Consecutive Prospective Trials Research Articles

The role of ALBI score in patients treated with stereotactic body radiotherapy for locally advanced primary liver tumors: a pooled analysis of two prospective studies.

To evaluate the outcomes after stereotactic body radiotherapy (SBRT) for locally advanced primary liver cancer. Patients with locally advanced liver cancer unsuitable for other loco-regional treatments were treated with SBRT with 50-60 Gy in 3-12 fractions in two consecutive prospective trials. A total of 83 patients were included, of whom 14 were excluded, leaving 69 evaluable patients with 74 treated lesions. A total of 50 patients had hepatocellular carcinoma (HCC), and 11 patients had cholangiocarcinoma (CCC). Approximately 76% had a Child-Pugh (CP) score of A, while 54% had an albumin-bilirubin (ALBI) score of 1. With a median follow-up of 29 months, the median overall survival (OS) was 11 months, and the progression-free survival (PFS) was 18 months. The ALBI score was an important predictor of overall survival (HR 2.094, p = 0.001), which remained significant also in the multivariate analysis. Patients with an ALBI grade of ≥1 had an OS of 4 months versus 23 months in patients with an ALBI grade of 1 (p ≤ 0.001). The local control at 1 and 2 years was 91%. Thirteen patients developed grade ≥ 3 toxicities, of whom nine patients experienced liver toxicities. Patients with a higher ALBI score had a high risk for developing hepatic failure (OR 6.136, p = 0.006). SBRT is a very effective treatment with low toxicity and should be considered as a local treatment option in patients with HCC and CCC. Patients with a higher ALBI grade are at risk for developing toxicities after SBRT and have a significantly lower survival rate.

Assessment of Tumor Burden and Response by RECIST vs. Volume Change in HPV+ Oropharyngeal Cancer – An Exploratory Analysis of Prospective Trials

<h3>Purpose/Objective(s)</h3> Tumor burden and response to therapy are commonly assessed using RECIST, however, unidimensional evaluation may not fully characterize disease dynamics. Using HPV+ oropharyngeal carcinoma as a tumor model, here we report a comparison of RECIST and volumetric measurements from 2 consecutive prospective trials of response-adaptive de-escalation of therapy. <h3>Materials/Methods</h3> Patients enrolled on 2 prospective phase II response adapted de-escalation trials for low- and high-risk HPV+ oropharynx cancer were included in the analysis. Patients received induction chemotherapy in trial 1 and induction chemoimmunotherapy in trial 2. Target lesions were initially assessed using RECIST 1.1 at baseline and post-induction therapy; patients with ≥ 50% response by RECIST received de-escalated radiation dose and treatment volume per protocol. Primary tumors and nodes were retrospectively delineated on diagnostic scans before and after induction therapy to ascertain volumetric tumor burden and response. Mean differences in RECIST and volume were evaluated with paired t-tests. Linear regression and chi-squared analysis were used to evaluate the correlation between percent change in tumor burden as well as de-escalation-concordance. Outcomes were overall excellent with use of 50% response by RECIST to guide de-escalation as reported previously. Analysis was thus done to identify proportion that responded 50% by volume. <h3>Results</h3> 104 patients (N=54 Trial 1, N=50 Trial 2) were evaluable. The mean post-induction therapy reduction in RECIST and volumetry was 3.13 cm and 25.18 cm³ respectively (<i>p</i><0.001). Primary tumor response to induction was greater than nodal response for both RECIST and volumetry. The mean percent difference in size post induction was 27.3% and 14.8% for RECIST and volumetry. Percent change in RECIST was correlated with volume change, <i>r</i> = 0.687 (<i>p</i><0.001). An increased proportion (<i>p</i>=0.008) of patients would be eligible for de-escalation based on response assessment (72% de-escalated by RECIST vs 89% by volumetry), and 4% (N=4) of patients who were de-escalated by RECIST would not meet criteria for de-escalation by volumetry. 2 of these 4 patients developed a local failure. <h3>Conclusion</h3> Here we report on volumetry as a novel response assessment tool. While volumetry was correlated with RECIST, a large proportion of variance in volume-based measurements was not accounted for by RECIST. Furthermore, volumetry-based assessment of tumor burden and response provided a more robust assessment of tumor response and subsequent decision to de-escalate therapy. Patients that responded by RECIST but not volume had higher rates of local failure. In addition, a higher proportion of patients met response criteria by volume and could have been considered for de-escalation.

Multimodal Treatment of Nasopharyngeal Carcinoma in Children, Adolescents and Young Adults-Extended Follow-Up of the NPC-2003-GPOH Study Cohort and Patients of the Interim Cohort.

