladder and bowel function. The majority of QOL aspects were similar in the two groups at long-term follow-up. However, diarrhea was more frequent and severe in CT/RT patients, while constipation was more frequent and severe in NACT + RS patients, and they showed a worse sexual life perception. Larger randomized trials addressing these issues are needed.

Ovarian cancer remains a major issue for gynecological oncologists, and most patients are diagnosed when the disease is already advanced with a poor chance of survival. Debulking surgery followed by platinum-taxane chemotherapy is the current standard of care, but based on several different strategies currently under evaluation, some encouraging data have been published in the last 4 to 5 years. This review provides a state-of-the-art overview of the available alternatives to conventional treatment and the most promising new combinations. For example, neoadjuvant chemotherapy does not seem to be inferior to primary debulking. Despite its outcome improvements, intraperitoneal chemotherapy struggles for acceptance due to the heavy toxicity. Dose-dense chemotherapy, after showing an impressive efficacy in Asian populations, has not produced equal results in a European cohort, and the results of alternative platinum doublets are not superior to those of carboplatin and paclitaxel. In this setting, adherence to a maintenance therapy after first-line treatment and multiple (primarily antiangiogenic) agents appears to be effective. Although many questions, including the duration of maintenance treatment and the use of bevacizumab beyond progression, remain unanswered, new biologic agents, such as poly(ADP-ribose) polymerase (PARP) inhibitors, nintedanib, and mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitors, have emerged as potential therapeutic options in the very near future. Based on the multiplicity of available strategies, the histological and molecular features of the tumor, in addition to patient’s clinical condition and disease state, continue to gain importance in guiding treatment choices.

The tumors of the female genital tract represent a leading cause of morbidity and mortality among women worldwide. Substantial progresses have been made in ovarian cancer, with the increasing knowledge about BRCA mutated tumors and the recent development of PARP inhibitors, and in cervical cancer, thanks to extensive screening and widespread of vaccination against Human Papilloma Virus. Nevertheless many needs remain unmet, advanced stage diseases are still incurable and cervical and endometrial carcinoma, as well as platinum-resistant ovarian carcinoma, can certainly be classifiable among the cancers with poor sensitivity to conventional chemotherapy. Immunotherapy, including a number of approaches, checkpoint inhibitors, adoptive cellular transfer, vaccines, has experienced a remarkable growth in the last few years and it is already an available option in melanoma, lung and renal malignancies. We reviewed the main findings about the immune microenvironment in ovarian, endometrial and cervical cancer with a special focus on the clinical data, the therapeutic implications and the most promising novel agents.

Objectives: The incidence of noncancer pain (NCP) in cancer patients is unknown. An analysis of incidence, severity, impact on quality of life (QoL), and appropriateness of NCP treatment in a cohort of cancer patients referred to a radiotherapy center is reported. Materials and Methods: Pain was scored from 0 (absence) to 3 (severe) and the adequacy of analgesic therapy was evaluated according to International Guidelines. Correlation between Pain Management Index and World Health Organization Analgesic Ladder was used to analyze the appropriateness of NCP treatment. In addition, pain was differentiated according to its origin and types and a comparison was performed between cancer pain (CP) and NCP. Results: A total of 903 patients were eligible and 865 (95.8%) were considered evaluable. Three hundred ninety-eight patients (46.0%) had pain. CP and NCP pain incidence was 11.2% and 34.8%, respectively. Pain intensity was higher in patients with CP versus NCP (P = 0.021). A neuropathic pain lower incidence (P = 0.024) in NCP versus CP was recorded. Moreover, NCP was more inadequately treated than CP (P < 0.001). QoL was significantly lower in patients with NCP when compared with patients without pain (P < 0.001). In addition, QoL of patients with CP was significantly lower than QoL of patients with NCP (P < 0.001). Discussion: In a cancer patients’ population referred to a radiotherapy center, the NCP incidence was higher than the CP incidence and NCP intensity was only slightly lower than CP. NCP was significantly pharmacologically undertreated and it was related to a decline in QoL.

Endometrial cancer is a highly curable malignancy when it presents as uterine-confined disease, but the prognosis for metastatic or recurrent endometrial cancer is poor. For those patients which are diagnosed at an early stage, surgery alone may be adequate for cure and clinical outcome is often favorable, with approximately 80 % of cases surviving at 5 years. However, after primary diagnosis and treatment, roughly 20-30% of patients are expected to recur within the following 5 years. Adjuvant treatment for endometrial cancer is not yet clearly defined. FIGO Stage I-III endometrial cancer patients, usually undergo surgery and some of them are offered adjuvant treatment based on risk assessment. Grade, age, stage are considered all independent risk factors for recurrence. Radiotherapy (RT) has been considered the adjuvant treatment of choice for decades, being able to reduce local recurrence rate and improving progression free survival, but without any impact on overall survival. In the last two decades, a shift toward the use of systemic chemotherapy (CT) in addition or instead of radiation has occurred, although few prospective studies have been performed in this field.

