A dose-dense short-term therapy for human immunodeficiency virus/acquired immunodeficiency syndrome patients with high-risk Burkitt lymphoma or high-grade B-cell lymphoma: safety and efficacy results of the "CARMEN" phase II trial.

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.

Performance of CT Colonography in Diagnosis of Synchronous Colonic Lesions in Patients With Occlusive Colorectal Cancer.

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%).

Impact of Metformin Use and Diabetic Status During Adjuvant Fluoropyrimidine-Oxaliplatin Chemotherapy on the Outcome of Patients with Resected Colon Cancer: A TOSCA Study Subanalysis.

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.

Disseminated cytomegalovirus disease after bendamustine: a case report and analysis of circulating B- and T-cell subsets.

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.

Systematic vs. on-demand early palliative care in gastric cancer patients: a randomized clinical trial assessing patient and healthcare service outcomes.

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 (12 weeks 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).

First-line FOLFIRI and bevacizumab in patients with advanced colorectal cancer prospectively stratified according to serum LDH: final results of the GISCAD (Italian Group for the Study of Digestive Tract Cancers) CENTRAL (ColorEctalavastiNTRiAlLdh) trial.

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.

Anti-epidermal growth factor receptor skin toxicity: a matter of topical hydration.

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.

Prognostic Value of Body Mass Index in Stage II/III Colon Cancer: Posthoc Analysis From the TOSCA Trial.

BACKGROUND: High body mass index (BMI) plays a key role in the development of colon cancer (CC). Our post-hoc analysis from the TOSCA trial analyzed the association between BMI and survival outcomes in terms of relapse-free survival (RFS) and overall survival (OS) in stage II/III CC patients. PATIENTS AND METHODS: Patients enrolled in the TOSCA trial between 2007-2013 with BMI data entered the study. The prognostic impact of BMI on survival outcomes was investigated through uni- and multivariable Cox regression analyses. RESULTS: Overall, 1455 patients with stage II/III CC patients were included. The median follow-up was of 61.5 months; 16.1% of patients relapsed, 11.2% died and 19.5% patients relapsed or died. No impact of BMI on RFS was detected at univariate or multivariable analyses. By univariate analysis for OS, a significantly impact of a BMI > 30 kg/m2 was reported (HR [>30 vs <25] 1.57, 95% CI 1.00-2.47, p = 0.049; HR [>30 vs <30] 1.55, 95% CI 1.01-2.37, p = 0.045). Multivariable analyses did not confirm this data. In the subgroup of stage III patients, a negative survival impact of BMI was found in univariate and multivariable models both for RFS and for OS. CONCLUSIONS: In our study, obesity with BMI > 30 kg/m2 was an independent prognostic factor for RFS and OS in CC patients treated with adjuvant chemotherapy, regardless of its duration (3 or 6 months). However, the prognostic impact of adiposity and body composition measurement should be considered to better classify patients with high visceral fat and refine their risk assessment.

Role of plasma EBV DNA levels in predicting recurrence of nasopharyngeal carcinoma in a Western population.

BACKGROUND: Loco-regionally advanced nasopharyngeal carcinomas can be cured by the combination of chemotherapy and radiotherapy. In Eastern countries, plasma levels of viral Epstein-Barr deoxyribonucleic acid (DNA) are accurate in predicting recurrence, but few data are available in Western populations. The aim of this prospective study was to evaluate the relationship between viral Epstein-Barr DNA copy numbers in plasma and the response rate, progression-free survival and overall survival in a cohort of Western patients with stage IIb-IVb nasopharyngeal cancer. METHODS: We evaluated plasma samples from 36 consecutive patients treated with induction chemotherapy followed by chemoradiation. EBV copy numbers were determined after DNA extraction using real-time quantitative polymerase chain reaction. Survival curves were estimated using the Kaplan-Meier method. RESULTS: Circulating Epstein-Barr virus DNA levels were measured before treatment, at the end of concomitant chemo- and radiotherapy, and during the follow-up period. Pre-treatment levels significantly correlated with the initial stage and probability of relapse. Their increase was 100% specific and 71.3% sensitive in detecting loco-regional or metastatic recurrence (an overall accuracy of 94.4%). Three-year progression-free and overall survival were respectively 78.2% and 97.1%. CONCLUSIONS: The results of this study confirm that patients from a Western country affected by loco-regionally advanced nasopharyngeal carcinoma have high plasma Epstein-Barr virus DNA levels at diagnosis. The monitoring of plasma levels is sensitive and highly specific in detecting disease recurrence and metastases.