Simple SummaryMultimodal treatment of nasopharyngeal carcinoma (NPC) in children and young adults with induction chemotherapy, followed by radiochemotherapy and interferon-β (IFN-β) maintenance, has been successfully applied in studies NPC-91 and NPC-2003 of the German Society of Pediatric Oncology and Hematology (GPOH). We, here, present updated survival rates of the NPC-2003 study cohort after longer follow-up and include 21 additional patients recruited after closure of the study and treated as per the NPC-2003 study protocol (interim cohort) in our survival analysis. Survival rates remain high after extended follow-up and in the larger cohort with EFS and OS of 94% and 97%, respectively, reinforcing the high antitumor efficacy of this multimodal treatment concept. Seven patients with CR after induction therapy received a reduced radiation dose of 54 Gy, and none of them relapsed. Thus, the reduction of radiation dose seems feasible and has the potential to reduce treatment-related late effects in this vulnerable population.Nasopharyngeal carcinoma (NPC) in children and young adults has been treated within two consecutive prospective trials in Germany, the NPC-91 and the NPC-2003 study of the German Society of Pediatric Oncology and Hematology (GPOH). In these studies, multimodal treatment with induction chemotherapy, followed by radio (chemo)therapy and interferon-beta maintenance, yielded promising survival rates even after adapting total radiation doses to tumor response. The outcome of 45 patients in the NPC-2003 study was reassessed after a median follow-up of 85 months. In addition, we analyzed 21 further patients after closure of the NPC-2003 study, recruited between 2011 and 2017, and treated as per the NPC-2003 study protocol. The EFS and OS of 66 patients with locoregionally advanced NPC were 93.6% and 96.7%, respectively, after a median follow-up of 73 months. Seven patients with CR after induction therapy received a reduced radiation dose of 54 Gy; none relapsed. In young patients with advanced locoregional NPC, excellent long-term survival rates can be achieved by multimodal treatment, including interferon-beta. Radiation doses may be reduced in patients with complete remission after induction chemotherapy and may limit radiogenic late effects.

Novel Intraoperative Imaging of Gastric Tube Perfusion during Oncologic Esophagectomy—A Pilot Study Comparing Hyperspectral Imaging (HSI) and Fluorescence Imaging (FI) with Indocyanine Green (ICG)

Simple SummaryOncologic esophagectomy with gastric conduit reconstruction is the gold standard in the curative treatment of localized esophageal cancer. Anastomotic leakage is one of the most significant postoperative complications and a predictor of increased postoperative mortality and deteriorated quality of life. Adequate perfusion is one of the essential prerequisites for anastomotic healing. An objective evaluation of the perfusion of the gastric conduit can be performed by hyperspectral imaging (HSI) and fluorescence imaging (FI) with indocyanine green (ICG) intraoperatively. The aim of this pilot study was to evaluate the feasibility and the potential of improved outcomes by simultaneous HSI and FI-ICG measurements of the gastric tube during esophagectomy.Background: Novel intraoperative imaging techniques, namely, hyperspectral (HSI) and fluorescence imaging (FI), are promising with respect to reducing severe postoperative complications, thus increasing patient safety. Both tools have already been used to evaluate perfusion of the gastric conduit after esophagectomy and before anastomosis. To our knowledge, this is the first study evaluating both modalities simultaneously during esophagectomy. Methods: In our pilot study, 13 patients, who underwent Ivor Lewis esophagectomy and gastric conduit reconstruction, were analyzed prospectively. HSI and FI were recorded before establishing the anastomosis in order to determine its optimum position. Results: No anastomotic leak occurred during this pilot study. In five patients, the imaging methods resulted in a more peripheral adaptation of the anastomosis. There were no significant differences between the two imaging tools, and no adverse events due to the imaging methods or indocyanine green (ICG) injection occurred. Conclusions: Simultaneous intraoperative application of both modalities was feasible and not time consuming. They are complementary with regard to the ideal anastomotic position and may contribute to better surgical outcomes. The impact of their simultaneous application will be proven in consecutive prospective trials with a large patient cohort.

Favorable radiation field decrease in gastric marginal zone lymphoma : Experience of the German Study Group on Gastrointestinal Lymphoma (DSGL).

Long-term impact of stage-adapted field reduction in alarge cohort of gastric marginal zone lymphoma (gMZL) patients treated conservatively with curative radiation therapy (RT). Prospective analysis of paper records of 290 patients with stage IE-IIE gMZL, treated in 78radiotherapeutic institutions in Germany from 1992-2013. Stage-adapted radiation fields decreased from extended field (EF) to involved field (IF) over the course of three consecutive prospective trials of the German Study Group on Gastrointestinal Lymphoma (DSGL). Treatment results were compared between the three cohorts. Overall collective with median age of 60years, slight male predominance (m:f = 1.1:1) and ratio of disease stageI:stage II = 2.1:1. Median follow-up 6.4years in total: 13.0 years in the first gastrointestinal study (GIT 1992), 8.2years in the second (GIT 1996) and 4.7years in the third study (DSGL 01/2003). Stage-adapted radiation field decrease together with further technological development led to reduced relative frequencies of acute/chronic adverse effects and until now was accompanied by lower disease recurrence. The third study design with smallest field size (IF in stageI, locoregional EF in stageII) achieved the best survival outcome at the 5‑year follow-up (overall survival 92.7%, event-free survival 89.5% and lymphoma-specific survival 100.0%). Disease relapse observed in 10patients. Cumulative incidence of disease-specific death was 1.7% of the followed patients. Primary disease stage associated with lymphoma-specific survival. Stage-adapted reduction towards IF in gMZL resulted in favorable adverse effects, local control and survival rates. These results support further decreases in modern RT of gMZL.