Among the pharmaceutical options available for treatment of ovarian cancer, increasing attention has been progressively focused on pegylated liposomal doxorubicin (PLD), whose unique formulation prolongs the persistence of the drug in the circulation and potentiates intratumor accumulation. Pegylated liposomal doxorubicin (PLD) has become a major component in the routine management of epithelial ovarian cancer. In 1999 it was first approved for platinum-refractory ovarian cancer and then received full approval for platinum-sensitive recurrent disease in 2005. PLD remains an important therapeutic tool in the management of recurrent ovarian cancer in 2012. Recent interest in PLD/carboplatin combination therapy has been the object of phase III trials in platinum-sensitive and chemonaïve ovarian cancer patients reporting response rates, progressive-free survival, and overall survival similar to other platinum-based combinations, but with a more favorable toxicity profile and convenient dosing schedule. This paper summarizes data clarifying the role of pegylated liposomal doxorubicin (PLD) in ovarian cancer, as well as researches focusing on adding novel targeted drugs to this cytotoxic agent.

Objective Hypersensitivity reactions (HSR) are frequently reported in patients rechallenged with carboplatin for recurrent ovarian cancer (ROC) and represent a critical issue, since discontinuation of the platinum-based therapy could affect prognosis. Several strategies to allow platinum rechallenge have been described, with controversial outcomes. The aim of this study is to illustrate a 10-year experience with cisplatin in patients with a previous HSR to carboplatin or at risk for allergy. Methods A retrospective review of all patients with platinum sensitive ROC retreated with carboplatin was performed between January 2007 and May 2016 at the Istituto Nazionale Tumori, Fondazione "G. Pascale", Naples. Results Among 183 patients, 49 (26.8%) presented HSR to carboplatin, mainly during second line therapy. Mean number of cycles before HSR was 8 (range 3–17). G2, G3 and G4 reaction were detected in 83%, 15% and 2% of patients, respectively. In a multivariate analysis including age, hystotype, BRCA status, previous known HSR, and combination drug administered, only the type of carboplatin-based doublet used as 2nd line therapy was found to significantly affect HSR development, with a protective effect of PLD (pegylated liposomal doxorubicin) (p = 0.014, OR=0.027). Thirty seven patients (77%) with a previous HSR to carboplatin were rechallenged with cisplatin. Treatment was generally well tolerated. 5 patients (13.1%) experienced mild HSR to cisplatin, successfully managed in all cases. 14 patients were treated with cisplatin even without a carboplatin-related HSR due to other allergies. Among these, only one developed HSR (7.1%). Conclusions Cisplatin rechallenge is a feasible approach in patients experiencing HSR to carboplatin to maintain the beneficial effect of platinum while reducing hypersensitivity-related risks.

Ovarian cancer (OC) is the leading cause of mortality among patients with gynecologic malignancies (Boyle 1992). More than half of all OC occurs in women older than 65 (Jemal A, Murray T, Samuels A, Ghafoor A, Ward E, Thun MJ. Cancer statistics, 2003. CA Cancer J Clin. 2003;53:5–26; Mcgonigle KF, Lagasse LD, Karlan BY. Ovarian, uterine, and cervical cancer in the elderly woman. Clin Geriatr Med. 1993;9:115–30). The vast majority of women with ovarian cancer present with advanced stages, and curative treatment requires both aggressive surgery and chemotherapy. This approach has resulted in an improvement of the survival rates in the general population over the last decades with a median survival exceeding 50 months in most published series; the improvement is not present in the elderly population (Bristow RE, Tomacruz RS, Armstrong DK, Trimble EL, Montz FJ. Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis. J Clin Oncol. 2002;20: 1248–59; Chi DS, Eisenhauer EL, Zivanovic O, et al. Improved progression-free and overall survival in advanced ovarian cancer as a result of a change in surgical paradigm. Gynecol Oncol. 2009;114:26–31).

Elderly patients constitute a subpopulation with special characteristics that differ from those of the general population and have been under-represented in clinical trials. We, prospectively, analyzed the toxicity and efficacy of the original FOLFOX4-regimen in the treatment of elderly patients affected by metastatic (m) colorectal cancer (CRC). Thirty-six consecutive patients aged 67–82 years (median age 72 years), 22 males and 14 females, with mCRC and measurable disease, were enrolled in the study. The primary site of metastases was the liver (36.1% of patients). The median ECOG Performance Status (PS) was 1. The main hematological and extra-hematological (grade 3 or 4) toxicities were neutropenia (38.9%) and neurological (13.9%), respectively. A total of 36 patients, aged 67–82 years were included. Twenty-two and 14 patients were male and female, respectively. The median age was 72 years (range 67–82). The primary site of metastases was the liver (36.1% of patients). The median ECOG Performance Status (PS) was 1. The overall response rate (ORR) was 44.4% and similar to original study. Median progression-free survival (PFS) was 7.5 months and median overall survival (OS) was 16 months. The main hematological and extra-hematological (grade 3 or 4) toxicities were neutropenia (38.9%) and neurological (13.9%), respectively. Tolerability, however, was manageable and no toxic death occurred. FOLFOX4-regimen maintains its efficacy, and safety ratio in elderly patients with mCRC and good performance status. It would be considered the treatment of choice in the treatment of this particular setting of patients.

