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Epidermal growth factor receptor (EGFR) pathway has been shown to play a crucial role in several inflammatory conditions and host immune-inflammation status is related to tumor prognosis. This study aims to evaluate the prognostic significance of a four-gene inflammatory signature in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients treated with the EGFR inhibitor cetuximab plus chemotherapy. The inflammatory signature was assessed on 123 R/M HNSCC patients, enrolled in the multicenter trial B490 receiving first-line cetuximab plus platinum-based chemotherapy. The primary endpoint of the study was progression free survival (PFS), while secondary endpoints were overall survival (OS) and objective response rate (ORR). The patient population was subdivided into 3 groups according to the signature score groups. The four-genes-signature proved a significant prognostic value, resulting in a median PFS of 9.2 months in patients with high vs. 6.2 months for intermediate vs. 3.9 months for low values (p = 0.0016). The same findings were confirmed for OS, with median time of 18.4, 13.4, and 7.5 months for high, intermediate, and low values of the score, respectively (p = 0.0001). When ORR was considered, the signature was significantly higher in responders than in non-responders (p = 0.0092), reaching an area under the curve (AUC) of 0.65 (95% CI: 0.55–0.75). Our findings highlight the role of inflammation in the response to cetuximab and chemotherapy in R/M-HNSCC and may have translational implications for improving treatment selection.

Recently major efforts have been made to define the oligometastatic setting, but for head and neck cancer (HNC) limited data are available. We aimed to evaluate outcome of oligometastatic HNC treated with Stereotactic body radiotherapy (SBRT) as metastasis-directed therapy. We analyzed patients treated with SBRT on a maximum of five oligometastases from HNC, in up to two organs. Concomitant treatment was allowed. End points were toxicity, local control of treated metastases (LC), progression-free survival (PFS) and overall survival (OS). 48 consecutive patients and 71 lesions were treated. With a follow-up of 20.2 months, most common primary tumors were larynx (29.2%) and salivary glands (29.2%), while common site of metastases was lung (59.1%). Median dose was 48 Gy (21–75) in 3–8 fractions. Treatment was well tolerated, with two patients reporting mild pain and nausea. LC rates at 1 and 2 years were 83.1% and 70.2%. Previous local therapy (HR 4.97; p = 0.002), oligoprogression (HR 4.07; p = 0.031) and untreated metastases (HR 4.19; p = 0.027) were associated with worse LC. PFS at 1 and 2 years were 42.2% and 20.0%. Increasing age (HR 1.03; p = 0.010), non-adenoid cystic carcinoma (HR 2.57; p = 0.034) and non-lung metastases (HR 2.20; p = 0.025) were associated with worse PFS. One- and 2-years OS were 81.0% and 67.1%. Worse performance status (HR 2.91; p = 0.049), non-salivary primary (HR 19.9; p = 0.005), non-lung metastases (HR 2.96; p = 0.040) were correlated with inferior OS. SBRT can be considered a safe metastasis-directed therapy in oligometastatic HNC. Efficacy of the treatment seems to be higher when administered upfront in the management of metastatic disease; however, selection of patients need to be improved due to the relevant risk of appearance of new metastatic site after SBRT.

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.

OBJECTIVE. The purpose of this study was to evaluate the accuracy of CT colonography (CTC) in the diagnosis of synchronous colonic lesions in a cohort of patients with an occlusive colorectal cancer (CRC) causing incomplete colonoscopy. SUBJECTS AND METHODS. Among 109 patients with CRC causing incomplete colonoscopy who underwent CTC with IV contrast enhancement after cathartic purgation, fecal tagging, and colon distention, 70 (mean age, 70 years) for whom reference standards (surgical reports, first surveillance colonoscopy) were available were evaluated. Per-patient and per-lesion sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) of CTC in the diagnosis of synchronous colonic lesions measuring 6 mm or larger were assessed. RESULTS. Twenty-seven of the 70 patients (39%) had at least one 6-mm or larger synchronous lesion, and four patients (6%) had a total of five synchronous CRCs. Per-patient sensitivity in diagnosing synchronous CRC was 1.00 (4/4). There were 59 lesions: 20 with a diameter of 10 mm or greater; 30, 6-9 mm; and nine, 5 mm or less. The overall per-patient CTC sensitivity in detecting synchronous lesions 6 mm or larger was 0.93 (25/27); specificity, 0.98 (42/43); PPV, 0.96; and NPV, 0.95. Per-patient sensitivity for the diagnosis of synchronous advanced neoplasia (advanced adenoma and colorectal cancers) was 0.94 (15/16). Per-lesion CTC sensitivity for detecting synchronous lesions 6 mm or larger was 0.88 (37/42); all adenomatous lesions, 0.89 (55/62); and advanced neoplasia, 0.92 (22/24). CONCLUSION. CTC is a highly accurate test for detecting synchronous colonic lesions in patients with occlusive CRC. The prevalence of advanced neoplasia is high (23%).

Background: nasopharyngeal carcinoma (NPC) is a complex disease entity that mainly predominates in endemic regions. Real-world data with immunotherapy from nonendemic regions are limited. Methods: we collected data from patients with recurrent/metastatic (R/M) NPC treated at a center in Greece and 8 centers in Italy. Between 2016 and 2021, 46 patients who were treated with at least one cycle of immune checkpoint inhibitors (ICI) were identified. Herein, we present our results and a review of the literature. Results: assessment of response was available in 42 patients. Overall, 11 patients responded to immunotherapy (Overall Response Rate-ORR 26.2%). Three patients had complete response (CR), and 8 patients had partial response (PR). Disease control rate (DCR) was 61.9%. Median Progression Free Survival (PFS) was 5.6 months and median Overall Survival (OS) was 19.1 months. Responders to ICI improved PFS and OS as compared to that of nonresponders. A lower probability of responding to ICI was shown in patients with more than three metastatic sites (p = 0.073), metastatic disease at initial diagnosis, (p = 0.039) or EBV DNA positive before ICI initiation, (p = 0.074). Decline in EBV DNA levels was found to be statistically significant associated with best response to ICI (p = 0.049). Safety was manageable. Conclusions: among 46 patients with R/M NPC treated with immunotherapy in two nonendemic regions, ORR was 26.2% and durable responses were observed. Low disease burden could serve as a biomarker for response to ICI.

Background Bendamustine, used for the treatment of indolent B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia, is known to cause prolonged myelosuppression and lymphocytopenia and has been associated with the risk of developing serious and fatal infections. While reports of localized CMV infections in asymptomatic patients exist, disseminated CMV disease has not been described. Case presentation We report the first case of disseminated CMV infection in a 75-year-old male diagnosed with lymphoplasmacytic lymphoma/Waldenström macroglobulinemia with massive bone marrow infiltration. Despite 6-cycle R-bendamustine chemotherapy resulted in a good partial response, the patient developed persistent fever and severe weight loss. Analysis of cerebrospinal fluid and peripheral blood revealed the presence of CMV-DNA, while the fundus oculi examination revealed bilateral CMV retinitis. Treatment with induction and maintenance drugs was complicated by neutropenia and deterioration of renal function with electrolyte imbalance. From an immunological standpoint, we observed a profound imbalances in phenotype and function of B- and T-cell subsets, with a high proportion of circulating total, activated CD69+ and CD80+ B-cells, a low γ/δ T-cell frequency with a high proportion of CD69- and CD38-expressing cells, and hyperactivated/exhausted CD4+ and CD8+ T-cell phenotypes unable to face CMV challenge. Conclusions We hereby describe a severe form of disseminated CMV disease after R-bendamustine treatment. Our observations strongly support the careful clinical monitoring of CMV reactivation/infection in oncologic patients undergoing this therapeutic regimen.