Pretreatment CT Based Emphysema and Fibrosis Scoring of Peri-Tumoral Lung Parenchyma Predicts Risk of Radiation Induced Lung Toxicity

Many patients receiving radiation (RT) for localized non-small cell lung cancer (NSCLC) harbor underlying pulmonary dysfunction secondary to emphysema, pulmonary fibrosis, or both. However, it is unclear whether this dysfunction leads to higher rates of radiation induced lung toxicity (RILT). We sought to assess whether baseline or change in baseline to mid-treatment spirometry based pulmonary function testing (PFTs) and/or pretreatment CT graded emphysema (EM) or pulmonary fibrosis (PF) scores were associated with RILT. We performed an institutional review board approved analysis of patients with localized NSCLC treated with non-SBRT external beam RT on 4 consecutive prospective trials from 2004-2013. The primary outcome was grade ≥2 RILT including pneumonitis and fibrosis. PFTs consisted of FEV1, FVC, FEV1/FVC, and DLCO. For baseline CT EM and PF grading, the lungs were divided into 6 zones. EM was scored from 0-4 and PF from 0-3, using existing clinical scoring schemes. Global EM and PF scores were created by summing the respective scores in each of the 6 defined zones. Regional tumor EM and PF scores were created using the highest score for each in the lung zone containing gross target volume. Multivariable analysis was performed with Cox-proportional hazard models. A total of 96 patients were available for analysis. Seventy-eight percent of patients received concurrent chemotherapy. Mean mean lung dose (MLD) was 14 Gy (2 Gy equivalent). Median FEV1/FVC and DLCO were 64 (interquartile range [IQR] 52-71) and 60 (IQR 49-74), respectively. Median global and regional tumor CT based EM scores were 6 (range 0-20) and 1 (range 0-3). Median global and regional tumor CT based PF scores were 0 (range 0-8) and 0 (range 0-3). 20 patients developed RILT with a 20 month freedom from RILT of 75%. 51 patients had mid treatment PFTs. PFTs changed minimally from baseline to mid-treatment, with no difference in changes when comparing patients with and without RILT. PFTs were not associated with RILT (all p >0.1). Global and regional tumor baseline CT EM and PF scores were individually associated with RILT when controlling for patient age, MLD, smoking status, and receipt of chemotherapy (all p<0.05). When controlling for EM and PF scores jointly, global scores no longer remained statistically significant (p>0.05), whereas regional tumor scores did (EM HR: 1.7, 95% CI: 1.1-2.8, p=0.03, PF HR: 2.2, 95% CI: 1.1-4.4, p=0.04). The severity of emphysema and fibrosis adjacent to tumor on pre-treatment CT imaging is associated with development of RILT, whereas global CT scores and PFTs are not. These findings suggest that peri-tumoral regional lung function and anatomy predict for risk of grade ≥2 RILT. This easily obtainable radiographic information combined with other clinical/dosimetric factors can help guide individualization of radiation treatment delivery.

Presence of bone metastases(BM) at diagnosis is associated with poor prognosis and coagulation disorders (CD) in patients (pts) with advanced gastric cancer (AGC).

e15538 Background: The presence of BM in AGC is a relatively uncommon finding and has a poor prognosis [Leporini C. 2015]. At diagnosis the presence of BM occurs in approximately 10-15% of pts with AGC.[Park 2011; Silvestris 2013]. Aim of this study is to describe the main features of pts with AGC and BM at diagnosis and the prognostic implications. Methods: A consecutive series of AGC followed at Cremona Oncology Division from November 2004 to Dicember 2016 and included in three consecutive prospective trials [Dalla Chiesa M. 2011; Tomasello G. 2013], were analyzed. All pts were treated with a modified DCF (docetaxel, cisplatin, fluorouracil) given as a dose-dense regimen, every 14 days. We analyzed pts with BM at diagnosis (BMaD) and pts without BMaD. We evaluated baseline clinical and pathological parameters, the presence of coagulation disorders (CD) together with efficacy measures in the two groups. Results:218 pts with AGC were identified (38 with BMaD and 180 without BMaD).Main pts characteristics and results are reported in the Table below. Conclusions: The presence of BM at diagnosis in pts with AGC is not a rare event (21%) and identifies a population with a significantly poorer outcome and a higher incidence of CD, that need a clinical monitoring of coagulation parameters. More efforts are required to understand the reasons of the different prognosis and to find specific treatments to improve the survival. [Table: see text]

Synovial Sarcoma Recurrence in Children and Young Adults.

Recurrence of synovial sarcoma (SS) has been associated with poor prognosis. Optimal treatment is unknown due to heterogeneous primary therapies with or without chemotherapy. Data of patients treated in consecutive prospective European Cooperative Weichteilsarkom Studiengruppe trials 1981-2010 with primary localized SS less than 21years were analyzed. Chemotherapy had been recommended for all SS patients during primary therapy. Of 220 patients, 52 experienced recurrence a median of 2.5years (range, 0.3-11.6years) after their initial diagnosis. Recurrence was local in 22 (42%), metastatic in 24 (46%), and combined in 6 (12%) of the 52 patients. If present, metastases involved the lungs in more than 90% of the patients. Second remission was achieved by 39 (75%) of the 52 patients, whereas only 12 (23%) of the 39 patients maintained it. The median follow-up period for 17 survivors was 6.7years (range, 3.2-19.6years). The 5-year post-relapse event-free survival probability was 26%, and the overall survival probability was 40%. In the univariable analyses, initial tumor smaller than 3cm, 2.5years or longer to recurrence, local relapse only, and R0/R1 resection at relapse correlated with improved survival expectancies. In the multivariable analysis, the only factor retaining significance was R0/R1 resection of the recurrence. No difference between R0 and R1 resections was evident. For the patients with metastatic relapse, maintenance therapy seemed to prolong the time to subsequent recurrences. Although 75% of the patients with first SS recurrence achieved a second remission, only a minority became long-term, disease-free survivors. They had small tumors at initial diagnosis, local relapse as the only site of involvement, and complete resection of their recurrence. Because the majority of patients relapse subsequently, quality-of-life-based treatment approaches prolonging disease-free intervals are needed.