The objective of this study was to evaluate the safety of escalating up to 55 Gy within five weeks, the dose of external beam radiotherapy to the previous tumor site concurrently with a fixed daily dose of capecitabine, in patients with resected pancreatic cancer. MATERIAL AND METHODS: Patients with resected pancreatic carcinoma were eligible for this study. Capecitabine was administered at a daily dose of 1600 mg/m (2). Regional lymph nodes received a total radiation dose of 45 Gy with 1.8 Gy per fractions. The starting radiation dose to the tumor bed was 50.0 Gy (2.0 Gy/fraction, 25 fractions). Escalation was achieved up to a total dose of 55.0 Gy by increasing the fraction size by 0.2 Gy (2.2 Gy/fraction), while keeping the duration of radiotherapy to five weeks (25 fractions). A concomitant boost technique was used. Dose limiting toxicity (DLT) was defined as any grade>3 hematologic toxicity, grade>2 liver, renal, neurologic, gastrointestinal, or skin toxicity, by RTOG criteria, or any toxicity producing prolonged (> 10 days) radiotherapy interruption. RESULTS AND DISCUSSION: Twelve patients entered the study (median age: 64 years). In the first cohort (six patients), no patient experienced DLT. Similarly in the second cohort, no DLT occurred. All 12 patients completed the planned regimen of therapy. Nine patients experienced grade 1-2 nausea and/or vomiting. Grade 2 hematological toxicity occurred in four patients. The results of our study indicate that a total radiation dose up to 55.0 Gy/5 weeks can be safely administered to the tumor bed, concurrently with capecitabine (1600 mg/m (2)) in patients with resected pancreatic carcinoma.

Background The Metabolic syndrome (MetS) is an emerging condition worldwide, consistently associated with an increased risk of several cancers. Some information exists on urothelial carcinoma of the bladder (UCB) and MetS. This study aims at further evaluating the association between the MetS and UCB. Methods Between 2003 and 2014 in Italy, we conducted a hospital-based case-control study, enrolling 690 incident UCB patients and 665 cancer-free matched patients. The MetS was defined as the presence of at least three of the four selected indicators: abdominal obesity, hypercholesterolemia, hypertension, and diabetes. Odds ratios (ORs) and corresponding 95 % confidence intervals (CIs) for MetS and its components were estimated through multiple logistic regression models, adjusting for potential confounders. Results Patients with MetS were at a 2-fold higher risk of UCB (95 % CI:1.38–3.19), compared to those without the MetS. In particular, ORs for bladder cancer were 2.20 (95 % CI:1.42–3.38) for diabetes, 0.88 (95 % CI: 0.66-1.17) for hypertension, 1.16 (95 % CI: 0.80-1.67) for hypercholesterolemia, and 1.63 (95 % CI:1.22–2.19) for abdominal obesity. No heterogeneity in risks emerged across strata of sex, age, education, geographical area, and smoking habits. Overall, 8.1 % (95 % CI: 3.9-12.4 %) of UCB cases were attributable to the MetS. Conclusions This study supports a positive association between the MetS and bladder cancer risk.

Several biosimilar versions of recombinant human erythropoietin are currently approved for use in Europe, including a biosimilar epoetin-alpha. The aim of this the study was to verify that biosimilar epoetin-alpha is similar in terms of efficacy, safety and cost to originator epoetin-alpha for the treatment of refractory anemia in patients with myelodysplastic syndrome. A total of 92 patients with myelodysplasia and refractory anemia were investigated. The patients received either originator (group A) or biosimilar (group B) epoetin-alpha. In addition, they received liposomal iron (Sideral (R)), calcium levofolinate and vitamin B12. Moreover, the median monthly overall costs were calculated for each group. The results demonstrated that hemoglobin (Hb) levels increased by 1 g/dl after a median time of 5 weeks in group A and 4 weeks in group B. In group A, a Hb level of >12 g/dl was achieved after 12 weeks, while in group B after 10.5 weeks. The median cost of therapy was 1,536 euros/month in group A and 1,354 euros/month in group B. A total of 5 patients required transfusion support in group A and 7 in group B. In conclusion, biosimilar epoetin-alpha appears to be comparable to originator epoetin-alpha in terms of efficacy and safety for the treatment of refractory anemia

Objectives: To assess the effectiveness of a SHort-course Accelerated RadiatiON therapy (SHARON) in the treatment of patients with multiple brain metastases. Materials and Methods: A phase II clinical trial was designed. Eligibility criteria included patients with at least 3 brain metastases or metastatic disease in >3 organ systems, and Eastern Cooperative Oncology Group performance status of ≤3. Fifty patients were treated with whole brain radiotherapy at 18 Gy (4.5 Gy per fraction) in 2 days with a twice daily fractionation. The primary endpoint was the assessment of efficacy in terms of overall survival. Results: Characteristics of the 50 enrolled patients were: male/female: 24/26; median age: 65 years (range, 45 to 80 y). Eastern Cooperative Oncology Group performance status was