Sopravvivenza libera da malattia a lungo termine nel tumore della lingua mobile operato: studio retrospettivo a 10 anni.Il tumore della lingua mobile, in fase iniziale o localmente avanzata, può essere trattato mediante chirurgia, da sola o seguita da radioterapia o chemio-radioterapia. Tuttavia, fino al 40% dei pazienti sviluppa una recidiva di malattia. Lo scopo del nostro studio è quello di valutare le caratteristiche anatomo-patologiche e cliniche associate ad una ridotta sopravvivenza libera da malattia (DFS) in pazienti con tumore della lingua mobile sottoposti a chirurgia. Sono stati identificati 106 pazienti operati per tumore della lingua mobile. Dopo un follow-up mediano di 8,9 anni, sono stati osservati 22 eventi, incluse 11 morti. Il tasso di DFS a 5 anni è stato dell’87,4%. La presenza di estensione extranodale (p = 0,023) ed invasione perineurale (p = 0,003) erano significativamente correlate ad una DFS ridotta (analisi univariata). Nell’analisi multivariata, sia l’estensione extranodale che l’invasione perineurale hanno confermato il loro ruolo quali fattori prognostici associati ad un aumentato rischio di recidiva di malattia [Hazard Ratio (HR) 2,87, 95% CI 1,11-7,42, p = 0,03; HR 3,85, 95% CI 1,49-9,96, p = 0,006]. L’espressione di p16 e p53 è stata identificata nel 12% (n = 9) e 46% (n = 40) dei casi, rispettivamente. Non sono state identificate differenze in termini di sopravvivenza tra tumori p53+ e p53-, né tra tumori p16+ e p16-. In conclusione, la chirurgia primaria, eventualmente seguita da radioterapia o chemio-radioterapia, può consentire alti livelli di guarigione nel tumore della lingua mobile. L’invasione perineurale e l’estensione extra-nodale si sono confermati fattori prognostici correlati ad una minore DFS.Early and loco-regionally advanced oral tongue squamous cell carcinoma (OTSCC) can be treated by surgery alone or followed by adjuvant radiotherapy or chemoradiotherapy. Nevertheless, up to 40% of patients develop tumour relapse. The aim of our study is to investigate the clinical and pathological features associated with reduced disease-free survival (DFS) in a cohort of surgically-resected OTSCC patients. One hundred and six patients surgically resected for OTSCC were retrospectively identified from clinical records. DFS was calculated according to the Kaplan–Meier method and differences between variables were assessed with Log-Rank test. A multivariable Cox regression model was used to analyse the impact of different prognostic factors on DFS. After a median of follow-up of 8.9 years, 22 events, including 11 deaths, were observed. Overall, the 5-year DFS-rate was 87.4%. The presence of extra-nodal extension (p = 0.023) and perineural invasion (p = 0.003) were significantly correlated with shorter DFS (in univariate analysis). In multivariable analysis, extra-nodal extension and perineural invasion confirmed their role as independent prognostic factors associated with an increased risk of disease recurrence [hazard ratio (HR) 2.87, 95% CI 1.11-7.42, p = 0.03; HR 3.85, 95% CI 1.49-9.96, p = 0.006, respectively]. p16 and p53 expressions in tumour cells were detected in 12% (n = 9) and 46% (n = 40) of cases, respectively. No differences in DFS were observed between p16+ and p16- (p = 0.125) and between p53+ and p53- tumours (p = 0.213). In conclusion, radical surgery, eventually followed by adjuvant radiotherapy or chemo-radiotherapy, can achieve high cure rates in OTSCC. After long-term follow-up, perineural invasion and extra-nodal extension confirmed their role as prognostic factors associated with reduced DFS in OTSCC patients.

In March 2020, northern Italy became the second country worldwide most affected by Covid-19 and the death toll overtook that in China. Hospital staff soon realized that Covid-19 was far more severe than expected from the few data available at that time. The Covid-19 pandemic forced hospitals to adjust to rapidly changing circumstances. We report our experience in a general teaching hospital in Milan, the capital of Lombardy, the most affected area in Italy. First, we briefly describe Lombardy's regional Covid-19-related health organizational changes as well as general hospital reorganization. We also provide a multidisciplinary report of the main clinical, radiological and pathological Covid-19 findings we observed in our patients.

Background: Previous studies on oxaliplatin and fluoropyrimidines as adjuvant therapy in older patients with stage III colon cancer (CC) produced conflicting results. Patients and methods: We assessed the impact of age on time to tumour recurrence (TTR), disease-free survival (DFS), cancer-specific survival (CSS), and overall survival (OS) in 2360 patients with stage III CC (1667 aged

Background The role of combination chemotherapy has not yet been established in unresectable locally advanced pancreatic cancer (LAPC) lacking dedicated randomized trials. Methods This phase II trial tested the efficacy of Nab-paclitaxel (NAB-P)/Gemcitabine (G) versus G alone. Patients were randomized, 1:1 to G 1000 mg/m2 on days 1, 8 and 15 every 28 days versus NAB-P 125 mg/m2 on days 1, 8 and 15 every 28 days plus G 1000 mg/m2 on days 1, 8 and 15 every 28 days. Disease progression rate after three cycles of chemotherapy was the primary end-point. Progression-free survival (PFS), overall survival (OS) and response rate were secondary end-points. Findings A total of124 patients were enrolled. The study showed a reduction of a progressive disease from 45.6% with G to 25.4% with NAB-P/G (P = 0.01) at 3 months. Noteworthy, at 6 months in the G arm, 35.6% of patients present a metastatic spread versus 20.8% in the NAB/G arm. The response rate was 5.3% in the G arm and 27% in the NAB/G arm. Median PFS was 4 months for the G arm and 7 months for the NAB-P/G arm. Median OS was 10.6 in the G arm and 12.7 months in the NAB-P/G arm. One patient died during treatment with G due to a stroke. Interpretation. NAB-P/G reduced the rate of LAPC patients progressing after three cycles of chemotherapy compared with G, especially in terms of distant relapses. It positively affects PFS. To the best of our knowledge, this is the first randomized trial providing evidence that combination chemotherapy is superior to gemcitabine alone in this setting. ClinicalTrials.gov Identifier NCT02043730 .

Background Oxaliplatin-based adjuvant chemotherapy is the standard treatment of high-risk colon cancer (CC). A shorter duration (3 months) can achieve a similar outcome [in terms of relapse-free survival (RFS)] to a longer duration. This study reports the overall survival (OS) analysis of the three or six colon adjuvant (TOSCA) phase III study. It assessed different adjuvant chemotherapy durations in patients with resected high-risk stage II and stage III CC. Material and methods TOSCA was an open-label, phase III, multicentre, non-inferiority trial conducted in 130 Italian centres. Patients were randomly assigned, in a 1 : 1 ratio, to receive 3 months of standard doses of FOLFOX/CAPOX, or 6 months of FOLFOX/CAPOX. Patients with histologically confirmed high-risk stage II and III CC were included, with RFS being the primary end point. OS was a secondary end point. Results From June 2007 to March 2013, 3759 patients were accrued. At a median follow-up of 7 years, the hazard ratio (HR) for RFS of the 3-month versus 6-month arms was 1.13; 95% confidence interval (CI) 0.99-1.29, P for non-inferiority = 0.380, P for superiority = 0.068, crossing the non-inferiority limit of 1.20. This result did not allow us to reject the null hypothesis of the inferiority of the 3-month arm. The HR for OS of the 3-month versus 6-month arms was 1.09 (95% CI 0.93-1.26, P for superiority = 0.288). At the last follow-up analysis, the absolute OS difference between arms was Conclusions The present analysis of the TOSCA trial does not indicate any significant difference in OS between the treatment groups. The extra benefit provided by the longer treatment should be balanced against the extra toxicity of more prolonged therapy. The trial is registered with ClinicalTrials.gov , registration number: NCT0064660.

Introduction: Head and neck cancer represents a variety of tumors involving different organs in the cervical district, burdened by poor prognosis when diagnosed in an advanced stage. Immunotherapy with both anti-PD-1 nivolumab and pembrolizumab has the aim of increasing overall survival for patients with this malignancy. We report the first case of immune-related encephalitis caused by nivolumab in this setting of disease and present a brief review of the literature. Case description: A 60-year-old woman had been treated with concomitant chemoradiotherapy for a locally advanced human papillomavirus–negative squamous cell carcinoma of the tonsil. After local recurrence, she was treated with platinum-based first-line chemotherapy, followed by nivolumab at further progression within 6 months. Nivolumab was administered for 19 weeks, then discontinued due to the occurrence of immune-related hypothyroidism and grade 2 diarrhea. A month after the onset of the endocrinopathy, the patient also developed steroid-responsive encephalitis, considered as a consequence of anti-PD-1 therapy. One year after discontinuation of immunotherapy, toxicities have resolved and the patient is maintaining a complete radiologic response. Conclusions: Immunotherapy is a relatively new and promising therapy in the field of oncology. Its mechanism of action, which aims to stimulate the immune system against cancer cells, is not comparable to systemic and cytotoxic chemotherapy, which directly attacks and destroys malignant cells. Despite these differences, immunotherapy is not to be considered free from side effects, sometimes life-threatening.