Influence of Renal Impairment and Genetic Risk Factors on Response to Induction Therapy in the HD4 and MM5 Trials of the GMMG

Background:In the HOVON65/GMMG HD4 trial in patients with newly diagnosed multiple myeloma we have previously shown that patients with renal impairment (RI) (creatinine > 2 mg/dl) have higher response rates and better survival when receiving bortezomib both in the induction and maintenance therapy before and after high-dose chemotherapy (HDT) (Scheid et al. Haematologica 2014). In addition patients with RI showed a higher prevalence of genetic high-risk features such as del17p or t(4;14). The aim of this analysis was to further elucidate the interaction between renal and genetic risk factors in well defined homogeneously treated myeloma patients.Methods:For this study we selected 2 cohorts of patients entered into 2 consecutive prospective trials with centralised FISH-assessement on CD138-selected bone marrow cells. The first cohort (1) comprises 395 patients from the HOVON65/GMMG HD4 trial having been treated in the German centers and the second cohort (2) consisted in the 601 patients (intention-to-treat population) from the recently closed GMMG MM5 trial. Patients lacking FISH results were excluded from the analysis, which was the case for 53 (13.4%) patients in cohort 1 and 43 (7.2%) patients in cohort 2. In cohort 1 induction treatment was vincristine or bortezomib + doxorubicin and dexamethason followed by tandem HDT followed by bortezomib or thalidomide maintenance. Cohort 2 received doxorubicin or cyclophosphamide + bortezomib and dexamethason as induction followed by 1- 2 HDT and consolidation and maintenance with lenalidomide.Results: In cohort 1 38 (10%) had RI and del 17p was found in 12/33 (36.4%) evaluable patients compared to 24/302 (7.9%) patients without RI (p<0.001). t(4;14) was present in 11/33 (33.3%) patients with RI and 38/304 (12.5%) without RI (p=0.005). Gain of 1q21 (> 2 copies) was present in 14/33 (42.4%) patients with RI and 92/298 (30.9%) without RI (n.s.). In cohort 2 68/601 (11.3%) had RI and 7/63 (11.1%) had del17p compared to 56/495 (11.3%) patients without RI (n.s.) while 29/63 (46%) patients with RI had t(4;14) versus 265/495 (53.5%) without RI (n.s.). Gain1q21 (>2 copies) was found in 36/63 (57.1%) with RI versus 209/495 (42.2%) without RI (p=0.025). In cohort 1 the response rate with at least VGPR after induction was low with and without RI in the VAD arm (15 vs 7.1 %) and reduced in patients with RI in the PAD arm compared to those without RI (22.2 vs 37.9%). This trend was not found in cohort 2: Patients with RI had VGPR or better in 42.4% in the PAD and 52.9% in the VCD arm, compared to 33.5% and 33.1% without RI respectively. Del17p and t(4;14) which were more frequent in patients with RI in cohort 1 did not have a negative impact on response rates after induction. Similarly gain1q was more frequent among patients in cohort 2 with RI but did not impact on response to induction.Conclusions:We analysed the effect of RI and genetic risk factors on the response to induction therapy in two different patient cohorts from two consecutive prospective trials. High-risk genetic features where found more frequently in patients with RI, but the pattern was entirely different between cohort 1 and 2 and they did not seem to influence response rates after induction. Our results confirm that bortezomib-based induction regimens achieve high response rates in myeloma patients with RI similar to those in patients without RI, independent of the presence of genetic risk factors. DisclosuresScheid:Janssen: Honoraria; Celgene: Honoraria. Salwender:Janssen: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Binding site: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Mai:Janssen: Travel support Other. Hose:Novartis: Research Funding. Weisel:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Onyx: Consultancy, Honoraria; BMS: Consultancy; Noxxon: Consultancy. Duerig:Janssen: Consultancy, Honoraria; Celgene: Honoraria. Goldschmidt:Janssen-Cilag: Honoraria, Research Funding, Speakers Bureau; Polyphor: Research Funding; Celgene: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Chugai: Research Funding, Speakers Bureau; Onyx: Consultancy, Speakers Bureau; Millenium: Consultancy, Speakers Bureau.

257O - Intense Dose-Dense Epirubicin (E), Paclitaxel (T), Cyclophosphamide (C) (Iddetc) is Highly Effective in Adjuvant Therapy of Node-Positive Breast Cancer Patients (Pts). an Analysis of the Gbg, Ago-B, and Noggo Study Groups