Background: Sabarubicin (MEN-10755) is a third generation anthracycline, with a remarkable antitumor activity in human tumor xenografts, including doxorubicin-resistant tumors. Phase I studies have shown that myelosuppression is the main toxicity of sabarubicin, while its cumulative cardiotoxicity is mild. Methods: The aim of the study was to evaluate the activity and safety profile of sabarubicin in patients with locally advanced or metastatic ovarian cancer failing 1st line platinum and/or taxane based chemotherapy, and relapsing earlier than 6 months after the last chemotherapy. Eligible patients received sabarubicin at the dose of 80 mg/m2 (dose level 0) every 3 weeks over 30 minutes. Dose was to be escalated to 90 mg/m2 (dose level +1) after the 1st cycle in case of grade 0-1 toxicity, while it was to be reduced to 60 mg/m2 (dose level −1) in case of toxicity. Response was assessed every 2 courses according to WHO criteria. Toxicity was graded according to Common Toxicity Criteria version 2.0. Gehan's design was used for sample size determination. Results: Nineteen patients were enrolled and received 65 courses. One patient had a confirmed partial response, 9 patients had stable disease, 5 patients had disease progression, 3 patients were not evaluable for response, while one patient had an early progressive disease. The duration of response was 88 days. Mean time to disease progression was 125 days (range 56–188). Median survival was 62 days (range 36–202). Hematologic toxicity was moderate, since grade 3–4 neutropenia was observed in 25 out of 52 courses at 80 mg/m2, and grade 4 neutropenia occurred in one out of 12 courses at 90 mg/m2. Other grade 3–4 toxicities were: fatigue (five cases), nausea (two cases), stomatitis, general health deterioration, anorexia, vomiting, abdominal pain, hyponatremia (one case each). Cardiac toxicity was observed in the study; in fact, left ventricular ejection fraction (LVEF) fell below 50% in 2 patients, and 3 patients had a >15% decrease of LVEF from baseline, but there were no signs/symptoms of congestive heart failure. Conclusions: Sabarubicin showed limited activity in patients with resistant ovarian cancer. However, the observed data on disease stabilization, together with the drug's overall manageable toxicity profile, may prompt to its further investigation in advanced ovarian cancer.

Background The aim of this study was to determine the maximum tolerated dose (MTD) of liposomal doxorubicin (LD)–vinorelbine (V) in patients with refractory or resistant ovarian cancer. Patients and methods Thirty patients were eligible. Seven levels were studied [LD 25–V20 (three patients enrolled); LD 30–V20 (three); LD 35–V20 (three); LD 20–V25 (three); LD 25–V25 (three); LD 30–V25 (10); LD 35–V25 (five)]. LD was given on day 1, while V was given on days 1 and 8 every 21 days. Cohorts of three patients were enrolled at each level, and another three patients were planned, if one dose-limiting toxicity (DLT) was registered. Results DLT was observed in four patients: two febrile neutropenia, one grade 4 thrombocytopenia and one grade 3 palmar-plantar erythrodysesthesia (PPE) at level 7 (LD 35–V25). Thus, liposomal doxorubicin 30 mg/m2 plus vinorelbine 25 mg/m2 was the MTD. The most frequent toxicity was neutropenia. Fifteen patients (50%) experienced grade 3 neutropenia and 10 (33.3%) grade 4 neutropenia. Non-hematological toxicity was mild. Mucositis and PPE were the most frequent toxicities, but in most cases were grade 1. Out of 29 assessable patients, six (20.7%; 95% confidence interval 10%–39%) experienced an objective response, with one complete response. Conclusions In patients with refractory or resistant ovarian cancer, the recommended doses for the combination studied are liposomal doxorubicin 30 mg/m2 (day 1) plus vinorelbine 25 mg/m2 (day 1 and 8). Neutropenia is the most frequent toxicity, while non-hematological toxicity is mild. Substantial activity was recorded and a phase II study is justified.