A few prospective trials in HIV-positive patients with Burkitt lymphoma (BL) or high-grade B-cell lymphoma (HGBL) have been reported. Investigated therapies have shown good efficacy but relevant safety problems, with high rates of interruptions, severe mucositis, septic complications, and fungal infections. Here, we report the results of a multicentre phase II trial addressing a new dose-dense, short-term therapy aimed at maintaining efficacy and improving tolerability. The experimental programme included a 36-day polychemotherapy induction followed by high-dose cytarabine-based consolidation and response-tailored BEAM (carmustine, etoposide, cyatarabine, and melphalan)- conditioned autologous stem cell transplantation (ASCT). This therapy would be considered active if ≥11 complete remissions (CR) after induction (primary endpoint) were recorded among 20 assessable patients. HIV-positive adults (median age 42, range 26-58; 16 males) with untreated BL (n = 16), HGBL (n = 3) or double-hit lymphoma (n = 1) were enrolled. All patients had high-risk features, with meningeal and bone marrow infiltration in five and nine patients respectively. The experimental programme was safe and active in a multicentre setting, with only two episodes of grade 4 non-haematological toxicity (hepatotoxicity and mucositis), and no cases of systemic fungal infections; two patients died of toxicity (bacterial infections). Response after induction (median duration: 47 days; interquartile range 41-54), was complete in 13 patients and partial in five [overall response rate = 90%; 95% confidence interval (CI) = 77-100]. All responders received consolidation, and five required autologous stem cell transplant. At a median follow-up of 55 (41-89) months, 14 patients are relapse-free and 15 are alive, with a five-year progression-free survival and an overall survival of 70% (95% CI = 60-80%) and 75% (95% CI = 66-84) respectively. No patient with cerebrospinal fluid (CSF)/meningeal lymphoma experienced central nervous system recurrence. With respect to previously reported regimens, this programme was delivered in a shorter period, and achieved the main goal of maintaining efficacy and improving tolerability.

Purpose Given the cumulative neurotoxicity associated with oxaliplatin, a shorter duration of adjuvant therapy, if equally efficacious, would be advantageous for patients and health-care systems. Methods The Three or Six Colon Adjuvant trial is an open-label, phase III, multicenter, noninferiority trial randomizing patients with high-risk stage II or stage III colon cancer to receive 3 months or 6 months of FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine plus oxaliplatin). Primary end-point is relapse-free survival. Results 3,759 patients were accrued from 130 Italian sites, 64% receiving FOLFOX and 36% CAPOX. Two-thirds were stage III. The median time of follow up was 62 months and 772 relapses or deaths have been observed. The hazard ratio (HR) of the 3 months versus 6 months for relapse/death was 1.14 (95% CI, 0.99 to 1.32; P [for noninferiority] = .514) and the CI crossed the noninferiority limit of 1.20. However, the absolute difference in 3-year RFS was 1.9% (95% CI, -0.7% to 4.4%). Counter-intuitively, while the RFS curves were similar for stage III (HR, 1.07; 95% CI, 0.91 to 1.26) and for CAPOX treated patients (HR, 0.98; 95% CI, 0.77 to 1.26), they were not for stage II and for FOLFOX treated patients, with HR of 1.41 (95% CI, 1.05 to 1.89) and 1.23 (95% CI, 1.03 to 1.46), respectively, favoring the 6 months of treatment. Conclusion The Three or Six Colon Adjuvant trial failed to formally show noninferiority of 3 versus 6 months of treatment to the predefined margin of 20% relative increase. The results depended on the adjuvant regimen and risk. For CAPOX, 3 months were as good as 6 months; for FOLFOX, 6 months added extra benefit. Counter-intuitively, the low-risk patients benefitted more than the high-risk population from the 6-month duration. The choice of regimen and duration should depend on patient characteristics and be balanced against the extra toxicity of longer therapy.

Background: Previous findings suggested that bevacizumab might be able to improve response rate (RR) in colorectal cancer patients with high lactic dehydrogenase (LDH) basal levels. Methods: We conducted a phase II trial to prospectively ascertain whether bevacizumab in combination with FOLFIRI could have an improved clinical activity in patients with high LDH serum levels. Primary end point of the study was RR; secondary end points were median overall survival and median progression-free survival (mPFS). Results: A total of 81 patients were enrolled. No difference in terms of ORR (39% vs 31% for low vs high LDH level stratum, P=0.78) and mPFS (14.16 vs 10.29 months, HR: 1.07, 95% CI: 0.51–2.24, P=0.83) between the strata was observed, whereas overall survival (OS) was significantly longer for patients with low LDH (24.85 vs 15.14 months, HR: 4.08, 95% CI: 1.14–14.61, P=0.0004). In a not-pre-planned exploratory analysis using different cut-off ranges for LDH, we observed RR up to 70%, with no improvement in progression-free survival or OS. Conclusions: The CENTRAL trial failed to demonstrate that high LDH levels were related to a significantly improved RR in patients receiving first-line FOLFIRI and bevacizumab. The LDH serum levels should then no further be investigated as a predictive factor in this setting.

Introduction Non–small-cell lung cancer (NSCLC) is predominantly a disease of the elderly population. Over the past few years, immunotherapy with monoclonal antibodies named checkpoint inhibitors (ICIs) greatly improved the clinical management of a significant proportion of patients with metastatic NSCLC. However, pivotal trials excluded older patients, although, given the favorable clinical profile of ICIs, this treatment may be revealed to be a most valuable option also for these patients. To this aim, a multicenter retrospective analysis was performed on patients aged ≥ 75 years with NSCLC treated with anti-programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) immunotherapy. Material and Methods Inclusion criteria were: diagnosis of locally advanced or metastatic NSCLC (stage IIIB or IV, according to the American Joint Committee on Cancer (AJCC) classification system, version 8.0); age ≥ 75 years; treatment with anti-PD-1/PD-L1 monoclonal antibodies in first or subsequent lines of treatment; absence of epidermal growth factor receptor-activating mutations or anaplastic lymphoma kinase and ROS-1 rearrangements. The primary endpoints of the study were the efficacy, in terms of overall response rate, progression-free survival, and overall survival, and safety, by means of evaluations of the incidence of immune-related adverse events. Results Eighty-six patients were considered for the final analysis; 71 (82.6%) were male. The mean age was 78.5 years (range, 75-86 years; SD, 3.12 years). Of the 86 patients, 69 (80.2%) of patients had a performance status of 0 or 1. The overall median progression-free survival was 5.6 months (range 1-36 months; SD, 7.5 months,) whereas the median overall survival was 10.1 months (range, 1.7-34.8 months; SD, 8 months). At the Cox regression analysis, the only parameter significantly associated with survival was the smoking status (P = .008). No difference in survival was found between patients younger and older than 80 years. Conclusions In the present real-world retrospective cohort, efficacy and toxicity profiles of ICIs in older patients with advanced NSCLC were comparable with those observed in younger patients enrolled in clinical trials.

Purpose: Early palliative care (EPC) has shown a positive impact on quality of life (QoL), quality of care, and healthcare costs. We evaluated such effects in patients with advanced gastric cancer. Methods: In this prospective, multicenter study, 186 advanced gastric cancer patients were randomized 1:1 to receive standard cancer care (SCC) plus on-demand EPC (standard arm) or SCC plus systematic EPC (interventional arm). Primary outcome was a change in QoL between randomization (T0) and T1 (12weeks after T0) in the Trial Outcome Index (TOI) scores evaluated through the Functional Assessment of Cancer Therapy-Gastric questionnaire. Secondary outcomes were patient mood, overall survival, and family satisfaction with healthcare and care aggressiveness. Results: The mean change in TOI scores from T0 to T1 was − 1.30 (standard deviation (SD) 20.01) for standard arm patients and 1.65 (SD 22.38) for the interventional group, with a difference of 2.95 (95% CI − 4.43 to 10.32) (p= 0.430). The change in mean Gastric Cancer Subscale values for the standard arm was 0.91 (SD 14.14) and 3.19 (SD 15.25) for the interventional group, with a difference of 2.29 (95% CI − 2.80 to 7.38) (p= 0.375). Forty-three percent of patients in the standard arm received EPC. Conclusions: Our results indicated a slight, albeit not significant, benefit from EPC. Findings on EPC studies may be underestimated in the event of suboptimally managed issues: type of intervention, shared decision-making process between oncologists and PC physicians, risk of standard arm contamination, study duration, timeliness of assessment of primary outcomes, timeliness of cohort inception, and recruitment of patients with a significant symptom burden. Clinical trial registration: ClinicalTrials.gov (NCT01996540).