Recent advances in small cell lung cancer: the future is now?

Small cell lung cancer is a relevant clinical issue as it is a highly malignant cancer, often diagnosed in advanced stage. Similarly to non-small cell lung cancer, tobacco smoking is currently the main risk factor. Its incidence, at least in males, has declined over the past decades, due to the worldwide decreased percentage of active smokers. The typical small cells of this tumor type are characterized by a high Proliferation Index, chromosomal deletions such as 3p(14-23) involving the tumor-suppressor gene FHIT, alterations of the MYC or Notch family proteins and the frequent expression of neuroendocrine markers. The combination of thoracic radiotherapy and chemotherapy is the standard treatment for limited stage disease, while platinum-based chemotherapy is the most effective choice for extensive stage disease. Unfortunately, whatever chemotherapy is used, the results are disappointing. No regimen has proved to be effective in the long run, indeed small cell lung cancer rapidly progresses after a frequent initial strong response, and the mortality rate remains still high. The advent of immunotherapy is actually changing the landscape in oncology. As well as in other cancers, recent trials have demonstrated the efficacy of the combination of immune checkpoint inhibitors and chemotherapy, opening new perspectives for the future of our patients.

An Inflammatory Signature to Predict the Clinical Benefit of First-Line Cetuximab Plus Platinum-Based Chemotherapy in Recurrent/Metastatic Head and Neck Cancer.

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.

Dynamics of RAS/BRAF Mutations in cfDNA from Metastatic Colorectal Carcinoma Patients Treated with Polychemotherapy and Anti-EGFR Monoclonal Antibodies.

Analysis of plasma-derived cell-free DNA (cfDNA) might allow for the early identification of resistance in metastatic colorectal carcinoma (mCRC) patients receiving anti-EGFR monoclonal antibodies. We tested plasma samples from the Erbitux Metastatic Colorectal Cancer Strategy (ERMES) phase III trial of FOLFIRI+Cetuximab in first-line treatment of RAS/BRAF wild-type mCRC. Samples were collected at baseline (n = 37), at 8 weeks of treatment (n = 32), progressive disease (PD; n = 36) and 3 months after PD (n = 21). cfDNA testing was performed using the Idylla™ ctKRAS and ctNRAS-BRAF tests and the Oncomine Pan-Cancer Cell-Free Assay. Analysis of basal samples revealed RAS/BRAF mutations in 6/37 cases. A transient RAS positivity not associated with PD was observed at 8 weeks in five cases that showed no mutations at baseline and PD. The frequency of mutant cases increased at PD (33.3%) and decreased again at 3 months after PD (9.5%). The median progression-free survival (mPFS) of patients RAS/BRAF mutant at PD was 7.13 months versus 7.71 months in wild-type patients (p = 0.3892). These data confirm that the occurrence of RAS/BRAF mutations in mCRC patients receiving anti-EGFR agents is relatively frequent. However, the cfDNA dynamics of RAS mutations in patients treated with anti-EGFR agents plus polychemotherapy are complex and might not be directly associated with resistance to treatment.

Management of skin toxicity associated with cetuximab treatment in combination with chemotherapy or radiotherapy.

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.

A CT-Based Radiomic Signature Can Be Prognostic for 10-Months Overall Survival in Metastatic Tumors Treated with Nivolumab: An Exploratory Study.

Baseline clinical prognostic factors for recurrent and/or metastatic (RM) head and neck squamous cell carcinoma (HNSCC) treated with immunotherapy are lacking. CT-based radiomics may provide additional prognostic information. A total of 85 patients with RM-HNSCC were enrolled for this study. For each tumor, radiomic features were extracted from the segmentation of the largest tumor mass. A pipeline including different feature selection steps was used to train a radiomic signature prognostic for 10-month overall survival (OS). Features were selected based on their stability to geometrical transformation of the segmentation (intraclass correlation coefficient, ICC > 0.75) and their predictive power (area under the curve, AUC > 0.7). The predictive model was developed using the least absolute shrinkage and selection operator (LASSO) in combination with the support vector machine. The model was developed based on the first 68 enrolled patients and tested on the last 17 patients. Classification performance of the radiomic risk was evaluated accuracy and the AUC. The same metrics were computed for some baseline predictors used in clinical practice (volume of largest lesion, total tumor volume, number of tumor lesions, number of affected organs, performance status). The AUC in the test set was 0.67, while accuracy was 0.82. The performance of the radiomic score was higher than the one obtainable with the clinical variables (largest lesion volume: accuracy 0.59, AUC = 0.55; number of tumoral lesions: accuracy 0.71, AUC 0.36; number of affected organs: accuracy 0.47; AUC 0.42; total tumor volume: accuracy 0.59, AUC 0.53; performance status: accuracy 0.41, AUC = 0.47). Radiomics may provide additional baseline prognostic value compared to the variables used in clinical practice.