Background Biosimilar drugs have a similar, but usually not inferior although not hidentical effects of old registred drugs. Safety is hidentical to old registred drug. Aims Aim of this study is to verify if in MDS patient with refractory anemia biosimilar erythropoietin alpha is not inferior to erythropoietin alpha in terms of safety, efficacy and costs. Methods This study is a dicentric, nonrandomized, retrospective study. Between july 2008 and june 2012, 92 patients affected by refractory anemia were studied. Median follow-up was 22 months (R3-34). Patients received in group A erythropoietin alpha 40000 IU sc/weekly. In group B patient received biosimilar erythropoietin alpha 40000 IU sc/weekly. In both groups patients received liposomal iron (Sideral®) 14 mg, 2 tablets orally/day calcium levofolinate 7.5 mg/day orally + Vitamin B12: 400 mg/day orally. In group A median age was 70 years (R63-75), M/F: 18/28; in group B median age was 64 years (R60-70), M/F: 25/21. IPSS was low in 30 patients and int-1 in 13 patients in group A, and low in 32 patients and int-1 in 11 patients, in group B. Patients with 5q- were excluded from this study. Median level of haemoglobin was 8.5 g/dl in group A (R8-11) and 9.2 g/dl (R8.5-11.5) in group B. Results Group A patients increased Hb level of 1 g/dl after a median time of 5 weeks (R4-9) and after a median time of 4 weeks (R3-8) in group B. No relevant side effects were observed in both groups. Erythropoietin alpha was reduced in group A because Hb achieved a level > 12g/dl after a median of 12 weeks (R 4-18). Biosimilar erythropoietin alpha was reduced in group B because Hb achieved a level > 12g/dl after a median of 10.5 weeks (R 3-16). In group A maintenance dose was administered with a median of every two weeks (2-4), In group B maintenance dose was administered with a median of every three weeks (2-5). Median cost for every month of erythropoietic therapy was 1536 euros/month (R1240-1850) in group A and 1354 euros/month (R954-1550) in group B. Five patients need transfusion support in group A and seven patients need transfusion support in group B Summary/conclusion Biosimilar erythropoietin alpha plus liposomal iron (Sideral®) and B12 and folates support seems to be safe, feasible, probably equally cost-effective and substantially not inferior to classical erythropoietin alpha support in patients affected by refractory anemia. This study needs confifrmation on a larger cohort of patients. Disclosures No relevant conflicts of interest to declare.

Background Biosimilar drugs, including erythropoirtin zed, have a similar, but usually not inferior although not hidentical effects of originator drugs. Safety is hidentical to originator drugs. Aims Aim of this study is to verify if in MDS patient with refractory anemia biosimilar erythropoietin alpha and erythropoietin zed, are not inferior to erythropoietin alpha in terms of safety, efficacy and costs. Methods This study is a retrospective study.Between july 2008 and december 2013, 101 patients affected by refractory anemia were studied.Median follow-up was 16 months (R10-28). Patients received in group A erythropoietin alpha 40000 IU sc/weekly. In group B patient received biosimilar erythropoietin alpha 40000 IU sc/weekly. In group C patient received biosimilar erythropoietin zed 40000 IU sc/weekly. In all three arms patients received liposomial iron (Sideral®) 14 mg 2 tablets orally/day calcium levofolinate 7.5 mg/day orally + Vitamin B12: 400 mg/day orally. In group A median age was 70 years (R63-73), M/F: 15/28. In group B median age was 64 years (R60-70), M/F: 24/19. In group C median age was 68 years (R62-73), M/F: 10/5.IPSS was low in 30 patients and int-1 in 12 patients, karyotype showed –Y in two patient, del 20q in one patient, trisomy 8 in two patients in group A. IPSS was low in 32 patients and int-1 in 10 patients, karyotype showed –Y in one patients, del 20q in one patient in group B.IPSS was low in 11 patients and int-1 in 4 patients, karyotype was normal in 9 patients and not evaluable in 6 patients. Patients with 5q- were excluded from this study. Median level of haemoglobin was 9 g/dl in group A (R8-11), 8.7 g/dl (R8.5-10.5) in group B and 8.5 in group C. Cost of every month of erythropoietinic therapy was calculed dividing for each patient the sum of complete erythropoietic therapy for each month of follow-up, then in each group of patients median cost of erythropoietic therapy was calculed. Results Group A patients increased Hb level of 1 g/dl after a median time of 5 weeks (R4-9), after a median time of 3.5 weeks (R3-8) in group B and after a memedian time of 4 weeks in group C. No relevant side effects were observed in all three groups groups. Erythropoietin alpha was reduced in group A because Hb achieved a level > 12g/dl after a median of 12 weeks (R 4-18).Biosimilar erythropoietin alpha was reduced in group B because Hb achieved a level > 12g/dl after a median of 10 weeks (R 3-16). Erythropoietin zed was reduced in group C because Hb achieved a level > 12g/dl after a median of 9.5 weeks (R 3-15). In group A maintenance dose was administered with a median of every two weeks (2-4), in group B maintenance dose was administered with a median of every three weeks (2-5), in group C maintenance dose was administered with a median of every three weeks (2-4). Median cost for every month of erythropoietic therapy was 1536 euros/month (R1240-1850) in group A, 1354 euros/month (R954-1550) in group B, 1300 euros/month (R1300-1380) in group C. Five patients need transfusion support in group A,6 patients need transfusion support in group B and 5 in group C. Summary/Conclusion Biosimilar erythropoietin alpha and erythropoietin zed plus liposomial iron (Sideral®) and B12 and folates support seems to be safe, feasible, probably equally cost-effective and substantially not inferior to classical erythropoietin alpha support in patients affected by refractory anemia. This study needs confifrmation on a larger cohort of patients. Disclosures No relevant conflicts of interest to declare.