Objectives Cetuximab was shown in phase III clinical trials to improve chemotherapy efficacy in patients with advanced colorectal and head-neck cancer. Appropriate management of skin reactions associated with epidermal growth factor receptor inhibitor therapy is necessary to allow adequate drug compliance and to improve patient quality of life and outcomes. Methods The RAND/UCLA Appropriateness Method was used by a group of experts to produce new Italian recommendations on the management of skin reactions in this setting. Statements were generated on the basis of an updated systematic review of the literature and rated twice by a panel of 38 expert physicians. A meeting of the panel was held after the first rating session. Results Skin reactions included acneiformic rash, skin dryness (xerosis), pruritus, paronychia, hair abnormalities, mucositis, and increased growth of eyelashes or facial hair. Updates of the previous recommendations on the prevention and treatment of each type of reaction were proposed. Conclusions This updated Expert Opinion focuses on how to assess and correctly grade skin reactions according to the latest National Cancer Institute Common Terminology Criteria for Adverse Events and on how to manage these adverse events in clinical practice.

Background: Oral mucositis (OM) due to radiotherapy and systemic therapies in head and neck cancer treatment represents a major problem causing a wide spectrum of clinical signs and symptoms. This adverse event may reduce quality of life, resulting from debilitating oral pain, bleeding, dysphagia, infections, impairment of food intake, high rate of hospitalization and may interfere with the delivery of programmed treatment plans, ultimately jeopardizing patient outcome. Globally, there is a lack of evidence on effective measures for the prevention and treatment of OM, and only scant uniform conclusions and recommendations can be derived from the existing literature and guidelines. A multidisciplinary team of Italian head and neck cancer experts met in Milan 17-18 February 2013 with the aim of reaching consensus on prophylaxis and management of mucositis. The results of the literature review and the statements that achieved consensus are reported and discussed in this paper. Material and methods: The Delphi Appropriateness Method was used as a structured communication method for achieving consensus. Subsequently, external expert reviewers evaluated the conclusions carefully according to their area of expertise. Results: This paper presents 13 clusters of statements on prophylaxis and treatment of mucositis that achieved consensus. Conclusions: OM represents a very stressful) situation for head and neck cancer patients submitted to chemo-radiation or exclusive radiation treatment. A multidisciplinary approach is mandatory, but there is still no gold-standard protocol that is prominently better than others. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

Aim The aims of the study are to evaluate the clinical outcomes of first-line treatment with platinum-based chemotherapy and cetuximab in patients with relapsing/metastatic head and neck cancer (RM HNC) and to identify predictors of treatment response. Methods This is a retrospective, observational, longitudinal, real-world study involving 6 oncology centres in Italy. All consecutive patients with RM HNC treated between January 2007 and December 2016 with a first-line therapy consisting of a platinum-based chemotherapy regimen plus cetuximab were included. The primary objective of the study was to assess overall survival (OS) and progression-free survival (PFS). Secondary objectives included the identification of predictors of treatment response. Results Overall, 297 patients were identified. Median OS was 10.8 months (95% confidence interval [CI] 9.3–12.2), whereas median PFS was 4.8 months (95% CI 4.3–5.5). On multivariable analysis, independent unfavourable prognostic factors for OS were performance status (PS) Eastern Cooperative Oncology Group (ECOG) >0, presence of residual tumour at primary site, platinum resistance and lack of objective response. Unfavourable predictors for PFS included cancer primary site (paranasal sinuses, hypopharynx), PS ECOG >0, presence of residual tumour at primary site, platinum resistance and lack of objective response. Independent unfavourable predictors of objective response were tumour site (oral cavity, larynx-hypopharynx), residual tumour at primary site and prior chemotherapy. Conclusions The availability of new treatment modalities and epidemiological changes make the periodic reassessment of prognostic factors of great relevance to guide clinical practice and the design of future randomised clinical trials.

Background Type 2 diabetes mellitus (T2DM) is associated with increased risk of colon cancer (CC), whereas metformin use seems to be protective. However, the impact of metformin use on the risk of death or disease recurrence after radical surgery for CC remains uncertain. Materials and Methods This is a substudy conducted in patients with high-risk stage II or stage III CC randomized in the TOSCA trial, which compared 3 versus 6 months of fluoropyrimidine-oxaliplatin adjuvant chemotherapy. Objective of the study was to investigate the impact of metformin exposure during adjuvant chemotherapy on overall survival (OS) and relapse-free survival (RFS). We also evaluated the impact of T2DM or metformin dosage on clinical outcomes. Results Out of 3,759 patients enrolled in the TOSCA trial, 133 patients with diabetes (9.2%) and 1,319 without diabetes (90.8%) were recruited in this study. After excluding 13 patients with diabetes without information on metformin exposure, 76 patients with T2DM (63.3%) were defined as metformin users and 44 (36.7%) as metformin nonusers. After a median follow-up of 60.4 months, 26 (21.7%) patients relapsed and 16 (13.3%) died. Metformin use was neither associated with OS (adjusted hazard ratio [HR], 1.51; 95% confidence interval [CI], 0.48–4.77; p = .4781) nor with RFS (HR, 1.56; 95% CI, 0.69–3.54; p = .2881). Similarly, we found no association between T2DM or metformin dosage and OS or RFS. Conclusions Metformin use and T2DM did not impact on OS or RFS in patients with resected CC treated with adjuvant fluoropyrimidine-oxaliplatin chemotherapy. Larger studies and longer follow-up are required to clarify the potential efficacy of metformin in improving the prognosis of patients with CC. Implications for Practice The role of the antidiabetic drug metformin in colon cancer prevention and treatment is highly debated. While low-dose metformin reduced the incidence of colorectal adenomas in two prospective studies, its effect in patients with already established colon cancer remains unclear. In this study, the potential impact of metformin on the survival of resected colon cancer patients who received adjuvant chemotherapy was investigated in the context of the TOSCA study. We did not find any association between metformin use or dosages and patient survival. Prospective studies are required to draw definitive conclusions about metformin impact on colon cancer recurrence and survival.

Head and neck cancer (HNC) is a fatal malignancy with an overall long-term survival of about 50% for all stages. The diagnosis is not rarely delayed, and the majority of patients present with loco-regionally advanced disease. The rate of second primary tumors after a diagnosis of HNC is about 3-7% per year, the highest rate among solid tumors. Currently, a single-modality or a combination of surgery, radiotherapy and chemotherapy (CHT), is the standard treatment for stage III-IV HNC. For the recurrent/metastatic setting, in the last 40 years great efforts have been made in order to develop a more effective CHT regimen, from the use of methotrexate alone, to the combination of cisplatin (CDDP) and 5-fluorouracile (5FU) or paclitaxel. Recently, the introduction of cetuximab, an anti-EGFR monoclonal antibody, to the CDDP-5FU doublet (EXTREME regimen) has improved the overall response rate, the progression-free survival and the overall survival (OS) compared to CHT alone. Nowadays, the EXTREME regimen is the standard of care for the first-line treatment of recurrent/metastatic head and neck carcinoma (RMHNC). In the last years, new promising therapies for RMHNC such as immune checkpoint inhibitors (ICIs), which have demonstrated favorable results in second-line clinical trials, gained special interest. Nivolumab and pembrolizumab are the first two ICIs able to prolong OS in the second-, later-line and platinum-refractory setting, with tolerable toxicities. This review summarizes the current state of the art in RMHNC treatment options.

The literature highlights the importance of involving the patient as a partner of care, using a patient-centered approach aimed at improving a process of share decision-making. However, there are clinical situations in which a shared decision-making process is difficult and its actual achievement is even more complex, as in the case of end-of-life decisions, in which a decision about death is a tremendous weight for both patients and their caregivers. In such situations, we wonder what kind of position physicians should assume in order to be patient-centered but also to reduce the patient suffering. Our proposal is to assume the perspective of palliative paternalism: doctors should provide a communication approach that determines the appropriate level of patient/parent autonomy in the process of decision making. In other words, doctors are required to share the information with patients, according to their desires, possibilities and resources, and to facilitate a share-decision making process. However, when the time of the decision comes, physicians should take full responsibility for giving voice to the patient's choices, putting them in action in his/her end of life and raising patients and their caregivers from the burden linked to the actual implementation of the decision.

Although lactate dehydrogenase (LDH) serum levels, indirect markers of angiogenesis, are associated with a worse outcome in several tumours, their prognostic value is not defined in pancreatic cancer. Moreover, high levels are associated even with a lack of efficacy of tyrosine kinase inhibitors, contributing to explain negative results in clinical trials. We assessed the role of LDH in advanced pancreatic cancer receiving sorafenib. Seventy-one of 114 patients included in the randomised phase II trial MAPS (chemotherapy plus or not sorafenib) and with available serum LDH levels, were included in this analysis. Patients were categorized according to serum LDH levels (LDH ≤ vs.> upper normal rate). A significant difference was found in progression free survival (PFS) and in overall survival (OS) between patients with LDH values under or above the cut-off (PFS: 5.2 vs. 2.7 months, p = 0.0287; OS: 10.7 vs. 5.9 months, p = 0.0021). After stratification according to LDH serum levels and sorafenib treatment, patients with low LDH serum levels treated with sorafenib showed an advantage in PFS (p = 0.05) and OS (p = 0.0012). LDH appears to be a reliable parameter to assess the prognosis of advanced pancreatic cancer patients, and it may be a predictive parameter to select patients candidate to receive sorafenib.

