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Background: Bevacizumab is approved in combination with chemotherapy for the treatment of ovarian cancer, either in first-line therapy or for patients with recurrent disease not previously treated with the same drug. We aimed to test the value of continuing bevacizumab beyond progression after first-line treatment with the same drug. Methods: In our open-label, randomised, phase 3 trial done at 82 sites in four countries, we enrolled women (aged ≥18 years) who had previously received first-line platinum-based therapy including bevacizumab, and had recurrent (≥6 months since last platinum dose), International Federation of Gynaecology and Obstetrics stage IIIB–IV ovarian cancer with an Eastern Cooperative Oncology Group performance status 0–2. Patients were randomly assigned (1:1) to receive a carboplatin-based doublet intravenously (carboplatin area under the concentration curve [AUC] 5 on day 1 plus paclitaxel 175 mg/m2 on day 1, every 21 days; carboplatin AUC 4 on day 1 plus gemcitabine 1000 mg/m2 on days 1 and 8, every 21 days; or carboplatin AUC 5 on day 1 plus pegylated liposomal doxorubicin 30 mg/m2 on day 1, every 28 days), or a carboplatin-based doublet plus bevacizumab (10 mg/kg intravenous every 14 days combined with pegylated liposomal doxorubicin–carboplatin, or 15 mg/kg every 21 days combined with gemcitabine–carboplatin or paclitaxel–carboplatin). Evaluable disease according to RECIST 1.1 guidelines was required before randomisation. Randomisation was done through the trial website with a minimisation procedure, stratified by centre, time of recurrence, performance status, and type of second-line chemotherapy. The primary endpoint was investigator-assessed progression-free survival, analysed on an intention-to-treat basis. Safety was assessed in all participants who received at least one dose. This trial is registered with ClinicalTrials.gov, NCT01802749 and EudraCT 2012-004362-17. Findings: Between Dec 6, 2013, and Nov 11, 2016, 406 patients were recruited (203 [50%] assigned to the bevacizumab group and 203 [50%] to the standard chemotherapy group). 130 patients (64%) in the bevacizumab group and 131 (65%) in the standard chemotherapy group had progressed after receiving a last dose of platinum more than 12 months before, and 146 patients (72%) in the bevacizumab group and 147 (72%) in the standard chemotherapy group had progressed after completion of first-line bevacizumab maintenance. 161 participants (79%) progressed in the standard chemotherapy group, as did 143 (70%) in the bevacizumab group. Median progression-free survival was 8·8 months (95% CI 8·4–9·3) in the standard chemotherapy group and 11·8 months (10·8–12·9) in the bevacizumab group (hazard ratio 0·51, 95% CI 0·41–0·65; log-rank p

BACKGROUND The standard treatment of locally advanced rectal cancers (LARC) consists on neoadjuvant chemoradiotherapy followed by total mesorectal excision. Different data in literature showed a benefit on tumor downstaging and pathological complete response (pCR) rate using radiotherapy dose escalation, however there is shortage of studies regarding dose escalation using the innovative techniques for LARC (T3-4 or N1-2). AIM To analyze the role of neoadjuvant radiotherapy dose escalation for LARC using innovative radiotherapy techniques. METHODS In December 2020, we conducted a comprehensive literature search of the following electronic databases: PubMed, Web of Science, Scopus and Cochrane library. The limit period of research included articles published from January 2009 to December 2020. Screening by title and abstract was carried out to identify only studies using radiation doses equivalent dose 2 Gy fraction (EQD2) ≥ 54 Gy and Volumetric Modulated Arc Therapy (VMAT), intensity-modulated radiotherapy or image-guided radiotherapy (IGRT) techniques. The authors’ searches generated a total of 2287 results and, according to PRISMA Group (2009) screening process, 21 publications fulfil selection criteria and were included for the review. RESULTS The main radiotherapy technique used consisted in VMAT and IGRT modality. The mainly dose prescription was 55 Gy to high risk volume and 45 Gy as prophylactic volume in 25 fractions given with simultaneous integrated boosts technique (42.85%). The mean pCR was 28.2% with no correlation between dose prescribed and response rates (P value ≥ 0.5). The R0 margins and sphincter preservation rates were 98.88% and 76.03%, respectively. After a mean follow-up of 35 months local control was 92.29%. G3 or higher toxicity was 11.06% with no correlation between dose prescription and toxicities. Patients receiving EQD2 dose > 58.9 Gy and BED > 70.7 Gy had higher surgical complications rates compared to other group (P value = 0.047). CONCLUSION Dose escalation neoadjuvant radiotherapy using innovative techniques is safe for LARC achieving higher rates of pCR. EQD2 doses > 58.9 Gy is associated with higher rate of surgical complications.

Summary Background The triplet FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus bevacizumab showed improved outcomes for patients with metastatic colorectal cancer, compared with FOLFIRI (fluorouracil, leucovorin, and irinotecan) plus bevacizumab. However, the actual benefit of the upfront exposure to the three cytotoxic drugs compared with a preplanned sequential strategy of doublets was not clear, and neither was the feasibility or efficacy of therapies after disease progression. We aimed to compare a preplanned strategy of upfront FOLFOXIRI followed by the reintroduction of the same regimen after disease progression versus a sequence of mFOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) and FOLFIRI doublets, in combination with bevacizumab. Methods TRIBE2 was an open-label, phase 3, randomised study of patients aged 18–75 years with an Eastern Cooperative Oncology Group (ECOG) performance status of 2, with unresectable, previously untreated metastatic colorectal cancer, recruited from 58 Italian oncology units. Patients were stratified according to centre, ECOG performance status, primary tumour location, and previous adjuvant chemotherapy. A randomisation system incorporating a minimisation algorithm was used to randomly assign patients (1:1) via a masked web-based allocation procedure to two different treatment strategies. In the control group, patients received first-line mFOLFOX6 (85 mg/m2 of intravenous oxaliplatin concurrently with 200 mg/m2 of leucovorin over 120 min; 400 mg/m2 intravenous bolus of fluorouracil; 2400 mg/m2 continuous infusion of fluorouracil for 48 h) plus bevacizumab (5 mg/kg intravenously over 30 min) followed by FOLFIRI (180 mg/m2 of intravenous irinotecan over 120 min concurrently with 200 mg/m2 of leucovorin; 400 mg/m2 intravenous bolus of fluorouracil; 2400 mg/m2 continuous infusion of fluorouracil for 48 h) plus bevacizumab after disease progression. In the experimental group, patients received FOLFOXIRI (165 mg/m2 of intravenous irinotecan over 60 min; 85 mg/m2 intravenous oxaliplatin concurrently with 200 mg/m2 of leucovorin over 120 min; 3200 mg/m2 continuous infusion of fluorouracil for 48 h) plus bevacizumab followed by the reintroduction of the same regimen after disease progression. Combination treatments were repeated every 14 days for up to eight cycles followed by fluorouracil and leucovorin (at the same dose administered at the last induction cycle) plus bevacizumab maintenance until disease progression, unacceptable adverse events, or consent withdrawal. Patients and investigators were not masked. The primary endpoint was progression-free survival 2, defined as the time from randomisation to disease progression on any treatment given after first disease progression, or death, analysed by intention to treat. Safety was assessed in patients who received at least one dose of their assigned treatment. Study recruitment is complete and follow-up is ongoing. This trial is registered with Clinicaltrials.gov , NCT02339116 . Findings Between Feb 26, 2015, and May 15, 2017, 679 patients were randomly assigned and received treatment (340 in the control group and 339 in the experimental group). At data cut-off (July 30, 2019) median follow-up was 35·9 months (IQR 30·1–41·4). Median progression-free survival 2 was 19·2 months (95% CI 17·3–21·4) in the experimental group and 16·4 months (15·1–17·5) in the control group (hazard ratio [HR] 0·74, 95% CI 0·63–0·88; p=0·0005). During the first-line treatment, the most frequent of all-cause grade 3–4 events were diarrhoea (57 [17%] vs 18 [5%]), neutropenia (168 [50%] vs 71 [21%]), and arterial hypertension (25 [7%] vs 35 [10%]) in the experimental group compared with the control group. Serious adverse events occurred in 84 (25%) patients in the experimental group and in 56 (17%) patients in the control group. Eight treatment-related deaths were reported in the experimental group (two intestinal occlusions, two intestinal perforations, two sepsis, one myocardial infarction, and one bleeding) and four in the control group (two occlusions, one perforation, and one pulmonary embolism). After first disease progression, no substantial differences in the incidence of grade 3 or 4 adverse events were reported between the control and experimental groups, with the exception of neurotoxicity, which was only reported in the experimental group (six [5%] of 132 patients). Serious adverse events after disease progression occurred in 20 (15%) patients in the experimental group and 25 (12%) in the control group. Three treatment-related deaths after first disease progression were reported in the experimental group (two intestinal occlusions and one sepsis) and four in the control group (one intestinal occlusion, one intestinal perforation, one cerebrovascular event, and one sepsis). Interpretation Upfront FOLFOXIRI plus bevacizumab followed by the reintroduction of the same regimen after disease progression seems to be a preferable therapeutic strategy to sequential administration of chemotherapy doublets, in combination with bevacizumab, for patients with metastatic colorectal cancer selected according to the study criteria. Funding The GONO Cooperative Group, the ARCO Foundation, and F Hoffmann–La Roche.