The aim of the current study was to compare Levovist-enhanced power Doppler (PD) imaging with contrast-enhanced spiral computed tomography (CT) in the evaluation of intratumoral vascularity of hepatocellular carcinomas at diagnosis and after percutaneous ethanol injection (PEI). Nineteen patients with hepatocellular carcinoma (HCC) underwent PD with and without Levovist and spiral CT at diagnosis and 1 month after PEI treatment. Compared to spiral CT at baseline evaluation, the PD showed intratumoral vascularity in 36.8% of the cases; this percentage reached 78.9% after Levovist enhancement. One month after PEI, only 5 out of 19 treated HCCs appeared as hypodense areas at CT and showed no contrast enhancement. Only 3 of the 14 patients with a positive spiral CT scan were positive at the PD performed without the Levovist administration (sensitivity, 21.4%). The use of contrast-enhanced ultrasonography led to detection of residual signal in six other HCCs treated by ethanol injection (sensitivity, 64.2%). We confirm that spiral CT is the most sensitive and accurate technique in evaluating the effect of ethanol injection in HCC. It correctly identifies most cases of treatment failure as enhanced areas within the lesion. The lower rate of detection of tumoral vascularity by Doppler sonography was significantly increased by Levovist. The evidence of residual vascularity within HCC at Levovist Doppler sonography allows the targeting of additional ethanol injections.

Summary Background Cisplatin and paclitaxel are active in cervical cancer and both are able to potentiate the effects of radiotherapy. In this study we evaluated the maximum-tolerated dose (MTD) of paclitaxel in combination with a fixed dose of cisplatin when given weekly concurrently with pelvic radiotherapy to patients with carcinoma of the cervix uteri. Patients and methods Eighteen patients with cervical cancer were enrolled in this study. Cisplatin (30 mg/m2) and paclitaxel (starting dose 40 mg/m2; 5 mg/m2 escalation per level) were given on day 1 of radiotherapy and then weekly for six times. Radiotherapy was given to the pelvis with a four-field box technique for five days each week. Patients received 65 Gy in 1.8 Gy fractions. Cohorts of three patients were enrolled at each level and three further patients were included if one or two dose-limiting severe adverse events (SAE) were recorded. SAE was defined as grade 3 or 4 nonhematologic toxicity, excluding nausea or vomiting and alopecia, grade 4 neutropenia or thrombocytopenia, and prolonged (> 1 week) neutropenia or thrombocytopenia. Results Four levels were studied (paclitaxel 40, 45, 50, 55 mg/m2) with three, five, four and six patients enrolled, respectively. The MTD of paclitaxel was found at 50 mg/m2/wk and cisplatin 30 mg/m2/wk. Diarrhea was the dose-limiting toxicity. Thirteen patients were evaluable for response: seven complete and five partial responses were obtained with an overall response rate of 92.3%. Conclusions The MTD of paclitaxel is 50 mg/m2/wk when associated to cisplatin 30 mg/m2/wk and concurrent pelvic radiotherapy. Diarrhea is the dose limiting side effect. Preliminary data suggest that concurrent chemoradiotherapy with paclitaxel and cisplatin could be a very active treatment for patients with locally advancedcarcinoma of the cervix.

e16031Background: To assess the clinical impact of VFL in pts with mTCCU and verify the prognostic factors in a large, unselected population treated according to routine clinical practice (CP). Met...

Purpose: To define the maximum tolerated dose (MTD) of a SHort-course Accelerated whole brain RadiatiON therapy (SHARON) in the treatment of patients with multiple brain metastases. Methods and Materials: A phase 1 trial in 4 dose-escalation steps was designed: 12 Gy (3 Gy per fraction), 14 Gy (3.5 Gy per fraction), 16 Gy (4 Gy per fraction), and 18 Gy (4.5 Gy per fraction). Eligibility criteria included patients with unfavorable recursive partitioning analysis (RPA) class > or Z2 with at least 3 brain metastases or metastatic disease in more than 3 organ systems, and Eastern Cooperative Oncology Group (ECOG) performance status ≤3. Treatment was delivered in 2 days with twice-daily fractionation. Patients were treated in cohorts of 6-12 to define the MTD. The dose-limiting toxicity (DLT) was defined as any acute toxicity ≥grade 3, according to the Radiation Therapy Oncology Group scale. Information on the status of the main neurologic symptoms and quality of life were recorded. Results: Characteristics of the 49 enrolled patients were as follows: male/female, 30/19; median age, 66 years (range, 23-83 years). ECOG performance status was

Purpose: The objective of this study was to determine the effect on resection rate and survival of neoadjuvant chemoradiotherapy for primarily unresectable locally advanced pancreatic carcinoma. Methods: A systematic review of recently published literature was performed. Resection rates and survival data were derived from reports published from 2000 onwards. Only recent studies, based on radiotherapy with standard dose and fractionation, have been analyzed. Results: Thirteen studies with a total of 510 patients met selection criteria. A resection rate of 8.3-64.2% was reported (median, 26.5%). Of the operated patients, 57.1-100% (median, 87.5%) had R0 tumor resection. Most papers reported occasional pathological complete responses (CR, 3.0-8.8%). When outcome in all patients was considered, median survival ranged from 9 to 23 (median, 13.3) months, comparing favorably with literature data based on concurrent chemoradiation alone (range, 8.6-13 months). Surprisingly, in patients with unresectable tumor at presentation, median survival after surgery ranged from 16.4 to 32.3 (median, 23.6) months. Conclusions: The finding of a high proportion of R0 resection among all resections performed confirms the activity of neoadjuvant radiochemotherapy and should not be neglected. Based on these data, patients with unresectable pancreatic cancer without disease progression after chemoradiotherapy should be considered for radical surgery. © 2009 Society of Surgical Oncology.