Some parameters of the Comprehensive Geriatric Assessment (CGA) are predictive of chemotherapy toxicity. The Vulnerable Elders Survey-13 (VES-13) is a short instrument that has been tested as a means of identifying patients who need a full CGA, but its ability to predict chemotherapy toxicity is still unclear. We performed a pooled analysis of four published clinical trials studying VES-13 as a means of diagnosing vulnerability, in order to evaluate its accuracy in predicting the risk of grade 3/4 toxicity in older patients undergoing chemotherapy.The study involved patients aged ≥ 66 years with a diagnosis of solid or hematological cancer, all of whom were administered VES-13. The number of medications taken by each patient, their comorbidities, their Cumulative Illness Rating Scale for Geriatrics (CIRS-G) score and index, the type of chemotherapy and treatment line, and their Mini Mental State Evaluation (MMSE), and Mini Nutritional Assessment (MNA) scores were recorded. Information was available concerning the grades 3-4 hematological and non-hematological toxicities experienced by each patient.The study involved 648 patients aged ≥ 66 years (mean age 76.2±4.5, range 66-90) of whom 336 (51.9%) were female. VES-13 identified 287 patients (44.3%) as vulnerable. Grades 3-4 hematological and non-hematological toxicities were more prevalent in the vulnerable subjects (35.2% vs 20.8%, p0.0001, and 18.5% vs 10.8%, p=0.0055), who were also at higher risk of both (adjusted ORs 2.15, 95% CI 1.46-3.17, p0.001); and 1.66 (95% CI 1.02-2.72, p=0.043).VES-13 could be considered to be a good candidate for future prospective studies to assess older patients with cancer at risk of toxicity.

Background B490 (EudraCT# 2011-002564-24) is a randomized, phase 2b, noninferiority study investigating the efficacy and safety of first-line cetuximab plus cisplatin with/without paclitaxel (CetCis versus CetCisPac) in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). Patients and methods Eligible patients had confirmed R/M SCCHN (oral cavity/oropharynx/larynx/hypopharynx/paranasal sinus) and no prior therapy for R/M disease. Cetuximab was administered on day 1 (2-h infusion, 400 mg/m2), then weekly (1-h infusions, 250 mg/m2). Cisplatin was given as a 1-h infusion (CetCis arm: 100 mg/m2; CetCisPac arm: 75 mg/m2) on day 1 of each cycle for a maximum of six cycles. Paclitaxel was administered as a 3-h infusion (175 mg/m2) on day 1 of each cycle. After six cycles, maintenance cetuximab was administered until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS). We assumed a noninferiority margin of 1.40 as compatible with efficacy. Results A total of 201 patients were randomized 1 : 1 to each regimen; 191 were assessable. PFS with CetCis (median, 6 months) was noninferior to PFS with CetCisPac (median, 7 months) [HR for CetCis versus CetCisPac 0.99; 95% CI: 0.72–1.36,P = 0.906; margin of noninferiority (90% CI of 1.4) not reached]. Median overall survival was 13 versus 11 months (HR = 0.77; 95% CI: 0.53–1.11,P = 0.117). The overall response rates were 41.8% versus 51.7%, respectively (OR = 0.69; 95% CI: 0.38–1.20,P = 0.181). Grade ≥3 adverse event rates were 76% and 73% for CetCis versus CetCisPac, respectively, while grade 4 toxicities were lower in the two-drug versus three-drug arm (14% versus 33%,P = 0.015). No toxic death or sepsis were reported and cardiac events were negligible (1%). Conclusion The two-drug CetCis regimen proved to be noninferior in PFS to a three-drug combination with CetCisPac. The median OS of both regimens is comparable with that observed in EXTREME, while the life-threatening toxicity rate appeared reduced. Clinical trial number EudraCT# 2011-002564-24.

Few data are available outlining outcomes of panitumumab in advanced colorectal cancer patients benefiting from prior cetuximab-based regimens.Thirty patients with KRAS wild type metastatic colorectal cancer with clinical benefit from prior cetuximab-based regimens between May 2004 and October 2011 were reviewed at nine Italian Institutions. Inclusion key criteria included interruption of cetuximab for reasons other than progressive disease. Patients were classified according to prior regimens (0 or ≥1), prior response or stabilization, surgery of metastases, and Köhne prognostic score. At the time of subsequent progression, patients were treated with single agent panitumumab until progressive disease, unacceptable toxicity, or consent withdrawal.Panitumumab obtained 67% disease control rate and 30% objective response rate, with median PFS of 4.2 and median OS of 9.6 mo. Patients with BRAF/NRAS/PI3KCA and KRAS (by mutant enriched technique) wild-type tumors had the best chance of response to panitumumab.Single agent panitumumab provided significant clinical benefit in heavily pretreated patients without acquired resistance to prior cetuximab-based regimens.

Cetuximab improves efficacy when added to chemotherapy for metastatic colorectal cancer (mCRC). Effective management of skin reactions from cetuximab improves quality of life (QoL), and treatment compliance in clinical trials. No data are available from real‐world settings. The ObservEr observational, multicenter, prospective study evaluated QoL, the incidence of skin reactions, and management of chemotherapy plus cetuximab in first‐line for mCRC. The primary endpoint was QoL measured with the Dermatology Life Quality Index (DLQI) and EORTC QLQ‐C30. Secondary endpoints were the incidence of skin and serious adverse events, median overall and progression‐free survival, tumor response, and resection rates. Between May 2011 and November 2012, 228 patients with KRASwt mCRC were enrolled at 28 Italian centers, 225 evaluable, median age 65 years. QoL did not change during treatment and was not affected by the choice of prophylactic or reactive skin management. The incidence of cetuximab‐specific grade ≥3 skin reactions was 14%, with no grade 4/5 events. Skin reactions correlated with survival (P = 0.016), and their incidence was influenced by chemotherapy regimen (oxaliplatin vs. irinotecan—Incidence rate ratio [IRR] 1.72, P

Aim Early palliative care (EPC) in oncology has shown sparse evidence of a positive impact on patient outcomes, quality of care outcomesand costs. Patients and methods Data for this secondary analysis were taken from a trial of 207 outpatients with metastatic pancreatic cancer randomly assigned to receive standard cancer care plus on-demand EPC (standard arm) or standard cancer care plus systematic EPC (interventional arm). After 20 months’ follow-up, 149 (80%) had died. Outcome measures were frequency, type and timing of chemotherapy administration, use of resources, place of death and overall survival. Results Some indices of end-of-life (EoL) aggressiveness had a favourable impact from systematic EPC. Interventional arm patients showed higher use of hospice services: a significantly longer median and mean period of hospice care (P=0.025 for both indexes) and a significantly higher median and mean number of hospice admissions (both P&nbsp

Background Early palliative care (EPC) in oncology has been shown to have a positive impact on clinical outcome, quality-of-care outcomes, and costs. However, the optimal way for activating EPC has yet to be defined. Methods This prospective, multicentre, randomised study was conducted on 207 outpatients with metastatic or locally advanced inoperable pancreatic cancer. Patients were randomised to receive ‘standard cancer care plus on-demand EPC’ (n=100) or ‘standard cancer care plus systematic EPC’ (n=107). Primary outcome was change in quality of life (QoL) evaluated through the Functional Assessment of Cancer Therapy – Hepatobiliary questionnaire between baseline (T0) and after 12 weeks (T1), in particular the integration of physical, functional, and Hepatic Cancer Subscale (HCS) combined in the Trial Outcome Index (TOI). Patient mood, survival, relatives' satisfaction with care, and indicators of aggressiveness of care were also evaluated. Findings The mean changes in TOI score and HCS score between T0 and T1 were −4.47 and −0.63, with a difference between groups of 3.83 (95% confidence interval [CI] 0.10–7.57) (p=0.041), and −2.23 and 0.28 (difference between groups of 2.51, 95% CI 0.40–4.61, p=0.013), in favour of interventional group. QoL scores at T1 of TOI scale and HCS were 84.4 versus 78.1 (p=0.022) and 52.0 versus 48.2 (p=0.008), respectively, for interventional and standard arm. Until February 2016, 143 (76.9%) of the 186 evaluable patients had died. There was no difference in overall survival between treatment arms. Interpretations Systematic EPC in advanced pancreatic cancer patients significantly improved QoL with respect to on-demand EPC.