Purpose To evaluate clinical outcomes in patients with localized prostate cancer (LPC) treated with 3D conformal high-dose-rate (HDR) brachytherapy (BT) as monotherapy. Material and methods From March 2004 to November 2017, 277 men with LPC underwent 3D conformal HDR-BT as monotherapy, with a temporary implant. The dose prescription was: 38 Gy in 4 fractions (149 patients), 27 Gy in 2 fractions (41 patients), and 19-20 Gy in a single fraction (87 patients). Biochemical progression-free survival (bPFS), progression-free survival (PFS), and cancer-specific survival (CSS) were calculated. Acute and late genitourinary (GU) and gastrointestinal (GI) toxicity assessment were performed using Common Terminology Criteria for Adverse Events v5.0. Results The mean age was 67 (range, 47-81) years. Overall, 145 patients were low-risk, 116 intermediate-risk, and 16 high-risk prostate cancer. After a median follow-up of six years (range, 6-160 months), bPFS, PFS, and CSS were 81%, 96%, and 97%, respectively. Dose prescription, initial prostate specific antigen (iPSA) ≥ 9,5 ng/ml, and high-risk disease resulted in prognostic factors regarding bPFS. Only G2-G3 acute or late GI and GU toxicities were observed. Conclusions HDR-BT as monotherapy is a valid and safe treatment modality for localized prostate cancer. After a long follow-up, patients receiving 19-20 Gy in a single fraction had a lower biochemical control rate compared to patients receiving 38 Gy in 4 fractions or 27 Gy in 2 fractions. Randomized prospective trials with a longer follow-up are necessary to confirm our results, and define total doses and dose per fraction for HDR-BT in patients with LPC.

Purpose: Chemotherapy-induced nausea and vomiting (CINV) is a common adverse event with cancer chemotherapy, despite the availability of effective antiemetic agents. This is a prospective observational study of Italian breast cancer patients treated with anthracycline plus cyclophosphamide (AC), assessed CINV incidence, adherence to national antiemetic guidelines (AIOM 2012), and the relationship with CINV outcomes. Methods: Patients with breast cancer scheduled to receive their first cycle of an AC-based regimen were enrolled at 12 Italian centers and their clinical data prospectively recorded. CINV incidence was assessed from patient diaries after the first chemotherapy cycle. The relationship between guideline adherence and CINV outcomes was examined using multiple logistic regression. Results: The overall incidence rates of nausea and vomiting among 246 evaluable patients were 63.0 and 25.4%, respectively. Most patients received a 5-HT3-RA agent and dexamethasone for acute phase CINV prophylaxis, whereas a triple combination including aprepitant (NK1-RA), consistent with national guidelines, was used in only 45.5% of cases. In the delayed phase, the guideline adherence was 48.8%, while the overall adherence was 43.5%. After adjusting for confounding factors, adherence to antiemetic prophylaxis guidelines was associated with a significant reduction in the odds of three endpoints, namely any nausea, “significant nausea,” and vomiting (OR = 0.49, OR = 0.54, and OR = 0.48, respectively), and a 90% increase in the odds of overall complete protection (OR = 1.90). Conclusions: CINV is still a critical issue in AC-treated patients, despite antiemetic treatment. Non-adherence to antiemetic guidelines may lead to poorer outcomes and indicates the need for strategies to enhance the use of guidelines in clinical practice.

Background and purpose: Glioblastoma (GBM) is the most aggressive and frequent subtype of all malignant gliomas. At the time of recurrence, therapeutic options are lacking. Ortataxel, a second-generation taxane was reported to be effective in pre-clinical and phase I clinical studies. The aim of this study was to evaluate a potential therapeutic activity of ortataxel in patients with GBM recurring after surgery and first line treatment. Methods: In this phase II study, according to a two stage design, adult patients with histologically confirmed GBM in recurrence after surgery or biopsy, standard radiotherapy and chemotherapy with temozolomide were considered eligible. Patients included were treated with ortataxel 75mg/m2 i.v. every 3weeks until disease progression. The primary objective of the study was to evaluate the activity of ortataxel in terms of progression free survival (PFS) at 6months after the enrollment. PFS, overall survival at 9months after the enrollment, objective response rate, compliance and safety were evaluated as secondary endpoints. Results: Between Nov 26, 2013 and Dec 12, 2015, 40 patients were recruited across six centres. The number of patients alive and free from progression at 6months after the enrollment, observed in the first stage was four (11.4%), out of 35 patients included in the analysis, below the minimum number of events (7 out of 33) required to continue the study with the second stage The most important toxicities were neutropenia and hepatotoxicity that occurred in 13.2% of patients and leukopenia that occurred in 15.8% of patients. Conclusion: Overall ortataxel treatment fail to demonstrate a significant activity in recurrent GBM patients. However in a limited number of patients the drug produced a benefit that lasted for a long time. Trial registration: This study is registered with ClinicalTrials.gov, number NCT01989884.

Background: Uncertainty exists about the optimal schedule of adjuvant treatment of breast cancer with aromatase inhibitors and, to our knowledge, no trial has directly compared the three aromatase inhibitors anastrozole, exemestane, and letrozole. We investigated the schedule and type of aromatase inhibitors to be used as adjuvant treatment for hormone receptor-positive early breast cancer. Methods: FATA-GIM3 is a multicentre, open-label, randomised, phase 3 trial of six different treatments in postmenopausal women with hormone receptor-positive early breast cancer. Eligible patients had histologically confirmed invasive hormone receptor-positive breast cancer that had been completely removed by surgery, any pathological tumour size, and axillary nodal status. Key exclusion criteria were hormone replacement therapy, recurrent or metastatic disease, previous treatment with tamoxifen, and another malignancy in the previous 10 years. Patients were randomly assigned in an equal ratio to one of six treatment groups: oral anastrozole (1 mg per day), exemestane (25 mg per day), or letrozole (2·5 mg per day) tablets upfront for 5 years (upfront strategy) or oral tamoxifen (20 mg per day) for 2 years followed by oral administration of one of the three aromatase inhibitors for 3 years (switch strategy). Randomisation was done by a computerised minimisation procedure stratified for oestrogen receptor, progesterone receptor, and HER2 status; previous chemotherapy; and pathological nodal status. Neither the patients nor the physicians were masked to treatment allocation. The primary endpoint was disease-free survival. The minimum cutoff to declare superiority of the upfront strategy over the switch strategy was assumed to be a 2% difference in disease-free survival at 5 years. Primary efficacy analyses were done by intention to treat; safety analyses included all patients for whom at least one safety case report form had been completed. Follow-up is ongoing. This trial is registered with the European Clinical Trials Database, number 2006-004018-42, and ClinicalTrials.gov, number NCT00541086. Findings: Between March 9, 2007, and July 31, 2012, 3697 patients were enrolled into the study. After a median follow-up of 60 months (IQR 46–72), 401 disease-free survival events were reported, including 211 (11%) of 1850 patients allocated to the switch strategy and 190 (10%) of 1847 patients allocated to upfront treatment. 5-year disease-free survival was 88·5% (95% CI 86·7–90·0) with the switch strategy and 89·8% (88·2–91·2) with upfront treatment (hazard ratio 0·89, 95% CI 0·73–1·08; p=0·23). 5-year disease-free survival was 90·0% (95% CI 87·9–91·7) with anastrozole (124 events), 88·0% (85·8–89·9) with exemestane (148 events), and 89·4% (87·3 to 91·1) with letrozole (129 events; p=0·24). No unexpected serious adverse reactions or treatment-related deaths occurred. Musculoskeletal side-effects were the most frequent grade 3–4 events, reported in 130 (7%) of 1761 patients who received the switch strategy and 128 (7%) of 1766 patients who received upfront treatment. Grade 1 musculoskeletal events were more frequent with the upfront schedule than with the switch schedule (924 [52%] of 1766 patients vs 745 [42%] of 1761 patients). All other grade 3–4 adverse events occurred in less than 2% of patients in either group. Interpretation: 5 years of treatment with aromatase inhibitors was not superior to 2 years of tamoxifen followed by 3 years of aromatase inhibitors. None of the three aromatase inhibitors was superior to the others in terms of efficacy. Therefore, patient preference, tolerability, and financial constraints should be considered when deciding the optimal treatment approach in this setting. Funding: Italian Drug Agency.

Purpose Single-agent oral chemotherapy is widely used in patients with bone metastases without visceral involvement, especially in hormone receptor–positive metastatic breast cancer (mBC). However, this option has been poorly evaluated in clinical trials. Methods Eligible patients had mBC with predominantly bone but not visceral metastases, were receiving bisphosphonate therapy, and had previously received endocrine therapy (any setting) but not chemotherapy for mBC. Patients received oral vinorelbine 60 mg/m2 on days 1, 8, 15, and 22 every 4 weeks (escalating to 80 mg/m2 from cycle 2 in the absence of grade 3/4 toxicity) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included clinical benefit rate (complete/partial response or ≥24 weeks' stable disease), overall survival, and safety. Results Seventy patients were treated for a median of 6 cycles (range 1-18). Most (73%) continued treatment until disease progression. After 43 months' median follow-up, median PFS was 8.2 months (95% confidence interval [CI], 5.5-9.8). The clinical benefit rate was 56% (95% CI, 43%-68%). Median overall survival was 35.2 months (95% CI, 26.8-47.1). The most common grade 3/4 adverse event was neutropenia (38% of patients); febrile neutropenia was absent. The most common grade 1/2 adverse events were bone pain, fatigue, and gastrointestinal toxicities. Alopecia was infrequent. Conclusions In patients with hormone receptor–positive mBC, bone disease, and prior endocrine therapy, first-line oral vinorelbine chemotherapy demonstrated long PFS and good tolerability. In this setting, it could be considered as an active oral alternative to intravenous chemotherapy.