Mucinous ovarian carcinoma has a poorer prognosis compared with other histological subtypes. The aim of this study was to evaluate, retrospectively, the activity of first-line and second-line chemotherapy in patients with mucinous ovarian cancer in a mono-institutional series.In the period under survey (1996-2003), 225 new patients with ovarian cancer were treated. Twenty-one out of these patients (9.3%) received a diagnosis of mucinous ovarian cancer. The median age, performance status, stage at diagnosis and residual disease after surgery were similar in the mucinous compared to the other histological groups (P=NS).In mucinous ovarian cancer the grading of the tumors was 2 in 76% of the cases, while grade 3 was more frequent in the other subtypes (p0.002). Eighty-five % of the patients had received carboplatin/paclitaxel, while the remaining cases had been treated with a cisplatin-based chemotherapy not containing paclitaxel. Two patients with early stage were treated with adjuvant chemotherapy and were not evaluable for response while 19 patients had measurable disease (12 pts) or were assessed at second-look (7 pts). Forty-seven % of the 19 patients experienced disease progression during first-line, while 31.5% and 10.5% complete and partial responses were recorded, respectively. Fifteen out of the 21 patients had progressed at the time of the analyses. Sixty % of the progressed patients were platinum-refractory, 3 cases were platinum-sensitive and 3 platinum-resistant. The 3 platinum-sensitive patients were treated with single agent carboplatin without any response. No response was recorded with topotecan or liposomal doxorubicin when given as second- or third-line treatment in platinum-refractory/resistant patients.Mucinous ovarian cancer has a poor response to chemotherapy both in the first-line and in the recurrence settings. Studies with alternative chemotherapy combinations are mandatory in this histological subgroup.

Cervical cancer is among the major health problems world-wide although advances in screening programs. Surgery and radiotherapy are the treatment modalities of choice for early and locally advanced cervical cancer. However, the role of chemotherapy in this setting has been better investigated in the latest years. To improve loco-regional control in locally advanced disease, authors have tested both neo-adjuvant chemotherapy and concurrent chemoradiotherapy. From 1999 NCI clinical announcement, concurrent cisplatin-based chemoradiation is considered the treatment of choice for cervical cancer patients requiring radiation therapy. Neo-adjuvant chemotherapy is reaching encouraging results in IB bulky-IIA cervical cancer, but further investigation are ongoing in locally advanced cervical setting. The optimal treatment for patients with metastatic or recurrent cervical cancer is still undefined and chemotherapy is used with palliation intent. Cisplatin remains the most active cytotoxic agents, although combinations of cisplatin with paclitaxel, topotecan, vinorelbine, have shown encouraging results in phase II and in early phase III studies. This paper reviews the role of chemotherapy in the management of patients with locally advanced, metastatic and recurrent cervical cancer. Studies discussed in this paper were selected trough a search in the med-line database performed in October 2003.

Fifty eight consecutive untreated patients with locally advanced cervical carcinoma (LACC) received neoadjuvant chemotherapy (NACT) with cisplatin (CDDP) 80 mg/sqm (day 1) + vinorelbine (VRL) 25 mg/sqm (day 1 and 8). Three cycles of chemotherapy were planned every 21 days. Within 28 days from the completion of chemotherapy patients in complete or partial response were submitted to radical hysterectomy with pelvic lymphadenectomy. On 155 cycles, hematologic toxicity was mild (G3-4 neutropenia and anemia occurred in 16% and 5%, respectively). Forty-seven patients (81%) were submitted to radical surgery; eight (14%) patients were deemed ineligible for surgery because of poor response to treatment, two (3%) for anesthesia contraindications and one (2%) refused surgery. At pathologic examination 12 patients (25%) had a complete response, one (2%) in-situ carcinoma, six (13%) residual microinvasive disease, and 28 (60%) a partial response. None had extracervical disease. Eight patients (14%) had microscopic lymph node metastases. The number of cycles administered was significantly associated with a good pathologic response. Association of CDDP and VRL as NACT in LACC appears safe and effective. Low cost and modest toxicity would support the initiation of a multicenter randomized phase III trial to compare this association with cisplatin alone.