ABSTRACT Aim: In locally advanced breast cancer pts (≥pN2), adjuvant iddETC resulted in superior disease-free (DFS) and overall survival (OS) compared to conventionally dosed EC > Tq3w (AGO-ETC; Mobus JCO 2010). In the GAIN trial, iddETC was compared to a 4-drug dose-dense regimen with capecitabine (ddEC > TwX). Using the GAIN data, here we want to confirm the iddETC-results of the AGO-ETC trial with regard to DFS, OS, and toxicity. Methods: In the AGO-ETC trial (1998-2003) 681 of 1,284, and in GAIN (2004-2008) 1,498 of 3,023 pts were treated with iddETC. Pts were included in AGO-ETC if ≥pN2 and in GAIN if ≥pN1; median number of positive nodes was 8 and 5, respectively; all other inclusion criteria were comparable. Median follow-up was 62 and 74 months, respectively, in both trials primary end point was DFS. IddETC consists of a sequence of 3 x E 150mg/m2, 3 x T 225 mg/m2, and 3 x C 2,5 g/m2 q2w, with primary G-CSF support. After 40% accrual in GAIN, a reduced dose of C (2,0 g/m2) and antibiotic prophylaxis was implemented. Pts were randomly assigned to anemia prophylaxis with ESF in AGO-ETC, and to adjuvant ibandronate in GAIN (von Minckwitz JCO 2013). Results: In the iddETC-arm of AGO-ETC, 5y-DFS was 70% (95% CI 68% - 75%) and 5y-OS was 82% (95% CI, 79%to 85%). Comparing to conventional EC > Tq3w, HR for DFS was 0.69 (95% CI, 0.57 - 0.84). In GAIN, 5y-DFS was 80% (95% CI 78% - 82%) and 5y-OS was 85%. DdEC > TwX was not superior to iddETC. Evaluating GAIN pts with ≥pN2 (n = 923) separately, in order to match with the AGO-ETC inclusion criteria, results were comparable: 5yr-DFS was 75% (95% CI 72% - 78%) and 5y-OS was 85% (95% CI 83% - 88%). In AGO-ETC, 47 pts (7%) had at least one episode of febrile neutropenia during iddETC, no toxic death was observed. In GAIN, three pts (0,2%) died from therapy related septicaemia during iddETC. In both trials, paclitaxel induced neuropathy was in the expected range, and no grade 3 congestive heart failure occurred. Treatment induced MDS/AML was rare in both, AGO-ETC (0,6%) and GAIN (0,3%). Conclusions: We consistently show high efficacy of adjuvant iddETC for node-positive breast cancer pts (≥pN2) in two consecutive prospective trials: DFS and OS-results were superior to those with conventionally dosed therapy. In the reported studies, iddETC was feasible without excessive toxicity. We suggest to add iddETC to the group of preferred regimens in current guidelines. Disclosure: C. Thomssen: has received compensated honoraria for presentations and participating in advisory boards from Roche, Amgen, Pfizer; G. von Minckwitz: has received research funds from Roche, BMS, Amgen, Speaker and consultancy honoraria from Roche and Amgen; H. Tesch: has received compensated honoraria from Roche; N. Harbeck has received compensated honoraria from Roche; V. Muller: has received speaker honoraria from Amgen, Celgene, Glaxo Smith Kline, Pierre-Fabre, Roche, Jannsen-Cilag I. Bauerfeind: speakers honoraria from Amgen and Bristol Myers Squibb; S. Loibl: has received compensated honoraria for presentations and participating in advisory boards from Roche, Amgen V. Moebus: has receivedCompensated honoraria from Amgen, Jannsen-Cilag, Roche for presentations and participation in advisory boards. All other authors have declared no conflicts of interest.

Bone metastases (BM) in patients (pts) with locally advanced or metastatic gastric cancer (AGC): Clinical and therapeutic implications.

e15006 Background: At diagnosis BM occur in approximately 10-15% of AGC pts and their prognosis is poor (Park 2011; Silvestris 2013). Aim of this study is to identify the main features of pts with AGC and BM at diagnosis together with their response to chemotherapy and clinical course. Methods: We reviewed the clinical records of all AGC pts followed at Cremona Oncology Division from November 2004 to January 2013 and included in three consecutive prospective trials (Dalla Chiesa M. 2011; Tomasello G. 2013). We compared pts with BM at diagnosis vs pts without BM. All pts received a first linetherapy with TCF-dd regimen + Pegfilgrastim. Baseline clinical and pathological parameters were evaluated, together with Overall Survival (OS), Response Rate (RR), Time to Progression (TTP), Time From first Progression to Death (TFPTD), and toxicity. Analysis was based on the intention to treat principle. Results: 151 AGC pts were identified: 21 with BM and 130 without BM.The presence of non-bone metastases was balance...

Opinion on ?Why should we use atraumatic needles in lumbar puncture??, by SLA Matas

Dear editors, In his recent paper published in this journal, Matas addresses one important and well-studied aspect of postdural puncture headache prevention, i.e., the use of atraumatic spinal needles. On the other hand, when focusing on standard post-lumbar puncture recommendations, particularly 24 hours bed rest and controlled fluid ingestion, the author refers to four papers in which not only these recommendations are not enforced but, indeed, are explicitly disregarded – as in the case of bed rest – or, at least, considered as unproved, as in the case of fluid ingestion. Although a remark is made about the lack of “experimental support” to the above recommendations, the author does not mention the existence of positive evidence showing the lack of effect of post-lumbar puncture bed rest on the incidence of post-puncture headache, gathered during the last years and analyzed in recent systematic and non systematic reviews. Considering that the inefficacy of these measures had by now been consistently demonstrated by consecutive prospective trials, as already acknowledged by the headache community, we think that scientific evidence must prevail and the standard bed rest and fluid intake advices following lumbar puncture should be abandoned, instead of reinforced.