© 2018 The Authors., [Background]: The present prospective, multinational, noninterventional study aimed to document and describe real-world treatment regimens and disease progression in multiple myeloma (MM) patients. [Patients and Methods]: Adult patients initiating any new MM therapy from October 2010 to October 2012 were eligible. A multistage patient/site recruitment model was applied to minimize the selection bias; enrollment was stratified by country, region, and practice type. The patient medical and disease features, treatment history, and remission status were recorded at baseline, and prospective data on treatment, efficacy, and safety were collected electronically every 3 months., [Results]: A total of 2358 patients were enrolled. Of these patients, 775 and 1583 did and did not undergo stem cell transplantation (SCT) at any time during treatment, respectively. Of the patients in the SCT and non-SCT groups, 49%, 21%, 14%, and 15% and 57%, 20%, 12% and 10% were enrolled at treatment line 1, 2, 3, and ≥ 4, respectively. In the SCT and non-SCT groups, 45% and 54% of the patients had received bortezomib-based therapy without thalidomide/lenalidomide, 12% and 18% had received thalidomide/lenalidomide-based therapy without bortezomib, and 30% and 4% had received bortezomib plus thalidomide/lenalidomide-based therapy as frontline treatment, respectively. The corresponding proportions of SCT and non-SCT patients in lines 2, 3, and ≥ 4 were 45% and 37%, 30% and 37%, and 12% and 3%, 33% and 27%, 35% and 32%, and 8% and 2%, and 27% and 27%, 27% and 23%, and 6% and 4%, respectively. In the SCT and non-SCT patients, the overall response rate was 86% to 97% and 64% to 85% in line 1, 74% to 78% and 59% to 68% in line 2, 55% to 83% and 48% to 60% in line 3, and 49% to 65% and 36% and 45% in line 4, respectively, for regimens that included bortezomib and/or thalidomide/lenalidomide., [Conclusion]: The results of our prospective study have revealed great diversity in the treatment regimens used to manage MM in real-life practice. This diversity was linked to factors such as novel agent accessibility and evolving treatment recommendations. Our results provide insight into associated clinical benefits., Writing support during the development of our report was provided by Laura Mulcahy and Catherine Crookes of FireKite, an Ashfield company, a part of UDG Healthcare plc, which was funded by Millennium Pharmaceuticals, Inc, and Janssen Global Services, LLC. The EMMOS study was supported by research funding from Janssen Pharmaceutical NV and Millennium Pharmaceuticals, Inc.

The appropriate treatment approach for elderly patients with glioblastoma multiforme (GBM) is unclear, although different studies suggest survival benefit in fit patients treated with radiotherapy and chemiotherapy after surgery. We performed a retrospective analysis of 151 patients older than 65years with GBM treated in 3 Lombardia Hospitals. In univariate regression analysis higher KPS (p=0.02), macroscopical total resection (p0.003), radiotherapy (p0.0001), chemotherapy (p0.0001) and second line chemotheraphy (p=0.02) were of positive prognostic value. On the contrary older age (70years), presence of seizure at onset and additional resection after tumor recurrence did not influence OS. Multivariate analysis revealed radiotherapy (HR 0.2 p0.0001) and extent of surgery (HR 0.3, p=0,0063) as positive independent prognostic factors. Patients receiving radio-chemiotherapy displayed more treatment-related toxicities with a slightly prolonged OS versus those receiving hypofractionated radiotherapy. With the limits of a retrospective study, our data suggest that in elderly fit patients extensive surgery should be considered, moreover adjuvant treatments led to an increase in OS. Randomized controlled study are needed to develop treatment guidelines for elderly GBM patients and to assess whether the combination of post-surgical radio and chemiotherapy may be superior to hypofractionated radiotherapy and chemiotherapy in fit patients.

Fatigue is one of the most distressing symptoms of cancer patients. Its characteristics and impact on quality of life have not been fully explored and treatment of cancer-related fatigue in Italian oncological centers has not been codified. A cross-sectional study was carried out on all patients attending for any reason the 24 participating centers in two non-consecutive days. Patients with fatigue filled out the Brief Fatigue Inventory (BFI) questionnaire and reported any pharmacological or non-pharmacological treatment for fatigue. From October 2014 to May 2015, 1394 cancer patients agreed to participate in the study. Fatigue was referred by 866 (62.1%) of patients; its duration was > 4 months in 441 patients (50.9%). In the investigators’ opinion, the most important (probable or almost sure) determinants of fatigue were reduced physical activity (271 patients), anxiety (149), pain (131), insomnia (125), anemia (123), and depression (123). Fatigue of moderate/severe intensity was reported by 43%/29.2% of patients, while usual fatigue in the last 24 h by 45%/33.1%, and the worst fatigue in the last 24 h by 33%/54.8%, respectively. Concerning the impact on quality of life, fatigue interfered moderately/severely with general activity in 30.8%/38.6% of patients, with mood in 26.1%/32.8%, with the ability to work in 27.9%/35.6%, with normal work in 26.7%/38.9%, with relationships with others in 21%/23.4% and with the ability to amuse themselves in 22.2%/33.1%. Only 117/866 patients (13.5%) received a pharmacological treatment represented by a corticosteroid in 101 patients (86.3%) while 188 patients (21.7%) received a non-pharmacological treatment such as physical exercise (120 patients, 63.8%) and various alimentary supplements (52 patients, 27.6%). Cancer-related fatigue is frequently reported by oncological patients; its intensity and impact on quality of life is relevant.

Objectives Non-small-cell-lung-cancer (NSCLC) patients harbouring epidermal growth factor receptor (EGFR) mutations develop drug resistance after 9–12 months of EGFR tyrosine kinase inhibitors (TKIs) therapy pointing out the issue of the second-line treatment choice. Materials and methods From June 2009 until May 2013 patients affected by advanced NSCLC harbouring EGFR mutations receiving first-line TKI were collected mainly retrospectively in 24 Italian Centers. Primary objective was to describe the percentage of EGFR mutated patients receiving second-line therapy after progression to first-line EGFR-TKIs assessing the type, the activity in terms of objective response rate (ORR), efficacy in terms of progression free survival (PFS) and overall survival (OS), and safety of second-line treatment. Secondary objective was to describe the efficacy of first-line EGFR-TKIs. Results 312 patients were included. Most of them were females (203, 65.1%), never smokers (200, 64.1%), with adenocarcinoma histology (290, 92.9%). The most common mutations were EGFR exon 19 deletion and L858R, detected in 186 and 97 cases (59.6% and 31.1%), respectively. At data cut-off, 274 patients (95.1%) received any second-line treatment (including best supportive care or local treatments only). A total of 163 patients received second-line systemic therapy with an ORR of 20.9% (95% CI:14.62–27.10), a median PFS and OS of 4.7 (95% CI:3.81–5.26) and 24.5 (95% CI:21.65–27.37) months, respectively. Grade 3–4 hematological and non-hematological toxicities were reported in 9% and 6.3% of 144 patients treated with chemotherapy while non-hematological toxicity was reported in 4 cases of the 17 patients receiving second-line target agents. Conclusions BE-Positive is the first multicenter observational study reporting outcomes of therapies in a "real-life Caucasian EGFR-mutated population", highlighting the need of further researches about new treatment strategies in this setting.

Purpose Adjuvant chemotherapy improves survival of patients with gastric cancer. Intergroup Trial of Adjuvant Chemotherapy in Adenocarcinoma of the Stomach (ITACA-S) was a phase III study comparing sequential FOLFIRI followed by docetaxel/cisplatin versus 5-fluorouracil monotherapy. The intensive regimen was not superior in terms of disease-free survival (DFS) and overall survival (OS). Methods The treatment was to be started within 8 weeks from surgery. This analysis evaluates the impact of time from surgery to chemotherapy start (TSC) on outcomes. Results Out of 1,106 randomized, 1,072 patients without major violations of eligibility criteria and receiving at least one treatment cycle were analyzed. Median TSC was 50 days. Chemotherapy was interrupted in 201 (18.8%) cases, whereas it was completed without or with modifications in 277 (25.8%) and 594 (55.4%), respectively. At a median follow-up of 56.9 months, 513 progressions and 472 deaths occurred. A longer TSC was significantly associated with longer DFS (hazard ratio [HR] 0.95; 95% confidence interval [CI] 0.89-1.00; p = 0.05) and OS (HR 0.91; 95% CI 0.86-0.97; p = 0.004), after adjustment for treatment arm, age, sex, primary tumor site, number of resected nodes, and tumor stage. Better treatment compliance was associated with improved survival. Conclusions Our findings suggest that longer TSC had at least no detrimental effect on DFS and OS, whereas treatment completion had a protective effect. Our findings need to be confirmed prospectively.

Purpose Renal impairment (RI) limits treatment options in patients with relapsed/refractory multiple myeloma (RRMM). Here, we prospectively studied pomalidomide plus low-dose dexamethasone (LoDEX) in patients with RRMM and moderate or severe RI, including those receiving hemodialysis. Patients and Methods MM-013, a noncomparative, European phase II trial, enrolled three patient cohorts: moderate RI (cohort A; estimated glomerular filtration rate, 30 to < 45 mL/min/1.73 m2); severe RI (cohort B; estimated glomerular filtration rate, < 30 mL/min/1.73 m2); and severe RI that requires hemodialysis (cohort C). Patients received pomalidomide 4 mg/d on days 1 to 21 and LoDEX 20 or 40 mg once per week in 28-day cycles. The primary end point was overall response rate. Results Of 81 enrolled patients (33, 34, and 14 patients in cohorts A, B, and C, respectively), 13 were still receiving treatment at data cutoff (January 28, 2017). Overall response rates were 39.4%, 32.4%, and 14.3%, with a median duration of response of 14.7 months, 4.6 months, and not estimable, respectively. Of importance, 100%, 79.4%, and 78.6% of patients, respectively, achieved disease control. With a median follow-up of 8.6 months, median overall survival was 16.4 months, 11.8 months, and 5.2 months, respectively. Complete renal responses were observed only in cohort A (18.2%), and no patients in cohort C became hemodialysis independent. Grade 3 and 4 hematologic treatment-emergent adverse events and pomalidomide discontinuations as a result of treatment-emergent adverse events occurred more frequently in cohort C. Pomalidomide pharmacokinetics were comparable among the three renal cohorts. Conclusion Pomalidomide 4 mg/d plus LoDEX is efficacious in patients with RRMM with moderate or severe RI, including those who had more advanced disease and required hemodialysis. The safety profile was acceptable among the three groups, and no new safety signals were observed.