Background: Colorectal cancer is one of the most common cancers in the elderly. Information on tolerability and efficacy of 5-Fluorouracil-based chemotherapy in such patients is limited. Primary aim of the study was to describe tolerability and activity of chemotherapy with the de Gramont schedule (FU bolus [400 mg/m 2 ] + FU continuous infusion [600 mg/m 2 ] + folinic acid [100 mg/m 2 ] on days I and 2, every 2 weeks), in patients with advanced colorectal cancer aged 70 or older. Patients and methods: Patients aged 70 or more, with stage IV colorectal cancer, ECOG performance status not worse than 2. Results: Thirty-four patients were treated at two participating centers. Seven (20.6%, 95% exact CI = 8.7-37.9) had an objective response, complete in 3 and partial in 4 patients. Five cases of unacceptable toxicity were registered ( 2 cardiac, 1 each for liver, anemia and diarrhea). Fitting the statistical model to the observed data indicated that the treatment was sufficiently active and tolerated. Conclusions: The de Gramont scheme is active and tolerated in elderly patients with advanced colorectal cancer.

The expression of transforming growth factor alpha (TGFalpha), amphiregulin (AR) and cripto-1 (CR-1) was assessed by immunohistochemistry in 83 specimens (59 primary ovarian tumors and 24 extra-ovarian carcinomas) that were obtained from 68 ovarian carcinoma patients. Within the 59 primary tumors, 54 (92%) expressed immunoreactive TGFalpha, 45 (76%) expressed AR, and 28 (47%) expressed CR-1. The expression of AR and CR-1 mRNAs in the ovarian carcinomas was also demonstrated by RT-PCR analysis. Seventeen extra-ovarian specimens (71%) were found to express CR-1, whereas AR and TGFalpha were expressed respectively in 21 (87%) and 22 (92%) extra-ovarian tissues. In 15 cases for whom both ovarian and extra-ovarian tissues were available, a statistically significant higher expression of CR-1 was found in extra-ovarian specimens. A statistically significant correlation was found between AR expression in the ovarian carcinomas and both low grade and low proliferative activity. Finally, expression of TGFalpha was predictive of longer progression-free survival. These data strongly suggest that the EGF-related peptides might be involved in the pathogenesis and outcome of human ovarian cancer.

The expression of transforming growth factor alpha (TGFalpha), amphiregulin (AR) and cripto-1 (CR-1) was assessed by immunohistochemistry in 83 specimens (59 primary ovarian tumors and 24 extra-ovarian carcinomas) that were obtained from 68 ovarian carcinoma patients. Within the 59 primary tumors, 54 (92%) expressed immunoreactive TGFalpha, 45 (76%) expressed AR, and 28 (47%) expressed CR-1. The expression of AR and CR-1 mRNAs in the ovarian carcinomas was also demonstrated by RT-PCR analysis. Seventeen extra-ovarian specimens (71%) were found to express CR-1, whereas AR and TGFalpha were expressed respectively in 21 (87%) and 22 (92%) extra-ovarian tissues. In 15 cases for whom both ovarian and extra-ovarian tissues were available, a statistically significant higher expression of CR-1 was found in extra-ovarian specimens. A statistically significant correlation was found between AR expression in the ovarian carcinomas and both low grade and low proliferative activity. Finally, expression of TGFalpha was predictive of longer progression-free survival. These data strongly suggest that the EGF-related peptides might be involved in the pathogenesis and outcome of human ovarian cancer.

Objective. One hundred and forty-eight consecutive gynecological oncological patients aged ≥70 were administered chemotherapy during the years 1990–2000. Methods. Median age was 73 years (range 70–84). Fifty-five (37.2%) women were over 75 years old. One or more comorbid conditions were present in 118 (79.7%) patients. Standard schedules were administered to 97.3% of cases, with a total number of 1046 cycles of therapy administered (median, 6; range, 1–35, per patient). Results. Of a total of 233 chemotherapy regimens globally administered, G3–G4 hematological toxicity was documented in 38.2% of cases. Only 10 (6.8%) of the 148 patients discontinued treatment because of G3–G4 hematological toxicity. No severe nonhematological toxicity was observed. Two dose reductions and three treatment delays, but no discontinuation of treatment, were required during second-line regimens. Treatment delay >7 days was required in 16.9% of cases. Conclusions. Chronological age did not adversely influence the ability to receive aggressive treatment.

5-Fluorouracil (5-FU), in association with leucovorin (LV), is the most used chemotherapy agent in the treatment of colorectal cancer. Response rate, as well as side-effect incidence, increases with the dose intensity of regimens that are used. The most common dose-limiting toxicity for 5-FU/LV modulation is diarrhea. To assess the modification of small intestinal function, we investigated the changes in intestinal permeability (IP) and intestinal absorption (IA) in 41 chemo-naive patients (21 men and 22 women; mean age, 61 +/- 9 years) with advanced colorectal cancer after treatment with the association of folinic acid and 5-FU. After chemotherapy administration, we found a marked increase in IP and a reduction in IA, measured as cellobiose-mannitol (CE-MA) ratio (p < 0.0001) and D-xylose absorption (p = 0.0001), respectively. Patients who experienced diarrhea have an increase in CE-MA ratio and a reduction in D-xylose absorption values, both statistically significant. Cellobiose-mannitol ratio and D-xylose absorption tests can be used for the assessment of toxic effect of 5-FU on mature intestinal epithelium and also for evaluating the role of cytoprotective agents.