Impact of Rituximab and Radiotherapy on Outcome of Patients With Aggressive B-Cell Lymphoma and Skeletal Involvement

To study clinical presentation, outcome, and the role of radiotherapy in patients with aggressive B-cell lymphoma and skeletal involvement treated with and without rituximab. Outcome of patients with skeletal involvement was analyzed in a retrospective study of nine consecutive prospective trials of the German High-Grade Non-Hodgkin lymphoma Study Group. Of 3,840 patients, 292 (7.6%) had skeletal involvement. In the MabThera International Trial (MInT) for young good-prognosis patients and the Rituximab With CHOP Over 60 Years (RICOVER-60) study for elderly patients, the randomized addition of rituximab improved event-free survival (EFS; hazard ratio for MInT [HRMInT] = 0.4, P > 001; hazard ratio for RICOVER-60 [HRRICOVER-60] = 0.6, P > .001) and overall survival (OS; HRMInT = 0.4, P < .001; HRRICOVER-60 = 0.7, P = .002) in patients without skeletal involvement, but failed to improve the outcome of patients with skeletal involvement (EFS: HRMInT = 1.4, P = .444; HRRICOVER-60 = 0.8, P = .449; OS: HRMInT = 0.6, P = .449; HRRICOVER-60 = 1.0, P = .935). Skeletal involvement was associated with a worse outcome after cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus rituximab (HREFS = 1.5, P = .048; HROS = 1.1; P = .828), but not after CHOP without rituximab (HREFS = 0.8, P = .181; HROS = 0.7, P = .083). In contrast to rituximab, additive radiotherapy to sites of skeletal involvement was associated with a decreased risk (HREFS = 0.3, P = .001; HROS = 0.5; P = .111). Rituximab failed to improve the outcome of patients with diffuse large B-cell lymphoma with skeletal involvement, although our data suggest a beneficial effect of radiotherapy to sites of skeletal involvement. Whether radiotherapy to sites of skeletal involvement can be spared in cases with a negative positron emission tomography after immunochemotherapy should be addressed in appropriately designed prospective trials.

The role of radiotherapy and intrathecal CNS prophylaxis in extralymphatic craniofacial diffuse large B-cell lymphoma.

8566 Background: The role of radiotherapy and intrathecal prophylaxis in extralymphatic craniofacial involvement of aggressive B-cell lymphoma remains to be determined in the rituximab era. Methods: In a retrospective subgroup analysis of 9 consecutive prospective DSHNHL trials covering all DLBCL risk groups from 18 to 60 years of age, patients with and without craniofacial involvement were compared with respect to clinical presentation, event-free and overall survival. Results: 336 sites of extralymphatic craniofacial involvement were observed in 284/3840 (7.4%) patients (orbita: 30, paranasal sinuses: 90; main nasal cavity: 38, tongue: 26, remaining oral cavity: 99, salivary glands: 53). In a multivariable analysis adjusting for IPI risk factors the addition of rituximab improved EFS and OS in both patients with and without craniofacial involvement. The 141 responding patients who received radiotherapy to sites of craniofacial involvement had a similar 3-year event-free (79% vs 79%; p=0.835) and 3-year overall survival (88% vs. 85%; p=0.311) when compared with the 56 patients who did not receive radiotherapy. Without rituximab, the 2-year-rate of cumulative risk of CNS disease was increased in 205 patients with compared to 2586 patients without craniofacial involvement (4.2% vs. 2.8%; p=0.038), while this difference disappeared in patients who received CHOP(like) chemotherapy in combination with rituximab (1.7% in 77 patients with compared to 2.9% in 946 patients without craniofacial involvement; p=0.868). Of 85 patients with craniofacial involvement who received intrathecal prophylaxis with methotrexate, the 2-year-rate of cumulative risk of CNS disease was 4.3% compared to 2.3% in 189 patients who did not (p=0.995). Conclusions: Rituximab eliminates the increased risk for CNS disease in patients with craniofacial involvement. As a practical consequence intrathecal prophylaxis and radiotherapy to sites of craniofacial involvement should not be given any more.

Non-Invasive Measurement of Hemoglobin: Assessment of Two Different Point-of-Care Technologies

BackgroundMeasurement of blood hemoglobin (Hb) concentration is a routine procedure. Using a non-invasive point-of-care device reduces pain and discomfort for the patient and allows time saving in patient care. The aims of the present study were to assess the concordance of Hb levels obtained non-invasively with the Pronto-7 monitor (version 2.1.9, Masimo Corporation, Irvine, USA) or with the NBM-200MP monitor (Orsense, Nes Ziona, Israel) and the values obtained from the usual colorimetric method using blood samples and to determine the source of discordance.Methods and FindingsWe conducted two consecutive prospective open trials enrolling patients presenting in the emergency department of a university hospital. The first was designed to assess Pronto-7™ and the second NBM-200MP™. In each study, the main outcome measure was the agreement between both methods. Independent factors associated with the bias were determined using multiple linear regression. Three hundred patients were prospectively enrolled in each study. For Pronto-7™, the absolute mean difference was 0.56 g.L−1 (95% confidence interval [CI] 0.41 to 0.69) with an upper agreement limit at 2.94 g.L−1 (95% CI [2.70;3.19]), a lower agreement limit at -1.84 g.L−1 (95% CI [-2.08;-1.58]) and an intra-class correlation coefficient at 0.80 (95% CI [0.74;0.84]). The corresponding values for the NBM-200MP™ were 0.21 [0.02;0.39], 3.42 [3.10;3.74], -3.01 [-3.32;-2.69] and 0.69 [0.62;0.75]. Multivariate analysis showed that age and laboratory values of hemoglobin were independently associated with the bias when using Pronto-7™, while perfusion index and laboratory value of hemoglobin were independently associated with the bias when using NBM-200MP™.ConclusionDespite a relatively limited bias in both cases, the large limits of agreement found in both cases render the clinical usefulness of such devices debatable. For both devices, the bias is independently and inversely associated with the true value of hemoglobin.Trial RegistrationClinicalTrials.gov NCT01321580 NCT01321593