Background Colorectal cancer screening may reduce disease-related mortality by early-stage detection of cancers. Aims To study the effect of a single immunochemical faecal occult blood test (i-FOBt) screening round on reduction in colorectal cancer-related-mortality among average risk subjects. Methods Comparison of 5-year mortality rates in 3 cohorts from a Northern Italian province: (1) colorectal cancers detected at the 1st biennial round of a mass-screening programme targeting 50–69 years old subjects, (2) non-screening cancers symptomatically diagnosed during the same time period, and (3) cancers detected in the pre-screening biennium. Multivariate analyses were performed with the Cox regression model including tumour node metastasis (TNM) stage at diagnosis, anatomical distribution of cancers, age at diagnosis, gender and patient group. Kaplan–Meyer survival estimates and log-rank test for equality of survivor functions were calculated. Results Stage distribution significantly differed between screening and non-screening colorectal cancers: 73% of screen-detected colorectal cancers were stages I and II versus 43% and 40% of non-screening and pre-screening colorectal cancers. Cumulative 5-year mortality rate was significantly lower in screening compared to non-screening or pre-screening colorectal cancers patients (19% versus 37% and 41%, p Conclusions Colorectal cancers were detected at earlier stages in i-FOBT-positive subjects in comparison with non-screening patients; colorectal cancers found at screening had a significantly improved 5-year survival.

Background Beyond progression after tyrosine kinase inhibitor in EGFR -positive non-small-cell lung cancer patients (BE-POSITIVE) was the first Italian multicenter observational study that reported the outcomes of first-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in a “real-life” Caucasian EGFR -mutated non-small-cell lung cancer (NSCLC) population. The sharing of multi-institutional experiences represents a crucial strategy to enrich knowledge about uncommon EGFR mutations. Therefore, we performed a post hoc analysis of the BE-POSITIVE study. Patients and Methods Data of advanced NSCLC patients with uncommon EGFR mutations who received first-line first-generation EGFR-TKIs in 24 Italian Hospitals were collected. In this analysis we aimed to evaluate overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) of EGFR-TKIs in NSCLC patients harboring uncommon EGFR mutations. Results Thirty-five patients harboring uncommon EGFR mutations (any mutation other than deletion 19 or substitution of leucine by arginine at codon 858) were included of the original 312 EGFR -mutated cases. Most of them were female (n = 20, 57.1%), former smokers (n = 23, 65.7%), with adenocarcinoma (n = 31, 88.6%). The most frequent EGFR mutations were G719X (n = 6, 17.2%) and L861Q (n = 5, 14.2%). The population presented an ORR of 25.7%, a median PFS of 5.19 months, and a median OS of 14.49 months. When stratified according to type of EGFR mutation, median OS ranged from 3.65 months for unspecified mutations to 21.29 for double EGFR mutations. Median PFS ranged from 1.77 months for unspecified mutations to 20.83 months for concomitant EGFR-anaplastic lymphoma kinase alteration. ORR varied from 0% in exon 18, 20 and double gene alteration to 66.6% in exon 19. Conclusion Our study supports the existence of a strong outcome heterogeneity within patients harboring uncommon EGFR mutations, which needs to be clarified to achieve a real personalized treatment strategy.

Background and study aims: Colorectal cancer (CRC) screening aims to reduce mortality by detecting cancers at an early stage and removing adenomatous polyps at an acceptable cost. The aim of the current study were to assess the outcomes and costs of the first two biennial rounds of a population-based CRC screening program using the immunochemical fecal occult blood test (i-FOBT) in a northern Italian province. Methods: All residents aged 50 – 69 years were invited to take part in a biennial screening program using a 1-day i-FOBT, followed by colonoscopy in positive individuals. The i-FOBT uptake, compliance to colonoscopy, detection rate for cancer or advanced adenomas according to age and sex, and direct cost analysis were carried out separately for the 1st and 2nd rounds of screening. Results: In 78 083 (1st round) and 81 619 (2nd round) individuals who were invited to screening, the participation rates were 49.7 % and 54.4 % and i-FOBT positivity rates were 6.2 % and 5.8 %, respectively. Detection rates for cancer and advanced adenomas were lower in the 2nd screening compared with the 1st one (1.6‰ vs. 2.5‰ for cancers and 15.8‰ vs. 17.9‰ for advanced adenomas, respectively), whereas positive predictive values for cancer and advanced adenoma were similar in both rounds. In 165 adenocarcinomas detected, 52 % were Dukes’ stage A and 21 % were stage B. All cost indicators were slightly higher in the 1st round of screening compared with the 2nd. The direct cost per cancer or advanced adenoma detection was similar in the two rounds (€ 1252 and € 1260, respectively). Conclusions: Compliance and diagnostic yield of i-FOBT screening were satisfactory. Most detected cancers were at a very early stage. Program costs were reasonable and did not increase with repeat screening. Screening could contribute to decreasing the cost of CRC care by improving the stage at diagnosis.

Background Promising findings obtained using a weekly regimen of 5-fluorouracil (5-FU), epidoxorubicin, leucovorin (LV), and cisplatin (PELFw) to treat locally advanced and metastatic gastric cancer prompted the Italian Group for the Study of Digestive Tract Cancer (GISCAD) to investigate the efficacy of this regimen as adjuvant treatment for high-risk radically resected gastric cancer patients. Methods From January 1998 to January 2003, 400 gastric cancer patients at high risk for recurrence including patients with serosal invasion (stage pT3 N0) and/or lymph node metastasis (stage pT2 or pT3 N1, N2, or N3), were enrolled in a trial of adjuvant chemotherapies; 201 patients were randomly assigned to receive the PELFw regimen, consisting of eight weekly administrations of cisplatin (40 mg/m 2 ), LV (250 mg/m 2 ), epidoxorubicin (35 mg/m 2 ), 5-FU (500 mg/m 2 ), and glutathione (1.5 g/m 2 ) with the support of filgrastim, and 196 patients were assigned to a regimen consisting of six monthly administrations of a 5-day course of 5-FU (375 mg/m 2 daily) and LV (20 mg/m 2 daily, 5-FU/LV). Disease-free and overall survival were estimated and compared between arms using hazard ratios (HRs) and Kaplan – Meier estimates. All statistical tests were two-sided. Results The 5-year survival rates were 52% in the PELFw arm and 50% in the 5-FU/LV arm. Compared with the 5-FU/LV regimen, the PELFw regimen did not reduce the risk of death (HR = 0.95, 95% confidence interval [CI] = 0.70 to 1.29) or relapse (HR = 0.98, 95% CI = 0.75 to 1.29). Less than 10% of patients in either arm experienced a grade 3 or 4 toxic episode. Neutropenia (occurring more often in the PELFw arm) and diarrhea and mucositis (more prevalent in the 5-FU/LV arm) were the most common serious side effects. Nevertheless, only 19 patients (9.4%) completed the treatment in the PELFw arm and 85 (43%) patients completed the treatment in the 5-FU/LV arm. Conclusions Our study found no benefit from an intensive weekly chemotherapy in gastric cancer. The extent of toxicity experienced by the patients in the adjuvant setting suggests that, in gastric cancer, chemotherapy may be more safely administered preoperatively.

Aims and Background To compare conventional fractionation (CF) radiation therapy (RT), arm A, versus a split-course accelerated hyperfractionated schedule (S-AHF), arm B, versus CFRT plus concomitant chemotherapy (CT), arm C, in terms of five-year survival and toxicity for squamous cell tumors of the oropharynx. Methods and Study Design Between January 1993 and June 1998, 192 previously untreated patients with stage III and IV oropharyngeal carcinoma (excluding T1N1 and T2N1) were enrolled in a multicenter randomized phase III trial (ORO 93-01). In arms A and C, 66 to 70 Gy in 33 to 35 fractions was administered five days a week for six and a half to seven weeks. In arm B, the dose delivered was 64 to 67.2 Gy in two fractions of 1.6 Gy every day, five days a week, with a planned two-week split at 38.4 Gy. In arm C the CT regimen consisted of three cycles of carboplatin and 5-fluorouracil (CBDCA 75 mg/m2 on days 1 to 4 and 5-FU 1000 mg/m2 i.v. on days 1 to 4 every 28 days). Results No statistically significant difference was found in five-year overall survival (P = 0.39): 21% for arm A, 21% for arm B, and 40% for arm C. Similarly, there was no statistically significant difference in terms of five-year relapse-free survival: 15% for arm A, 17% for arm B, and 36% for arm C. There was a slight trend towards better five-year locoregional control (P = 0.07) for the combined arm: patients without locoregional relapse were 48% in arm C, 21% in arm A and 18% in arm B. Locoregional control was significantly better when arm C was compared with arms A and B combined (P = 0.02; arm A+B 20%; arm C 48%). Distant metastases were fairly balanced in the three arms (A: 14; B: 9; C: 11), with a tendency towards more frequent isolated distant metastasis development in arm C (8 of 11 [72%] versus 7 of 23 [30%] in arms A+B). Five-year second-tumor-free survival was 85%. The 13 second tumors were equally distributed and were mainly correlated with tobacco and alcohol consumption (five lung, two esophagus, two oral cavity, one larynx, one pancreas, one hepatocarcinoma, one myeloma). Arm C showed slightly more G3+ late side effects involving subcutaneous tissues and mucosa, although significant late sequelae were relatively uncommon and the mucosal side effects were mostly transient. The occurrence of persistent G3 xerostomia was comparable in the three treatment arms. Conclusions The results obtained with the combination of CT and RT compared with RT alone did not reach statistical significance, but combined treatment almost doubled the five-year overall survival, relapse-free survival and locoregional control rate. Patients with advanced squamous cell carcinomas of the oropharynx who are medically suitable for the combined approach should be treated with a combination of radiotherapy and chemotherapy. The occurrence of second tumors is relatively common in these patients and may contribute substantially to the causes of death.