Background. Cetuximab was demonstrated by clinical trials to improve response rate and survival of patients with metastatic and nonresectable colorectal cancer or carcinoma of the head and neck. Appropriate management of skin toxicity associated with epidermal growth factor receptor inhibitor (EGFR-i) therapy is necessary to allow adequate drug administration and to improve quality of life and outcomes. Methods. A group of Italian Experts produced recommendations for skin toxicity management using the RAND/UCLA Appropriateness Method. Statements were generated on the basis of a systematic revision of the literature and voted twice by a panel of 40 expert physicians; the second vote was preceded by a meeting of the panelists. Results. Skin toxicity included skin rash, skin dryness, pruritus, paronychia, hair abnormality, and mucositis. Recommendations for prophylaxis and therapeutic interventions for each type of toxicity were proposed. Conclusions. Interventions that were considered appropriate to improve compliance and outcomes of cancer patients treated with EGFR-i were identified.

The efficacy of traditional chemotherapy in inducing objective responses and prolonging survival in recurrent or metastatic head and neck cancer has been disappointing. More recent drugs have not proven superior to the classic regimen of cisplatin and 5-fluorouracil. Anti-EGFR monoclonal antibodies, either as single agents or associated to chemotherapy, have been shown to be active and little toxic. Among them, cetuximab has proven to be the most promising. Indeed the Extreme study, which compared the classic couple cisplatin (CDDP) + 5-fluorouracil with the same regimen plus cetuximab, has constituted a remarkable innovation. The results of that trial seem to indicate a third agent added to CDDP and 5-fluorouracil improved both progression-free survival and overall survival in the recurrent or metastatic setting. Unfortunately, the results obtained with the tyrosine kinase inhibitors are less impressive, and additional studies are needed to explore the potentiality of this class of drug. As far as antiangiogenetics are concerned, the research is insufficient for any conclusion to be drawn in terms of efficacy. It is hoped that, in the near future, the most active combination between biological agents and traditional chemotherapy will be found, so that the path successfully taken in other neoplastic diseases may be retraced.

The aim of this study was to investigate the activity and safety of a regimen containing carboplatin and paclitaxel in patients affected by recurrent or metastatic head and neck cancer. Eligible patients were treated with a 3-week combination of paclitaxel 175 mg/m2 and carboplatin area under the concentration time curve 5 mg/ml/min for a maximum of four cycles. A total of 27 patients entered the study. One patient (3.7%) had a complete response, whereas six patients (22.2%) obtained a partial response. Stable disease was observed in seven patients (25.9%). The disease control rate was 51.8% (95% confidence interval: 32.0-71.3), whereas overall response rate was 25.9% (95% confidence interval: 11.1-46.3). The median overall survival was 8.0 months (range: 2-27), with a 1-year survival of 30.5%. The median progression-free survival was 1.0 month (range: 0-14). Treatment-related deaths or episodes of neutropenic fever were not registered. Grades 3-4 neutropenia was observed in two patients (7.4%), grades 3-4 anaemia and thrombocytopenia in four (14.8%) and one (3.7%) patients, respectively. Nine patients (33.3%) experienced grades 1-2 and one patient (3.7%) grade 3 peripheral neuropathy. The combination of carboplatin and paclitaxel is safe and moderately effective for the treatment of recurrent or metastatic head and neck cancer.

Purpose Unresponsiveness to erythropoiesis-stimulating agents, occurring in 30% to 50% of patients, is a major limitation to the treatment of chemotherapy-related anemia. We have prospectively evaluated whether intravenous iron can increase the proportion of patients with chemotherapy-related anemia who respond to darbepoetin. Patients and Methods Between December 2004 and February 2006, 149 patients with lung, gynecologic, breast, and colorectal cancers and ≥ 12 weeks of planned chemotherapy were enrolled from 33 institutions. Patients were required to have hemoglobin ≤ 11 g/L and no absolute or functional iron deficiency. All patients received darbepoetin 150 μg subcutaneously once weekly for 12 weeks and were randomly assigned to sodium ferric gluconate 125 mg intravenously (IV) weekly for the first 6 weeks (n = 73) or no iron (n = 76). Primary end point of the study was the percentage of patients achieving hematopoietic response (hemoglobin ≥ 12 g/dL or ≥ 2 g/dL increase). Results Hematopoietic response by intention-to-treat analysis was 76.7% (95%CI, 65.4% to 85.8%) in the darbepoetin/iron group and 61.8% (95%CI, 50.0% to 72.7%) in the darbepoetin group (P = .0495). Among patients fulfilling eligibility criteria and having received at least four darbepoetin administrations, hematopoietic responses in the darbepoetin/iron group (n = 53) and in the darbepoetin-only group (n = 50) were 92.5% (95% CI, 81.8% to 97.9%) and 70% (95% CI, 55.4% to 82.1%), respectively (P = .0033). Increase of hemoglobin during treatment period showed a time profile favoring darbepoetin/iron with statistically significant effect from week 5 on. The safety profile was comparable in the two arms. Conclusion In patients with chemotherapy-related anemia and no iron deficiency, IV iron supplementation significantly reduces treatment failures to darbepoetin without additional toxicity.

Skin toxicity is a frequent complication of anti-epidermal growth factor receptor therapy, which can be an obstacle in maintaining the dose intensity and may negatively impact on the clinical outcome of cancer patients. Skin lesions depend on the disruption of the keratinocyte development pathways and no treatment is clearly effective in resolving the cutaneous alterations frequently found during anti-epidermal growth factor receptor therapy. Among systemic treatments, oral tetracycline proved to be useful in preventing skin manifestations. We describe the case of a patient affected by metastatic colorectal cancer, for whom a combination of chemotherapy and cetuximab was used as second-line treatment. The patient developed a symptomatic papulopustular skin rash that disappeared completely after a twice-daily application of a hydrating and moisturizing cream, mainly consisting of a mixture of paraffin, silicone compounds, and macrogol. The marked cutaneous amelioration allowed the patient to continue cetuximab without any further symptoms and was associated with a partial radiological response.

Arteriovenous malformations (AVMs) are high-flow vascular malformations characterised by a complex vessel network directly connecting feeding arteries and draining veins, typically featured by a natural history of progression, while spontaneous regressions are purely anecdotal. AVMs are very aggressive entities that possess a locally infiltrative behaviour like neoplasms. Complete "radical" surgical excision presents the highest chance of cure, but nowadays there is still considerable controversy on how to treat large AVMs that are not amenable of "radical" excision. The aim of this paper is to propose a different approach to treat vast AVMs that cannot be removed radically. The association of an antiangiogenic drug (to be initiated before surgery and to be continued in the post-operative period), could prevent the feared "explosive" growth of the remaining nidus after its partial removal. This could make recontouring and other "aesthetically" focused procedures feasible in these patients, with an obvious leap in their quality of life. The most promising antiangiogenic drug seems to be Thalidomide, but other drugs such as Sirolimus, VEGF pathway inhibitors, Interferon or Matrix Metalloproteinase (MMP) Inhibitors could serve the purpose just as well. Even Propranolol could prove useful in this sense as suggested by some recent researches on retinopathy of prematurity and tumour biology.

Vandetanib did not demonstrate any superiority alone or in combination with gemcitabine in the progression-free survival of patients affected by advanced biliary tract cancer compared with gemcitabine alone. The safety profile of vandetanib given (alone or in combination with gemcitabine) does not show any additional adverse events (AEs) or worsening of already known AEs. Background The management of biliary tract cancers (BTCs) is complex due to limited data on the optimal therapeutic approach. This phase II multicenter study evaluated the efficacy and tolerability of vandetanib monotherapy compared with vandetanib plus gemcitabine or gemcitabine plus placebo in patients with advanced BTC. Patients and methods Patients were randomized in a 1 : 1 : 1 ratio to three treatment groups: vandetanib 300 mg monotherapy (V), vandetanib 100 mg plus gemcitabine (V/G), gemcitabine plus placebo (G/P). Vandetanib (300 mg or 100 mg) or placebo was given in single oral daily doses. Gemcitabine 1000 mg/m2 was i.v. infused on day 1 and day 8 of each 21-day cycle. The primary end point was progression-free survival (PFS). Secondary end points were: objective response rate (ORR), disease control rate, overall survival, duration of response, performance status and safety outcomes. Results A total of 173 patients (mean age 63.6 years) were recruited at 19 centers across Italy. Median (95% confidence intervals) PFS (days) were 105 (72–155), 114 (91–193) and 148 (71–225), respectively, for the V, V/G and G/P treatment groups, with no statistical difference among them (P = 0.18). No statistical difference between treatments was observed for secondary end points, except ORR, which slightly favored the V/G combination over other treatments. The proportion of patients reporting adverse events (AEs) was similar for the three groups (96.6% in V arm, 91.4% in the V/G arm and 89.3% in the G/P arm). Conclusions Vandetanib treatment did not improve PFS in patients with advanced BTC. The safety profile of vandetanib did not show any additional AEs or worsening of already known AEs. Clinical trial number NCT00753675.