Concomitant Cisplatin, Paclitaxel, and Hyperfractionated Radiotherapy in Locally Advanced Head and Neck Cancer

To determine feasibility and efficacy of concurrent paclitaxel and cisplatin with definitive hyperfractionated radiotherapy (HFRT) in locally advanced head-and-neck squamous cell carcinoma (HNSCC). Forty-two patients stages III to IV head-and-neck squamous cell carcinoma were enrolled in 2 consecutive prospective trials from August 1998 to January 2006. In study 1, 16 patients received HFRT in 2 courses of 39.6 Gy each with a split of 2 weeks with concurrent paclitaxel (175 mg/m) and cisplatin (100 mg/m) on days 1, 21, 36, and 57. In study 2, 26 patients received a continuous course of 74.4 Gy of HFRT with concurrent weekly paclitaxel (50 mg/m) and cisplatin (30 mg/m). Tumor locations included oropharynx 48%, hypopharynx 24%, larynx 12%, paranasal sinuses 7%, salivary gland 2%, oral cavity 2% and unknown primary 5%. In study 1, all patients received 3 to 4 cycles of chemotherapy and completed the programmed radiotherapy course. In study 2, 69% received 5 to 6 cycles of chemotherapy and 92% completed the irradiation. Overall, 93% of objective responses were observed (complete 76%, partial 17%). Median follow-up was 50 months (range: 12-97). Pattern of recurrence was local 8%, distant 13%, and combined 3%. Acute toxicity grades 3 to 4 in studies 1 and 2 was 75% and 88%, respectively (P = ns). Globally, 5-year overall survival were 68%, with a median of 71 months (range: 50-91). On multivariate analysis, male gender (P = 0.04) and complete response (P = 0.01) were predictive of improved survival. HFRT combined with cisplatin and paclitaxel is very active but at the expense of severe toxicity. Efficacy and toxicity in studies.1 and 2 were not different despite completely different treatment strategies (chemotherapy dose intensity vs. radiotherapy dose intensity).

A Recent Update of Three Consecutive Prospective Trials with High-Dose Therapy and Autograft, without or with Rituximab, as Primary Treatment for Advanced-Stage Follicular Lymphoma (FL) Shows a Sizeable Group of Patients Surviving in Continuous Complete Remission up to 16 Years After the End of Treatment: Should We Still Consider FL An Incurable Disease ?.

Abstract 882 Background.Three consecutive trials have been performed in Italy over the last 18 years, to verify the efficacy of the use of High-Dose Sequential Chemotherapy (HDS) and autograft as first-line therapy for high-risk Follicular Lymphoma (FL) <60 yrs. We present the last update with 10 yrs. of median follow-up. Patients and Methods.The HDS regimen has been previously described (Corradini P et al, Blood 1997; Tarella C et al, Stem Cells 1998). Briefly, it consists of intensive debulking (2 APO courses +/− 2 DHAP courses) followed by the high-dose phase, including the sequential administration of etoposide (2 g/sqm), methotrexate (MTX) (8 g/sqm) and cyclophosphamide (CY) (7 g/sqm). PBPC collection is scheduled after the last course to maximize the “in vivo purging effect” operated by high-dose chemotherapy. The final autologous stem cell transplant (auto-SCT) conclude the program, two conditioning regimen have been employed, either the BEAM schedule or the Mitoxantrone/L-PAM combination. In the most recent schedule, Rituximab was included in place of MTX. In details, 2 Rituximab doses were administered before CY, after CY and after auto-SCT, with the aim of further improving disease control and the in-vivo purging. The first trial was a single Center phase II study exploring both feasibility and efficacy of the HDS program as first line therapy in advanced-stage indolent lymphoma (1991-1998, 26 FL patients) (Tarella C et al, Leukemia 2000); a subsequent multicenter phase 2 trial was then started at national level (GITMO, Gruppo Italiano Trapianto Midollo Osseo), to verify the efficacy of HDS in advanced-stage FL in a multicenter setting (1996-1999, 92 patients) (Ladetto M et al, Blood 2002); lastly, a muticenter phase 3 study was performed together with GITMO and IIL (Intergruppo Italiano Linfomi) Centers, comparing Rituximab supplemented HDS (R-HDS) vs. CHOP-R in aaIPI 2-3 FL (2000-2005, 68 patients in the R-HDS arm) (Ladetto M et al, Blood 2008). Overall, 186 patients have been treated with HDS, updated results have been obtained for 168 of them. They all had a diagnosis of FL (grade 1-2: 71%) and always presented with advanced stage, their median age was 48 yrs., LDH was high in 48%, BM involved in 77%. Results.140 patients out of 168 (83%) attained Complete Remission (CR); there were 6 early toxic deaths (3.6%); 8 patients had Partial Remission (4.8%) and 14 had no response (8.3%), soon followed by disease progression. So far 14 patients (8.3%) developed secondary myelodysplasia or acute leukemia (sMDS/AL), and 7 patients (4.2%) had a secondary solid neoplasia. As of July 2008, 50 of 168 patients died, due to: i. early toxicity (6 patients); ii. disease progression (25 patients, 15%); iii. second neoplasia (12 patients, 7.1%); iv. other causes (7 patients, 4.2%). Thus, at a median follow-up of 10 yrs., 118 patients (70.2%) are alive, and 80 (48%) are in their 1st continuous CR (CCR), and most of them are also in molecular remission. The actuarial OS and DFS curves are reported in Figures 1A and B. The latest relapse has been recorded at 8 yrs since HDS. So far, 50 patients (30%) are presently in their 1st CCR between 8 and 16 yrs after HDS. Conclusions.i. advanced stage FL treated upfront with the intensive HDS regimen had a prolonged survival, with median survival not yet reached after 10 yrs. of follow-up; ii. main causes of death were disease progression and both early and late toxic side effects; iii. approximately half of the patients are long-term survivors without any sign of disease recurrence. This suggest that a prolonged PFS and possibly the disease eradication should be pursued also in advanced-stage FL. Future studies will verify whether these therapeutic goals may be achieved with chemo-immunotherapeutic schemes at least as effective but less toxic and laborious than HDS program with autograft. [Display omitted] Disclosures:Tarella:Roche: Honoraria, research financial support. Ladetto:Roche: research financial support. Vitolo:Roche: Lecture fees. Rambaldi:Roche: Honoraria. Corradini:Roche: Honoraria.