Colonoscopy workload for endoscopy services in Western countries is increasing markedly because of the implementation of faecal occult blood-based mass screening programmes against colorectal cancer (CRC). We therefore explored the possibility of using a combination of faecal tests to prioritize the access to colonoscopy with criteria other than symptoms and/or time of referral.We tested a combination of faecal tests [immunochemical faecal occult blood test (i-FOBT), M2-PK, calprotectin] as markers for advanced neoplasia in a selected series of patients requiring colonoscopy for the suspicion of CRC. All the tests were performed in a 1-day stool sample of patients aged 50-80 years, without any dietary restriction, before colonoscopy.A total of 280 patients' stool single samples were analysed. Forty-seven patients had CRC and 85 patients had one or more advanced adenoma(s) at colonoscopy/histology. CRCs were associated with a highly significant increase (P0.001) in faecal tumour M2-PK (mean 24.2 kU/l), which correlated with Dukes' staging. For CRC detection, i-FOBT was the test with the highest specificity and positive predictive value (0.89 and 0.53), whereas M2-PK had the highest sensitivity and negative predictive value (0.87 and 0.96). Calprotectin showed performance similar to M2-PK in terms of sensitivity and negative predictive value (0.93), but had lower specificity (0.39). The best combination of tests to predict the risk of CRC in this series was i-FOBT+M2-PK, as in patients showing positivity to both markers, the risk of cancer was as high as 79%.The combination of i-FOBT and M2-PK is a sensitive tool in clinical practice for the appropriate management of waiting lists for colonoscopy, as it allows the classification of patients into different degrees of priority for investigation, according to their foreseeable risk of CRC.

Objective: Single-agent epirubicin was tested as primary chemotherapy treatment in patients with early breast cancer >3 cm. Methods: 100 women with locally advanced breast cancer >3 cm were treated with three cycles of single-agent epirubicin at a dose of 120 mg/m2. All patients showing tumor shrinkage to less than 3 cm were considered candidates for conservative surgery (quadrantectomy); in the remaining patients modified radical mastectomy was carried out. Postsurgical treatment consisted of CMF chemotherapy except for postmenopausal node-positive, estrogen-positive patients who were assigned to hormonal treatment with tamoxifen and postmenopausal node-negative, estrogen-positive ones who did not receive any treatment. Results: Quadrantectomy was carried out in 71 patients. At the median follow-up time of 69 months, the relapse rate was 29.6% among patients who underwent quadrantectomy (21 out of 71) and 58.6% among patients who underwent modified radical mastectomy (17 out of 29). Conclusions: Single-agent chemotherapy with anthracyclines could appear to be an effective treatment in inducing a tumor downstaging in patients with early breast cancer >3 cm. This treatment can be administered outside clinical trials in patients who desire to preserve their body integrity. Further prospective, randomized trials are needed in order to validate and better define the role of epirubicin in the neoadjuvant strategy of breast cancer patients.

Purpose: Lonidamine (LND) can enhance the activity of anthracyclines in patients with metastatic breast cancer. A multicenter, prospective, randomized trial was designed to determine whether the association of LND with high-dose epirubicin plus cyclophosphamide (EC) could improve disease-free survival (DFS) in patients with early breast cancer (BC) compared with EC alone. Granulocyte colony-stimulating factor (G-CSF) was added to maintain the EC dose-intensity. Patients and Methods: From October 1991 to April 1994, 506 patients with stage I/II BC were randomly assigned to four groups: (A) epirubicin 120 mg/m2 and cyclophosphamide 600 mg/m2 administered intravenously on day 1 every 21 days for four cycles (124 patients); (B) EC plus LND 450 mg/d administered orally (125 patients); (C) EC plus G-CSF administered subcutaneously (129 patients); (D) EC plus LND plus G-CSF (128 patients). Results: Median follow-up was 55 months. Five-year DFS rate was similar for LND (B+D groups; 69.6%) versus non-LND arms (A+C groups; 70.3%) and G-CSF (C+D groups; 67.2%) versus non–G-CSF arms (A+B groups; 72.9%). Five-year overall survival (OS) was comparable in LND (79.1%) versus non-LND arms (81.3%) and in G-CSF (80.6%) versus non–G-CSF arms (79.6%). DFS and OS distributions in LND and G-CSF arms did not change according to tumor size, node, receptor, and menopausal status. G-CSF dramatically reduced hematologic toxicity without having a significant impact on dose-intensity (98.1% v 95.5% for C+D and A+B groups, respectively). Conclusion: EC is active and well tolerated in patients with early breast cancer. The addition of LND or G-CSF does not improve DFS or OS.

Purpose: To compare conventional fractionation radiation therapy (RT), Arm A, vs. split-course accelerated hyperfractionated RT (S-AHF), Arm B, vs. conventional fractionation RT plus concomitant chemotherapy (CT), Arm C, in terms of survival and toxicity for advanced, unresectable epidermoid tumors of oropharynx. Methods and Materials: Between January 1993 and June 1998, 192 previously untreated patients affected with Stage III and IV oropharyngeal carcinoma (excluding T1N1 and T2N1) were accrued in a multicenter, randomized Phase III trial (ORO 93-01). For Arms A and C, 66–70 Gy in 33–35 fractions, 5 days a week, were administered in 6.5–7 weeks to tumor and positive nodes. In Arm B, the dose delivered to tumor and involved nodes was 64–67.2 Gy, giving 2 fractions of 1.6 Gy every day with an interfraction interval of at least 4 h and preferably 6 h, 5 days a week. At 38.4 Gy, a 2-week split was planned; after the split, RT was resumed with the same modality. In Arm C, CT regimen consisted of carboplatin and 5-fluorouracil (CBDCA 75 mg/m 2 , Days 1–4; 5-FU 1,000 mg/m 2 i.v. over 96 h, Days 1–4, recycling every 28 days (at 1st, 5th, and 9th week). Results: No statistically significant difference was detected in overall survival ( p = 0.129): 40% Arm A vs. 37% Arm B vs. 51% Arm C were alive at 24 months. Similarly, there was no statistically significant difference in terms of event-free survival ( p = 0.196): 20% for Arm A, 19% for Arm B, and 37% for Arm C were event free at 24 months. On the contrary, the 2-year disease-free survival was significantly different among the three arms ( p = 0.022), with a superiority for Arm C. At 24 months, the proportion of patients without relapse was 42% for Arm C vs. 23% for Arm A and 20% for Arm B. Patients in Arm A less frequently developed G3+ acute mucositis than their counterparts in Arm B or C (14.7% vs. 40.3% vs. 44%). Regarding the CT-related acute toxicity, apart from 1 case of fatal nephrotoxicity, only hematologic G3+ (Grade 3 or higher) acute sequelae were observed (World Health Organization scale), most commonly leukopenia (22.7%). Arm C showed slightly more G3+ skin, s.c. tissue, and mucosal late side effects (RTOG scale), although significant sequelae were relatively uncommon, and mucosal sequelae were most commonly transient. The occurrence of persistent G3 xerostomia was comparable in all three treatment arms. Conclusions: The combination of simultaneous CT and RT with the regimen of this trial is better than RT alone in advanced oropharyngeal squamous-cell carcinomas, by increasing disease-free survival. This improvement, however, did not translate into an overall survival improvement, and was associated with a higher incidence of acute morbidity.

BACKGROUND: Concomitant chemoradiotherapy (CT/RT) is the standard treatment of locally advanced squamous cell carcinoma of the head and neck (SCCHN). We evaluated the efficacy of induction docetaxel (Taxotere), cisplatin, and 5-fluorouracil (TPF) before CT/RT versus CT/RT alone. PATIENTS AND METHODS: Patients with stage III-IVM0 SCCHN, Eastern Cooperative Oncology Group performance status of zero to one, were randomly assigned to receive CT/RT alone (arm A: two cycles of cisplatin 20 mg/m(2), days1-4, plus 5-fluorouracil 800 mg/m(2)/day 96 h continuous infusion, during weeks 1 and 6 of radiotherapy) or three cycles of TPF (arm B: docetaxel 75 mg/m(2) and cisplatin 80 mg/m(2), day 1, and 5-fluorouracil 800 mg/m(2)/day 96 h continuous infusion, every 3 weeks) followed by the same CT/RT. The primary end point was the rate of radiologic complete response (CR) at 6-8 weeks after the end of CT/RT. RESULTS: A total of 101 patients were randomly allocated to the study (51 arm A; 50 arm B). CR rates were 21.2% (arm A) versus 50% (arm B). Median progression-free survival and overall survival were, respectively, 19.7 and 33.3 months (arm A) and 30.4 and 39.6 months (arm B). Hematologic and non-hematologic toxic effects during CT/RT were similar in the two arms. CONCLUSION: Induction TPF followed by CT/RT was associated with higher radiologic CR in patients with locally advanced SCCHN with no negative impact on CT/RT feasibility.