Background: Elderly patients rarely receive adequate dose intensity (DI) using conventional regimens. Possible causes are improper patient assessment, the chemotherapy (CT) regimen chosen, the number and severity of comorbidities, patient compliance and physician experience. To explore this issue, DI was retrospectively analyzed in elderly patients treated with conventional CT regimens for advanced solid cancer. Patients and Methods: Patients ≧69 years were evaluated. All patients had metastatic solid tumors. Comorbidities, performance status (PS), toxicities, number of CT cycles, dose reduction and discontinuation of treatment were recorded. Relative DI (RDI) was calculated and regressed against these parameters. Results: 108 patients were eligible. The most frequent diagnoses were: lung, head-and-neck and colorectal cancer. In 48 patients (44%), their initially scheduled treatment was modified. Mean RDI was 79% (range 19–100%, SD 20.6). Grade 3/4 non-hematological and hematological toxicity occurred in 27 (35/130) and 8% of patients (11/130), respectively. In regression analysis, RDI was significantly associated with hematological toxicity. RDI affected response rate but not overall survival. Conclusions: RDI is significantly affected by toxicity. These data suggest the importance of the treatment schedule and patient selection as predictorsof adequate treatment. Some non-ratable variables, however, might also play a role regarding the dose intensity delivered.

Osteosarcomas of the jaws are rare mesenchymal tumors frequently diagnosed in the fourth decade of life which account for 6 % of all osteosarcomas. This study evaluated the efficacy on the patients outcome of multimodality treatment consisting of surgery, chemotherapy and radiotherapy. The records of 22 patients affected by jaw osteosarcoma treated with a combination of surgery, poly-chemotherapy and adjuvant radiotherapy in selected cases were reviewed. Response rate, progression-free survival and overall survival were evaluated. Neoadjuvant chemotherapy resulted in an overall response rate of 83.3 %, necrosis of grade I or II was obtained, respectively, in 44.4 and 55.6 % of the patients, and surgery was radical in all patients. At a median follow-up of 60 months, the 5-year progression-free survival and overall survival were 73.5 and 77.4 %, respectively. These outcome parameters significantly correlated with age at diagnosis and grade of chemotherapy-induced necrosis. A complex multimodality approach including chemotherapy and radiotherapy, along with radical surgery, can maximize the outcome of patients affected by osteosarcoma of the jaws.

Background: The RAF-MEK-ERK pathway is commonly activated in pancreatic cancer because of a high frequency of KRAS-BRAF mutations. A phase II randomized trial was designed to investigate the activity of sorafenib in combination with chemotherapy in advanced pancreatic cancer. Methods: Locally advanced or metastatic pancreatic adenocarcinoma patients were randomized in a 1:1 ratio to receive cisplatin plus gemcitabine with sorafenib 400. mg bid (arm A) or without sorafenib (arm B). Results: One hundred and fourteen patients were enrolled; of these, 43 (74.6%) patients progressed in arm A and 44 (82.4%) in arm B. Median progression-free survival was 4.3 months (95% CI: 2.7-6.5) and 4.5 months (95% CI: 2.5-5.2), respectively (HR = 0.92; 95% CI: 0.62-1.35). Median overall survival was 7.5 (95% CI: 5.6-9.7) and 8.3 months (95% CI: 6.2-8.7), respectively (HR = 0.95; 95% CI: 0.62-1.48). Response rates were 3.4% in arm A and 3.6% in arm B. Conclusions: Sorafenib does not significantly enhance activity of chemotherapy in advanced pancreatic cancer patients, and therefore should not be assessed in phase III trials. © 2013 Editrice Gastroenterologica Italiana S.r.l.

Gemcitabine is a purine analog with known activity in many solid tumors, namely lung, breast, pancreatic, genitourinary and head/neck cancers. Cardiac toxicity is a rare event and only one report previously described atrial fibrillation (AF) as a consequence of gemcitabine infusion. We report two cases of women suffering from lung cancer who were treated with gemcitabine. Both patients were admitted to hospital for paroxysmal AF occurring 12-24 h after the infusion of the drug. In the first case a sinus rhythm was spontaneously repristinated when AF occurred for the first time, while the second episode required an anti-arrhythmic drug to interrupt the dysrhythmia. In the second case, the patient had to be treated with digitalis glycoside to control the ventricular response without attaining a sinus rhythm. We could not recognize any other precipitating factor beyond the infusion of gemcitabine as a cause for the arrhythmia. Both cases were treated with gemcitabine for lung cancer and we observed the appearance of AF less than 24 h after drug administration. We assume that 2',2'-difluorodeoxyuridine, an active metabolite of gemcitabine, could be responsible for the toxic effect. We conclude that AF is an unusual, but potentially dangerous, side-effect of gemcitabine infusion. The arrhythmia should be suspected whenever patients complain of dyspnea and palpitations beginning 12-24 h after treatment. In these cases, the treatment of AF consists of anti-arrhythmic drugs in order to repristinate a sinus rhythm or control the heart rate.

Background Sorafenib has shown survival benefits in patients with advanced hepatocellular carcinoma (HCC) and Child-Pugh (CP) class A liver function. There are few prospective data on sorafenib in patients with HCC and CP class B. Patients and methods A consecutive prospective series of 300 patients with CP class A or B HCC were enrolled in a dual-phase trial to determine survival and safety data according to liver function (class A or B) in patients receiving oral sorafenib 800 mg daily. [Results of this study were presented in part at the ASCO 2012 Gastrointestinal Cancers Symposium, 19–21 January 2012. J Clin Oncol 2012; 30 (Suppl 4): abstract 306.] Results Overall progression-free survival (PFS), time to progression (TTP) and overall survival (OS) were 3.9, 4.1 and 9.1 months, respectively. For patients with CP class A versus B status, PFS was 4.3 versus 2.1 months, TTP was 4.2 versus 3.8 months and OS was 10.0 versus 3. 8 months. Extrahepatic spread was associated with worse outcomes but taken together with CP class, liver function played a greater role in reducing survival. Adverse events for the two CP groups were similar. Conclusion Although patients with HCC and CP class B liver function have poorer outcomes than those with CP class A function, data suggest that patients with CP class B liver function can tolerate treatment and may still benefit from sorafenib.

BACKGROUND Comprehensive geriatric assessment (CGA) is a multidimensional tool aimed at detecting multiple age-related problems; the study of osteoporotic fractures (SOF) index is a 3-item instrument designed to measure frailty and pre-frailty status. The aim of this prospective cohort study was to evaluate the accuracy of the SOF index and CGA in predicting the disability status in elderly cancer patients. PATIENTS AND METHODS Patients aged ≥ 70 years with a confirmed diagnosis of a solid or hematologic tumor underwent both CGA and SOF assessment. The sensitivity and specificity of SOF in determining the presence of frailty were analyzed using the CGA as the reference standard. The diagnostic accuracy of SOF < 80% was considered not acceptable. RESULTS The study involved 400 patients aged ≥ 70 years (median age 77.2, range 70-97).The SOF and CGA classified, respectively, 33.2% and 31.8% of patients as fit, 67.8% and 68.2% as unfit. The SOF showed a sensibility and a specificity of 89.0 [95% confidence interval (CI) 84.7-92.5] and 81.1 (73.2-87.5) with an accuracy of 86.5 (82.8-89.7). The negative predictive value (NPV) was 103/133, i.e. 77.4% (95% CI 69.4-84.2). CONCLUSIONS As the SOF proved to reach the end-point of our study, we support its use as a means of screening elderly cancer patients in everyday clinical practice.