Large cell/anaplastic medulloblastoma: Outcome according to myc status, histopathological, and clinical risk factors

To evaluate the prognostic impact of large cell/anaplastic (LC/A) histology together with molecular and clinical risk factors in childhood medulloblastoma. Three consecutive prospective medulloblastoma trials were screened for patients with the histological diagnosis of LC/A medulloblastoma. Tumors were considered as LC/A if they displayed areas of severe cytological anaplasia or a significant or predominant large cell component. Histology was centrally confirmed. Genomic DNA amplification of c-myc and n-myc, and mRNA expression of c-myc and trkC were analyzed. Twenty-eight patients with LC/A medulloblastoma with a median age of 6.1 years (1.4-16.5 years) and a median follow-up of 4.5 years were identified (5% of all medulloblastoma). Four-year event-free (EFS) and overall survival (OS) were 58% and 67%. Young age and metastases (n = 13, 4-year EFS 31% vs. 82% in 15 children >4 years and without metastases, P = 0.001), large cell histology (n = 9, 4-year EFS 22% vs. 75%, P = 0.005) and c-myc amplification (n = 9, 4-year EFS 22% vs. 89%, P < 0.0001) were negative prognostic factors. C-myc amplification was highly correlated with young age (P < 0.001), metastases (P = 0.002) and large cell histology (P = 0.007). Outcome of 12 patients with severely anaplastic tumors without these risk factors was not impaired (4-year EFS 86%). In a subgroup of patients without clinical and molecular risk factors outcome was favorable despite severely anaplastic histology. In contrast, c-myc amplification and large-cell histology were associated with an inferior outcome. Intensified treatment strategies should be considered for children with LC/A medulloblastoma and these characteristics.

Pretreatment Prognostic Factors Influencing Distant Metastasis-Free Survival in Locally Advanced Squamous Cell Carcinoma of the Head and Neck Treated With Radiation Therapy With or Without Concurrent Chemotherapy

To investigate impact of various pretreatment prognostic factors influencing distant metastasis-free survival (DMFS), in patients with locally advanced (stage III/IV), nonmetastatic squamous cell carcinoma of the head and neck. During 2 consecutive prospective randomized trials, a total of 289 patients were treated with standard fraction (conventionally fractionated [CF]) or hyperfractionated radiation therapy with or without concurrent low-dose daily platinum chemotherapy (CHT). : Kaplan-Meier analysis showed that gender (P = 0.96) and age (P = 0.88) did not influence DMFS, similarly to Karnofsky Performance Status (KPS) (P = 0.55), T stage (P = 0.12), and primary tumor location (P = 0.94). N stage (P = 0.0274), stage grouping (P = 0.0016), treatment (P = 0.0008), and concurrent CHT (P = 0.0001) influenced DMFS. Univariate Cox analysis showed that treatment lost its significance, whereas N staging became marginally insignificant (P = 0.061). Multivariate Cox analysis showed that only lower stage grouping (P = 0.014) and the addition of concurrent CHT (P < 0.001) were independent prognosticator of improved DMFS. This analysis showed that only stage grouping and concurrent CHT predicted DMFS in patients with locally advanced squamous cell carcinoma of the head and neck treated with RT with and without concurrent low-dose daily CHT. These results may have implication for future studies in this disease.

Factors associated with detection failure and false‐negative sentinel node biopsy findings in gastric cancer: Results of prospective single center trials

The factors associated with successful sentinel node biopsy (SNB) are limited in gastric cancer despite a wide range of sensitivities reported. This study was performed to identify the factors associated with detection failure and SNB false-negativity in gastric cancer. SNB was performed on 156 gastric cancer patients from May 2002 to April 2007 at the Korean National Cancer Center during three consecutive prospective trials. Indications for SNB were determined preoperatively in cT1-2N0 patients. Dissected SNs and non-SNs after D2 lymphadenectomy were pathologically evaluated for metastasis. Clinical, pathological, and technical factors were analyzed for detection failure and false-negativity. SNs were detected in 147 patients (94.2%) and the median number of SNs detected per patient was 3 (1-12). Twenty-five of 37 with nodal metastasis were diagnosed by SNB (sensitivity, 67.6%). Surgeon's inexperience (<or=30 procedures) and a male patient gender were significantly associated with detection failure (P = 0.014 and 0.031, respectively). A small number of SNs (<or= 3) was found to be significantly associated with false-negativity (P = 0.027). SNB requires experience for successful detection and should be performed cautiously in male patients. Harvesting of more than three SNs is warranted to reduce false-negatives when diagnosing nodal metastasis.