Infections in cancer patients after implantation of a central venous device (CVD) are not infrequent and are potentially serious. The possibility of limiting this complication with antithrombotic drugs is still debated. For this observational study, we recorded the routine management of CVD in cancer patients in 18 oncology centers in Lombardy (northern Italy), assessing the effect of antithrombotic prophylaxis on catheter-related infections. Out of 1410 patients enrolled, 451 received antithrombotic prophylaxis continuously after implantation of the central line. During a median follow-up of 30 months, 57 catheter-related infections were reported in the 1390 patients seen at least once at follow-up visits (4.1 % of the whole series), giving an overall incidence of 0.10 infections per 1000 catheter days. This complication was significantly more frequent among patients with an indwelling central venous catheter, or peripherally inserted catheter, than among those with a port device, and the group not given antithrombotic prophylaxis had 0.14 infective complications/1000 CVD days compared with 0.05/1000 CVD days (odds ratio 2.4; 95% confidence interval 1.7-5.0) for those treated. Antithrombotic prophylaxis protected against infections at the catheter exit site and track but not against systemic infections. Confirming earlier evidence, this study found a reduction in catheter-related infections in patients given antithrombotic prophylaxis. However, this reduction, reflecting local infections, seems unlikely to be one of the mechanisms explaining the lower mortality among our patients treated with anticoagulants.

Background: Some trial have demonstrated a benefit of adjuvant fluoropirimidine with or without platinum compounds compared with surgery alone. ITACA-S study was designed to evaluate whether a sequential treatment of FOLFIRI [irinotecan plus 5-fluorouracil/folinic acid (5-FU/LV)] followed by docetaxel plus cisplatin improves disease-free survival in comparison with 5-FU/LV in patients with radically resected gastric cancer. Patients and methods: Patients with resectable adenocarcinoma of the stomach or gastroesophageal junction were randomly assigned to either FOLFIRI (irinotecan 180 mg/m 2 day 1, LV 100 mg/m 2 as 2 h infusion and 5-FU 400 mg/m 2 as bolus, days 1 and 2 followed by 600 mg/m 2 /day as 22 h continuous infusion, q14 for four cycles) followed by docetaxel 75 mg/m 2 day 1, cisplatin 75 mg/m 2 day 1, q21 for three cycles (sequential arm) or De Gramont regimen (5-FU/LV arm). Results: From February 2005 to August 2009, 1106 patients were enrolled, and 1100 included in the analysis: 562 in the sequential arm and 538 in the 5-FU/LV arm. With a median follow-up of 57.4 months, 581 patients recurred or died (297 sequential arm and 284 5-FU/LV arm), and 483 died (243 and 240, respectively). No statistically significant difference was detected for both disease-free [hazard ratio (HR) 1.00; 95% confidence interval (CI): 0.85–1.17; P= 0.974] and overall survival (OS) (HR 0.98; 95% CI: 0.82–1.18; P= 0.865). Five-year disease-free and OS rates were 44.6% and 44.6%, 51.0% and 50.6% in the sequential and 5-FU/LV arm, respectively. Conclusions: A more intensive regimen failed to show any benefit in disease-free and OS versus monotherapy. Clinical trial registration: ClinicalTrials.gov Identifier: NCT01640782.

PurposeBreast cancer follow-up procedures after primary treatment are still a controversial issue. Aim of this study was to investigate, through a web-based survey, surveillance methodologies selected by Italian oncologists in everyday clinical practice.MethodsReferents of Italian medical oncology units were invited to participate to the study via e-mail through the SurveyMonkey website. Participants were asked how, in their institution, exams of disease staging and follow-up are planned in asymptomatic women and if surveillance continues beyond the 5th year.ResultsBetween February and May 2013, 125 out of 233 (53.6%) invited referents of Italian medical oncology units agreed to participate in the survey. Ninety-seven (77.6%) referents state that modalities of breast cancer follow-up are planned according to the risk of disease progression at diagnosis and only 12 (9.6%) oncology units apply the minimal follow-up procedures according to international guidelines. Minimal follow-up is never applied in high risk asymptomatic women. Ninety-eight (78.4%) oncology units continue follow-up in all patients beyond 5 years.ConclusionsOur survey shows that 90.4% of participating Italian oncology units declare they do not apply the minimal breast cancer follow-up procedures after primary treatment in asymptomatic women, as suggested by national and international guidelines. Interestingly, about 80.0% of interviewed referents performs the so called "tailored follow-up", high intensity for high risk, low intensity for low risk patients. There is an urgent need of randomized clinical trials able to determine the effectiveness of risk-based follow-up modalities, their ideal frequency and persistence in time.

Angiogenesis is essential for tumor growth. Since vascular endothelial growth factor (VEGF) represents the main angiogenic factor, the control of VEGF secretion could constitute the most important mechanism to achieve the inhibition of angiogenesis-related processes. High blood concentrations have been proven to correlate with poor prognosis in advanced cancer. In experimental conditions, chemotherapeutic agents such as taxol appeared to inhibit VEGF-induced angiogenesis, while at present there are no data about the influence of chemotherapy on VEGF secretion in cancer patients. This preliminary study was performed to evaluate the effect of taxol therapy on VEGF secretion in advanced cancer patients in relation to the clinical response. The study included 14 patients with metastatic breast cancer who were treated with taxol monochemotherapy (175 mg/m2 i.v. every 21 days for three cycles). Serum levels of VEGF were measured by ELISA in blood samples collected before therapy and at 21-day intervals. The clinical response consisted of partial response (PR) in three and stable disease (SD) in six patients, whereas the other five patients had progressive disease (PD). Abnormally high pre-treatment levels of VEGF were seen in 8/14 patients. VEGF mean values significantly decreased during taxol therapy in patients with PR or SD, whereas no decline was observed in patients with PD. Moreover, the percent of normalization or decline greater than 50% in VEGF levels was significantly higher in patients with PR or SD than in those with PD (5/9 vs. 0/5). This preliminary study would suggest that the efficacy of taxol therapy in metastatic breast cancer - at least in terms of disease stabilization - may be associated with a decrease in VEGF blood levels followed by potential inhibition of cancer-related neovascularization.

Aims and Background Prolactin (PRL) may be a growth factor for breast cancer. Abnormally high levels of PRL have been proven to be associated with a poor prognosis in metastatic breast cancer. However, most studies have been limited to the evaluation of basal levels of PRL rather than its response to the classical endocrine dynamic tests. This study was performed to analyse the dynamic secretion of PRL under stimulatory and inhibitory tests in metastatic breast cancer. Methods The study included 10 untreated metastatic breast cancer women, who were evaluated after the classical stimulatory and inhibitory tests for PRL secretion with the antidopaminergic agent Metoclopramide (10 mg iv as a bolus) and with L-dopa, respectively. Serum levels of PRL were measured by RIA before and at subsequent intervals after drug administration. PRL levels were considered to be elevated when they were higher than 25 ng/ml. Results Abnormally high basal levels of PRL were seen in 6/10 patients. L-dopa was unable to inhibit PRL secretion, whose mean concentrations paradoxically significantly increased in response to L-dopa, with values comparable to those observed after the classical stimulatory test with metoclopramide. Conclusions This study confirm the existence of hyperprolactinemia associated with metastatic breast cancer. In addition, by showing a paradoxical rise of PRL in response to L-dopa, which inhibits PRL secretion in physiological conditions, this study would suggest that breast cancer-related hyperprolactinemia may depend at least in part on endogenous disease-related neuroendocrine alterations.

The evidence of lymphocytopenia has been demonstrated to predict a poor prognosis in terms of survival in advanced cancer patients. This finding is not surprising because of the fundamental role of lymphocytes in mediating tumor cell destruction. Despite the importance of lymphocytes in the pathogenesis of cancer, there are only few data about the profile and the function of lymphocytes during the various antitumor therapies, and in particular the relation between lymphocyte pretreatment number and response to chemotherapy remains to be established. The present study was performed to evaluate whether the evidence of lymphocytopenia before the onset of treatment may influence the efficacy of chemotherapy in metastatic cancer patients affected by the most frequent tumor types. The study included 183 patients (lung cancer: 89; colorectal cancer: 63; breast cancer: 31), 95 of whom had been previously treated with chemotherapy. The chemotherapeutic regimens consisted of oxaliplatin plus 5-fluorouracil and folates in untreated colorectal cancer, weekly irinotecan in pretreated colorectal cancer, cisplatin plus gemcitabine or etoposide in untreated lung cancer, weekly vinorelbine in pretreated lung cancer, and taxotere in breast cancer patients who had been previously treated with anthracyclines. Lymphocyte count was considered to be abnormally low for values below 1500/mm3. Lymphocytopenia was found in 79/183 (43%) patients, without any significant differences in relation to tumor histology. A complete response (CR) was achieved in 6/104 patients with a normal lymphocyte count and in none of the 79 lymphocytopenic patients. A partial response (PR) was obtained in 39 patients with a normal lymphocyte count and in only eight patients with a low lymphocyte count prior to therapy. Therefore, irrespective of the type of chemotherapy, the objective tumor response rate (CR + PR) in lymphocytopenic patients was significantly lower than in patients with normal pretreatment lymphocyte counts (8/79 vs 45/104; p

Recent studies suggest that the pineal hormone melatonin may reduce chemotherapy-induced immune and bone marrow damage. In addition, melatonin may exert potential oncostatic effects either by stimulating host anticancer immune defenses or by inhibiting tumor growth factor production. On this basis, we have performed a randomized study of chemotherapy alone vs. chemotherapy plus melatonin in advanced non-small cell lung cancer patients (NSCLC) with poor clinical status. The study included 70 consecutive advanced NSCLC patients who were randomized to receive chemotherapy alone with cisplatin (20 mg/m2/day i.v. for 3 days) and etoposide (100 mg/m2/day i.v. for 3 days) or chemotherapy plus melatonin (20 mg/day orally in the evening). Cycles were repeated at 21-day intervals. Clinical response and toxicity were evaluated according to World Health Organization criteria. A complete response (CR) was achieved in 1/34 patients concomitantly treated with melatonin and in none of the patients receiving chemotherapy alone. Partial response (PR) occurred in 10/34 and in 6/36 patients treated with or without melatonin, respectively. Thus, the tumor response rate was higher in patients receiving melatonin (11/34 vs. 6/35), without, however, statistically significant differences. The percent of 1-year survival was significantly higher in patients treated with melatonin plus chemotherapy than in those who received chemotherapy alone (15/34 vs. 7/36, P < 0.05). Finally, chemotherapy was well tolerated in patients receiving melatonin, and in particular the frequency of myelosuppression, neuropathy, and cachexia was significantly lower in the melatonin group. This study shows that the concomitant administration of melatonin may improve the efficacy of chemotherapy, mainly in terms of survival time, and reduce chemotherapeutic toxicity in advanced NSCLC, at least in patients in poor clinical condition.