Oxaliplatin plus fluoropyrimidines as adjuvant therapy for colon cancer in older patients: A subgroup analysis from the TOSCA trial.

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 <70 years and 693 ≥ 70 years) randomised to receive 3 or 6 months of FOLFOX or CAPOX within the frame of the phase III, TOSCA study. RESULTS: Older patients compared with younger ones presented more frequently an Eastern Cooperative Oncology Group performance status equal to 1 (10.5% vs 3.3%, p < 0.001), a greater number of right-sided tumours (40.9% vs 26.6%, p < 0.001), and were at higher clinical risk (37.2% vs 33.2%, p = 0.062). The treatments were almost identical in the two cohorts (p = 0.965). We found a greater proportion of dose reductions (46.7% vs 41.4%, p = 0.018), treatment interruptions (26.1% vs 19.3%, p < 0.001) and a higher proportion of recurrences (24.2% vs 20.3%, p = 0.033) in the older patients. The multivariable analysis of the TTR did not indicate a statistically significant effect of age (hazard ratio [HR]: 1.19; 95% confidence interval [CI]: 0.98-1.44; p = 0.082). The HR comparing older with younger patients was 1.34 (95% CI: 1.12-1.59; p = 0.001) for DFS, 1.58 (95% CI: 1.26-1.99; p < 0.001) for OS, and 1.28 (95% CI: 0.96-1.70; p = 0.089) for CSS. CONCLUSIONS: Worse prognostic factors and reduced treatment compliance have a negative impact on the efficacy of oxaliplatin-based adjuvant therapy in older patients.

Nab-paclitaxel/gemcitabine combination is more effective than gemcitabine alone in locally advanced, unresectable pancreatic cancer - A GISCAD phase II randomized trial.

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.

Immunotherapy in Nonendemic Nasopharyngeal Carcinoma: Real-World Data from Two Nonendemic Regions.

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.

Autoimmune-related encephalitis during treatment with nivolumab for advanced head and neck cancer: a case report.

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.

The Slippery Role of Induction Chemotherapy in Head and Neck Cancer: Myth and Reality.

Chemoradiotherapy as an alternative to surgery can be offered to patients affected by loco-regionally advanced head and neck cancer (HNC). Induction chemotherapy is a valid option, supported by few positive trials, but its real efficacy is still a matter of debate. The standard regimen for induction chemotherapy in Europe is a combination of docetaxel (75 mg/m2) and reduced dose doses of cisplatin (75 mg/m2) and 5-fluorouracil (750 mg/m2 day, for five consecutive days) (TPF). It is less toxic and more effective than the historical therapy PF (cisplatin 100 mg/m2 and fluorouracil 1,000 mg/m2/day for five consecutive days). However, in some studies treatment-related mortality has been reported to be as high as 6%. Therefore, some less toxic combinations, such as a modified TPF regimen and the combination of carboplatin plus paclitaxel have been studied. These regimens are showing promising results but deserve further validation in comparative trials. Furthermore, several trials are underway in order to enhance TPF with immune checkpoints inhibitors. Compared to chemoradiotherapy, induction chemotherapy followed by chemoradiation was shown to be non-inferior, and it could decrease the distant metastatic progression, especially in high-risk populations. For selected patients, induction chemotherapy could be a strong option. The chemoselective process that leads to immediate surgery for non-responders, the high response rate (complete responses are sometimes observed), and the survival data, are all arguments in favor of induction chemotherapy, if performed in experienced centers involving health professionals in the context of a skilled multidisciplinary team.

Correction to: Immunohistochemical evaluation of microsatellite instability in resected colorectal liver metastases: a preliminary experience.

The original version of this article unfortunately contained a mistake. All the authors first name and second name has been inadvertently interchanged. Now the authors name are corrected.