The purpose of the present study was to evaluate the activity and the tolerability of the FOLFIRI regimen, administered as second-line chemotherapy in patients with locally advanced or metastatic pancreatic cancer after the failure of a gemcitabine-based regimen.Patients with locally advanced/metastatic disease who received a first-line chemotherapy (one line only) with gemcitabine±platinoid (cisplatin, oxaliplatin) and who had measurable disease conform with the RECIST criteria were eligible for the study. FOLFIRI consists of irinotecan 180mg/m(2) iv on day 1, leucovorin (l-form) 200mg/m(2) iv on day 1 and 2, 5-FU 400mg/m(2) iv bolus on days 1 and 2, and 5-FU 600mg/m(2) iv by ci for 22h on days 1 and 2, repeated every 2weeks. The primary end point was the response rate.Among the 50 enrolled patients, 4 partial responses (PR) (8%) and 14 stable diseases were observed, for a disease control rate of 18/50 (36%). Forty-one patients (82%) have been pretreated with cisplatin/oxaliplatin+gemcitabine as first-line chemotherapy. The median progression-free and overall survivals were 3.2 and 5months, respectively. The 6-month survival rate was 32%. Grade 3-4 neutropenia and diarrhea occurred in 10 (20%) and 6 (12%) patients, respectively.The FOLFIRI regimen showed a modest clinical activity in this quite heavily pretreated patients' population with locally advanced or metastatic pancreatic cancer with a manageable toxicity profile.

Cetuximab plus radiotherapy (RT) may be an effective alternative to chemoradiation in locally advanced head and neck squamous cell carcinoma (LASCCHN) patients. We analyzed a group of patients treated at our institute with cetuximab plus volumetric modulation arc therapy (VMAT) with the RapidArc technique in a simultaneous integrated boost (SIB) regime. The primary end point was the assessment of acute toxicity and the feasibility of the combined approach.Between December 2008 and March 2010, 22 patients were submitted to IMRT-SIB plus cetuximab for radical intent in case of LASCCHN. None of the patients was suitable for chemotherapy because of important comorbidities (the majority suffered of heart chronic diseases). All patients underwent planning CT (additional image modalities were acquired for contouring purposes in the same treatment position: MRI in 12 and FDG-PET in 4 out of 22 patients). VMAT, by means of RapidArc, and SIB with two dose levels of 54.45 Gy and 69.96 Gy in 33 fractions were adopted. All patients included in the analysis were concomitantly treated with cetuximab: administration of the drug was initiated 1 week before RT at a loading dose of 400 mg/m(2) body surface area over a period of 120 min, follow by a weekly 60 min infusion of 250 mg/m(2) for the duration of RT. Patients were assessed for toxicities according to the Radiation Therapy Oncology Group (RTOG) criteria.All but 2 patients completed treatment and achieved the minimum follow-up of 12 months after the end of the treatment. Of the 22 patients, 18% (4 patients) showed grade 1, 36% (8 patients) grade 2, and 36% (8 patients) showed grade 3 dermatitis, while 9% (2 patients) had grade 1, 36% (8 patients) grade 2, and 45% (10 patients) had grade 3 mucositis/stomatitis. No grade 4 toxicities were recorded. Considering blood parameters, 3 cases of grade 1 anemia and 1 case of grade 2 thrombocytopenia were observed. Nobody required feeding tube placement during treatment.The here reported toxicity data are promising and encouraging in regard to the adoption of moderate hypofractionation with VMAT-SIB techniques, when cetuximab is concomitantly administered.

Purpose Comprehensive geriatric assessment (CGA) is a multidimensional method used by geriatricians and oncologists to detect and evaluate multiple age-related problems and to plan and coordinate interventions. Because its main drawback is the time required, efforts have been made to evaluate screening instruments suitable for preliminarily assessing elderly patients. The main aim of this study was to establish the accuracy of the Vulnerable Elders Survey-13 (VES-13) in predicting the presence of abnormalities revealed by CGA. Patients and Methods Patients age ≥ 70 years with a histologically or cytologically confirmed diagnosis of a solid or hematologic tumor underwent both CGA and a VES-13 assessment, and the reliability and validity of VES-13 were analyzed. Results Fifty-three percent of the 419 elderly patients with cancer (mean age, 76.8 years) were vulnerable on VES-13; the rates of disabilities on CGA and activities of daily living (ADLs)/instrumental activities of daily living (IADLs) scales were 30% and 25%, respectively. The sensitivity and specificity of VES-13 were 87% and 62%, respectively, versus CGA and 90% and 70%, respectively, versus ADL/IADL scales. Conclusions On the basis of our data, VES-13 is highly predictive of impaired functional status and can thus be considered a useful preliminary means of assessing older patients with cancer before undertaking a full CGA.

Prognosis of advanced hepatocellular carcinoma is dismal when locoregional treatments have failed. Systemic chemotherapy is seldom effective in inducing objective response and prolonging survival. We report a case of complete pathological remission of hepatocellular carcinoma after three cycles of systemic chemotherapy. A 64-year-old woman presented with histologically documented hepatocellular carcinoma without associated liver disease, relapsed after earlier locoregional therapy. Surgery was not performed as thoracic computerized tomography (CT) demonstrated pulmonary bilateral nodules. The patient was treated with chemotherapy consisting of three cycles of epirubicin, cisplatin, and infusional 5-fluorouracil (ECF regimen); stable lung disease and a good partial response in the liver were obtained as documented by CT scan. Hepatic segmentectomy was therefore performed and the histologic examination revealed necrosis without evidence of residual disease. Two more cycles of adjuvant chemotherapy were infused after surgery. At 1-year follow-up the patient is alive and free of disease according to a positron emission tomography/CT scan. It is suggested that an aggressive regimen like ECF should be considered in fit patients who are not affected by concomitant liver disease.

Background: Chemoradiotherapy is the current standard of care for locoregionally advanced nasopharyngeal carcinoma. The purpose of this study was to assess the feasibility and efficacy of induction chemotherapy (CHT) followed by concomitant chemoradiotherapy in this patient population. Patients and Methods: In this single-arm, phase II study, patients with locoregionally advanced nasopharyngeal carcinoma were treated with 3 cycles of induction CHT with cisplatin (100 mg/m2 on day 1) and 5-fluorouracil (1,000 mg/m2 continuous infusion on days 1–4) followed by 3 cycles of cisplatin (100 mg/m2 on days 1, 22 and 43) and concurrent radiotherapy up to 70 Gy. The primary endpoint was objective response. Results: Thirty-four patients were enrolled, and all completed both induction treatment and subsequent chemoradiotherapy. Objective response rates were 79.4% (95% CI 62.1–91.3) and 85.3% (95% CI 68.9–95.0) after induction CHT and chemoradiation, respectively. Treatment was well tolerated and toxicity was manageable. At a median follow-up of 29 months, 3-year overall survival and progression-free survival rates are 80.0% (95% CI 0.64–0.95) and 54.0% (95% CI 0.36–0.73), respectively. Conclusions: Induction CHT with cisplatin and 5-fluorouracil followed by concomitant chemoradiotherapy is a feasible and active regimen for patients with stage IIB–IVB nasopharyngeal carcinoma. This regimen resulted in excellent locoregional disease control and overall survival.

Background Cancer incidence raises progressively during life span; it is estimated that by the year 2030 almost 70% of all neoplasms will occur in people over 65 years old. As carcinogenesis is a multistep, time-requiring process, it is expected that as people live longer they are more likely to develop cancer, and therefore, the prevalence of multiple primary malignancies (MPM) is destined to increase with age. Patients and methods Records of all consecutive cancer patients referred to our center from January 2004 to January 2007 were reviewed. We chose the definition of MPM proposed by Warren and Gates. Multiple malignancies were assessed for elderly (≥70 years old) and younger patients. t-Test and Mc Nemar test were used; subgroup analysis was also performed according to age stratification. Results A total of 1,503 consecutive patients were considered; 566 were 70 years old or more (mean age 76.5 years, range 70–96 years) and 878 were younger (mean age 57 years, range 18–69 years). The prevalence of multiple malignancies in the elderly people versus younger ones was 15% and 6%, respectively (P = 0.001). As far as the elderly population is concerned, 21% (56/271) of males compared with 14% (42/295) of females had developed MPM; no significant difference was found between the subgroups with MPM or not as far as age (P = 0.16), comorbidities (P = 0.79), medications (P = 0.76), CIRS-G score and index (P = 0.47, P = 0.54), and PS (P = 0.93) are concerned. Most frequent associations among cancer types were prostate with lung (10/87, 11%), prostate with colorectal cancer (10/87, 11%), and smoking-related cancer, namely lung and head and neck cancer (X/Y, 6%). Conclusions Elderly patients are more likely to develop MPM compared to younger ones. Significant cancer association according to field cancerogenesis concept was the one of smoking-related cancer; other MPM patterns were apparently a random phenomenon.