Diarrhea is one of the dose-limiting toxicities for administration of fluorouracil (5FU) in patients with colorectal cancer and can result in severe morbidity and mortality. No well-defined prognostic factors influencing 5FU-associated diarrhea have been identified, which means its occurrence is unforeseeable. The aim of this study was to check whether any characteristics related to patients or chemotherapy could allow the identification of subsets of patients at higher risk of developing diarrhea while receiving a regimen containing 5FU. A logistic regression analysis was performed with age, sex, site of primary tumor, presence of primary tumor, presence of colostomy, time since surgery, number of courses of chemotherapy, diarrhea in previous courses, season of treatment, and chemotherapeutic regimens used as model parameters to predict occurrence of diarrhea in 258 colorectal cancer patients receiving a 5FU-containing regimen. Presence of primary tumor (P=0.004), previous episodes of chemotherapy-related diarrhea (P=0.00005) and summer season (P=0.014) were found to be significant risk factors for developing diarrhea. The other variables examined, such as age, sex, chemotherapeutic regimen, site of primary tumor, presence of colostomy, and time since surgery, were not significantly correlated to diarrhea. Chemotherapeutic regimen was the only parameter that allowed prediction of the severity of diarrhea : 5FU/6S-leucovorin/interferon caused more severe diarrhea, followed by 5FU/leucovorin weekly. Although the analysis of these clinical features does not seem to allow the definition of a well-defined subset of colorectal cancer patients at higher risk of 5FU-induced diarrhea, it can be recommended that patients with primary tumor, or who have experienced diarrhea in earlier courses of chemotherapy or are receiving treatment in summer should be carefully monitored, especially in the first cycles.

Subsite-specific incidence rates of colorectal cancer (CRC) and adenomas may vary considerably by race, sex and age as well as due to different screening strategies. We assessed variations in the anatomical distribution of adenomas according to age and sex in an average-risk screening cohort testing positive at immunological faecal occult blood test (i-FOBT) in northern Italy. Data from 2,281 consecutive asymptomatic i-FOBT-positive subjects ageing 50–70 years undergone colonoscopy were reviewed. Size, number, macroscopic and histological features of all adenomas found as well as their proximal or distal location in relation to the splenic flexure were examined. Odds ratios (OR) of proximal neoplasms, according to the presence of distal neoplasms and other selected covariates were assessed by multiple logistic regression analysis. A total of 2,599 neoplasms were found in 1,396 patients. Of these, 116 (5 %) were colorectal cancers, diagnosed in 106 patients. Out of 2,483 adenomas found, 1,564 (63 %) were sessile, 795 (32 %) were peduncolated and 124 (5 %) were flat-type; 54 % of all adenomas were tubular, 36 % were tubulovillous or villous, and 10 % were serrated adenomas. The majority of neoplasms (66 %) were located in the distal colon. Tumour subsite distribution was consistent in both sexes, whereas significant proximal migration of neoplasms occurred in the older age cohort. Indeed, the rate of proximal neoplasms in patients aged ≥60 years was 37 % as compared with 29 % in those ageing 50–59 years. Male gender (OR 1.84), age of 60 years or older (OR 1.44), having a family history of colorectal neoplasms (OR 1.47) and presence of at least 1 distal advanced adenoma (OR 1.63) were all significant predictors of advanced proximal neoplasms. A left to right shift of colorectal adenomas with increasing age is evident in northern Italian asymptomatic i-FOBT-positive population. Advanced proximal neoplasms are not uncommon in subjects with or without distal adenomas, especially after 60 years of age. This should be carefully considered when implementing public screening strategies for CRC since the use of flexible sigmoidoscopy as a screening tool, particularly in older age groups, appears to be less effective.

It is known that neoplastic cachexia shows metabolic characteristics different from other common causes of malnutrition, and that it is mainly due to an abnormal secretion of TNF, whose levels are often high in patients with advanced neoplasia. Previous clinical studies have suggested that the pineal hormone melatonin (MLT), which plays an essential role in the neuroendocrine regulation of biological systems, may improve the clinical status of advanced cancer patients and inhibit TNF secretion. To investigate the relationship between MLT, TNF and cancer-related weight loss, 100 untreatable metastatic solid tumour patients entered this study to receive either supportive care alone, or supportive care plus MLT (20 mg/day orally in the evening). Patients were observed for 3 months, and were considered evaluable when they were observed for at least 2 months. There were 86 evaluable patients, the other 14 patients having died from rapid progression of disease. The per cent of weight loss greater than 10% was significantly higher in patients treated by supportive care alone than in those concomitantly treated by MLT, with no difference in food intake (P < 0.01). Mean serum levels of TNF progressively increased in the supportive care group, but to levels that were not significantly different from pretreatment values. In contrast, TNF mean concentrations significantly decreased (P < 0.05) in patients concomitantly treated by MLT. These results suggest that the pineal hormone MLT may be effective in the treatment of the neoplastic cachexia by decreasing TNF blood concentrations.

Aims and backgroundIGF-1 has been proven to be one of the most important growth factors for normal and neoplastic cells. Abnormally high levels of IGF-1 have been observed in cancer patients. Since it has been demonstrated that some growth factors may counteract the action of antitumor cytokines, the presence of increased IGF-1 concentrations could reduce the efficacy of cancer biotherapies with cytokines, such as IL-2. The present study was performed to evaluate the efficacy of IL-2 immunotherapy in relation to the pretreatment levels of IGF-1 in advanced cancer patients.MethodsThe study included 20 consecutive patients with metastatic renal cell cancer who were treated subcutaneously with IL-2 at 6 million IU/day for 5 days/week for 6 weeks. IGF-1 serum levels were measured by RIA on venous blood samples collected before the immunotherapy, after 3 weeks, and at the end of IL-2 injection.ResultsObjective tumor regressions were obtained in 5/20 patients, consisting of 1 complete response (CR) and 4 partial responses (PR). Nine patients had stable disease and the last 6 patients progressed. Abnormally high pretreatment levels of IGF-1 were seen in 13/20 patients. The percent of clinical responses (CR + PR) was significantly higher in patients with normal pretreatment concentrations of IGF-1 than in those with elevated levels (4/7 vs 1/13, P < 0.01). No significant changes in mean IGF-1 levels occurred during IL-2 therapy. However, mean IGF-1 levels increased in progressing patients and decreased in those with a response or stable disease, even though none of the differences was statistically significant.ConclusionsThe study showed that high pretreatment levels of IGF-1 are associated with a reduced efficacy of IL-2 immunotherapy of renal cancer. Further studies are required to establish whether IGF-1 levels simply reflect the extension of disease, or whether they may influence per se the action of IL-2.

Recent advances in our knowledge of psychoneuroimmune interactions involved in the control of tumour growth have shown the possibility of manipulating host anticancer defences through a neuroimmunotherapeutic strategy. In particular, our previous studies have demonstrated that the concomitant administration of the pineal neurohormone melatonin may amplify the antitumour efficacy of interleukin-2 (IL-2) in humans. On this basis, a study was planned to investigate the influence of neuroimmunotherapy with low-dose IL-2 plus melatonin on survival time and on performance status in untreatable metastatic cancer patients. The study included 100 patients with metastatic solid tumours, for whom no standard therapy was available. They were randomized to receive IL-2 (3 x 106 IU/day subcutaneously for 4 weeks) plus melatonin (40 mg/day orally) or supportive care alone. Partial tumour regressions were seen in 9/52 (17%) patients treated with the immunotherapy, and in none of the patients treated with supportive care alone. The percentage of survival at 1 year was significantly higher in patients treated with IL-2 and melatonin than in those receiving the supportive care alone (21/52 versus 5/48, P

It has been demonstrated that breast surgery may induce prolactin (PRL) increase. Because of the potential stimulatory role of PRL on breast cancer cells, its postoperative increase may influence the prognosis of breast cancer patients. This study was performed to evaluate the influence of surgery-induced hyperprolactinemia on recurrence rate in operable breast cancer. The study included 250 consecutive breast cancer patients, clinical stage T1-3 N0-2M0, who were observed for a median follow-up of 72 months. Surgery-induced hyperprolactinemia occurred in 108/250 patients (43%). Irrespectively of node involvement, hormonal receptor, type of surgery and adjuvant therapies, the relapse rate was significantly higher in patients who had no surgery-induced hyperprolactinemia than in those with postoperative PRL increase (64/142 vs. 23/108; p0.001). This difference was also significant in relation to node status (N0:22/63 vs. 5/56, p0.001; N+:42/79 vs. 18/52, p0.05). The present study shows that a surgery-induced rise of PRL, despite its potential stimulation of cancer cell growth, is paradoxically associated with a longer disease-free survival in operable breast carcinoma in both patients with or without axillary node involvement. Moreover, this study suggests that the prognosis of node-negative patients who did not show postoperative hyperprolactinemia tends to be similar to that of patients with node involvement and surgery-induced PRL enhancement. Therefore, the lack of surgery-induced hyperprolactinemia would have to be grouped together with the unfavorable prognostic factors of breast cancer.

Our preliminary studies in humans have shown that the pineal neurohormone melatonin (MLT) may enhance the antitumor activity of IL-2, by confirming the existence of a neuroendocrine control on cytokine effects. On this basis, a study was started to evaluate the influence of a concomitant administration of MLT and low-dose IL-2 in cancer patients, who had progressed during a previous immunotherapy with IL-2 alone. The study included 14 patients with advanced solid tumors (lung 6; kidney 4; stomach 2; liver 1; melanoma 1). IL-2 was given at a daily dose of 3 million IU s.c. for 6 days/week for 4 weeks. MLT was given orally at a daily dose of 40 mg every day, starting 7 days prior to IL-2. Objective tumor regression, consisting of a partial remission (PR), was achieved in 3/14 (21%) patients (lung 1; kidney 1; liver 1). Six other patients had a stable disease (SD), while the remaining 5 cases progressed. PR and SD were associated either with a significantly longer survival at 1 year, or with a significantly higher increase in lymphocyte and eosinophil mean number with respect to the patients with disease progression. This preliminary study suggests that advanced solid neoplasms resistant to IL-2 may become responsive to IL-2 therapy by a concomitant administration of the pineal hormone MLT, which could act by enhancing IL-2 antitumor immune effects and/or by increasing the susceptibility of cancer cells to the cytolysis mediated by IL-2-induced cytotoxic lymphocytes.

In 2005, the National Health Service recommended a population-based colorectal cancer (CRC) screening program using biennial fecal occult blood testing (FOBT), followed by total colonoscopy in positive patients. So far, no studies have been performed to evaluate the impact of a mass-screening CRC campaign on the health system services at the community level in Italy. We have therefore assessed the workload generated by the first two biennial rounds of screening program on the activity of hospital services involved in CRC diagnosis in the Lecco province.Routine data from all hospital services of our province were collected on activity levels related to CRC diagnosis from January 2003 to December 2009. This time span covered the 2 years prior to, as well as the two biennial rounds of the CRC screening program. In particular, we focused on the volume of outpatient FOBTs and colonoscopies (both diagnostic and interventional) performed among subjects outside the screening program. Joinpoint models were used to test whether an apparent change in trend of examination over time was statistically significant in different age cohorts of the population (50 years, 50-69 years, and ≥70 years).The volume of "extra-screening" per-patient/FOBTs and colonoscopies increased significantly over the evaluated periods in all ages, until year 2008, when a steady trend was beginning; the AAPCs (average of the annual percent changes) values were 5.7, 3.1, and 8.4 for FOBT and 14.6, 13.4, and 16.7 for colonoscopy in the three age cohorts, respectively. However, the increase in both FOBT and colonoscopy demand was maximal in the cohort ≥70 years, where three statistically significant annual percent changes (APCs) were identified (in 2003-2005, 2005-2006, and 2006-2007 APCs were 12.3, 14.9, and 15.9 for FOBT, and 18.7, 36.8, and 25.4 for colonoscopy, respectively).After the implementation of a FOBT-based mass-screening program for CRC, careful consideration must be given to the significant increase in the workload of hospital services involved in CRC diagnosis, outside the screening campaign. The extra-work mainly involves gastroenterologists performing colonoscopy, whose activity increased over the 5-year period by 118%, as well as laboratory services, where the demand of FOBTs rose by 40%. This phenomenon, mainly attributable to a profound change in the attitude toward CRC screening by those age cohorts outside the program, covers a time span of two full rounds of screening, whereupon a steady trend for colonoscopy is apparent.

Background. The concomitant activation of macrophage-mediated immunosuppressive events might represent one of the most important biologic factors responsible for the decreased efficacy of cancer immunotherapies, including that of interleukin (IL)-2. In previous studies, the authors observed that the increase in the soluble IL-2 receptor (SIL-2R) and neopterin levels was related to the generation of macrophage-mediated immuno-suppression and associated with a reduced clinical efficacy during IL-2 cancer immunotherapy. Because both cytokines and neurohormones may influence the macrophage system, the current study was done to evaluate the effects of IL-3 and of the pineal hormone melatonin (MLT) on monocyte response to IL-2 administration. Methods. Peripheral blood monocytes were incubated with different concentrations of IL-2, IL-3, and MLT, either alone or in association. Results. SIL-2R, neopterin, and tumor necrosis factor-alpha mean concentrations in the medium significantly increased during incubation with IL-2 at a concentration of 100 Cetus units/ml. IL-3 alone, at a dose of 10 ng/ml, also stimulated tumor necrosis factor release; no effect was found on SIL-2R and neopterin. The IL-2–induced neopterin rise was blocked by a concomitant incubation with IL-3 at a dose of 10 ng/ml. Finally, the concomitant incubation with IL-3 and MLT further inhibited neopterin release and significantly decreased IL-2-induced SIL-2R secretion. Conclusions. These results suggest that IL-3 alone or in association with MLT may modulate macrophage functions during cancer immunotherapy with IL-2 and decrease the IL-2-induced macrophage activation.

Aims and background Isolated vaginal recurrences of endometrial carcinoma are rare, and prognostic factors that predict treatment outcome are still not well defined. The aim of the present study was to evaluate the results of brachytherapy in isolated vaginal recurrences from endometrial carcinoma. Methods Thirty-five patients with isolated vaginal recurrences were treated with brachytherapy with intravaginal ovoids or cylinders that were calculated to deliver 6000 to 7000 cGy at the surface. Patients were assessed for size and location of recurrence at presentation, response and complications from therapy. Results Treatment was well tolerated by most patients. Grade 2 toxicity occurred in 4 patients (3 cases of partial vaginal stenosis and one proctitis). Complete response to radiation was observed in all patients, and an overall 9 failures were observed (4 local, 4 distant and 1 local plus distant). Twenty patients (57%) were alive without evidence of disease at 3 to 11 years following treatment. Site of vaginal recurrence (upper third versus others) and long (more than 12 months versus less than 12 months) interval from hysterectomy were the only factors significantly related to local failures. Conclusions Isolated vaginal recurrences following hysterectomy for endometrial carcinoma can be treated with brachytherapy with a low rate of severe toxicity.

We present the rationale and study design of the Tarceva Italian Lung Optimization trial phase III, multicenter, open-label, randomized trial on efficacy of second-line therapies in different subgroups of non-small-cell lung cancer (NSCLC) patients identified using molecular and clinical evaluations. To date, we can assume that advanced NSCLC epidermal growth factor receptor (EGFR)-mutated patients benefit from EGFR tyrosine kinase inhibitors, such as gefitinib and erlotinib, whereas their role in the treatment of patients who do not have EGFR mutations is controversial. The aim of this study is to assess whether it is possible to optimize second-line treatment in NSCLC patients with absence of EGFR mutations. Moreover, the predictive value of the K-ras mutation, EGFR protein expression, and EGFR gene copy number, as well as a smoking habit and histotype for determining a different effect of erlotinib compared with chemotherapy will be assessed in patients who do not have EGFR mutations. The primary endpoint is overall survival; the secondary endpoints are progression-free survival, response rate, quality of life, and toxicity. We have planned to collect blood samples to identify different prognosis-related polymorphisms and to assess their sensitivity and specificity in the detection of EGFR and K-ras mutations with respect to histologic samples.

On the basis of our previous preliminary data which showed that the pineal hormone melatonin (MLT) may potentiate IL-2 activity and reduce the dose of IL-2 required to determine an effective host antitumor response, we performed a clinical study with low-dose IL-2 given once/day subcutaneously (3 million IU/day for 6 days/week for 4 weeks) in association with MLT (50 mg/day orally at 8.00 p.m. every day) as a second-line therapy in metastatic colorectal cancer patients pretreated with 5-fluorouracil. Evaluable patients were 13/14, and most of them showed disseminated liver metastases. No objective tumor regression was seen. A stabilization of disease was achieved in 4/13 patients (median duration 5+ months), and the other 9 patients progressed. Mean number of lymphocytes and eosinophils significantly increased during the treatment. Moreover, the mean increase in lymphocyte number was significantly higher in patients with stable disease than in those with progressive disease, whereas there was no difference as regards eosinophils. Serum levels of neopterin and tumor necrosis factor (TNF) significantly increased during therapy, and TNF increase was correlated to the side effects rather than to the control of cancer development. This study shows that neuroimmunotherapy with low-dose interleukin-2 and MLT, even though capable of determining an evident expansion of immune cells involved in host antitumor response, does not seem to be effective in terms of tumor regression in metastatic colon cancer patients pretreated with 5-fluorouracil.

It is known that several cytokines can exert hormonal effects. At present, no data are available about the possible influence of IL-3 on the endocrine system. In order to investigate the endocrine effects of IL-3 in humans, we have evaluated serum levels of Cortisol, β-endorphin, GH, PRL, FSH, LH, TSH and melatonin in response to intravenous injection of IL-3 at a dose of 1 mcg/kg b.w. at 6.00 p.m. The study was performed in 5 non-small cell lung cancer patients. GH increased significantly in response to IL-3. PRL showed a progressive decrease after IL-3 injection, but its variations were not statistically significant. All other hormones, including Cortisol, were not affected by IL-3. This preliminary study shows that IL-3 may exert endocrine effects in humans, which would seem at variance with previously reported results on most other cytokines.