bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of continuation of bevacizumab following disease progression in patients with metastatic colorectal cancer on survival
Authors: Samelis G. F. , Tsiakou A. , Karamanidi M. , Pelechrini M. , Zaganides A. , Ekmektzoglou K.
Published: August 2020

e15143

Background: The management of patients with metastatic colorectal cancer (mCRC) has evolved dramatically over the last decade, with several “targeted” agents having entered the treatment arena. Multiple-line treatment is now considered as an important step towards the optimal therapeutic strategy for this patient population. Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, has shown clinical activity in patients with mCRC when used either as a first-line or second-line treatment. Currently, there is limited information in the literature on the use of bevacizumab combination chemotherapy in multiple lines with regimens including irinotecan and oxaliplatin, in mCRC patients who have progressed. Methods: We evaluated the efficacy and safety of bevacizumab in combination with standard chemotherapy (irinotecan, capecitabine, oxaliplatin, cetuximab) in 21 patients with metastatic colorectal cancer with a median age of 69 (range: 47–85) years old with PS: 0–1, included in the study. The metastatic sites were liver in 13 patients, liver and lung in 4 patients, lung in 2 patients, intra-abdominal in 1 patient and urinary-bladder in 1 patient. Bevacizumab treatment was continuously dispensed after disease progression and only other combined drugs were altered. Subgroup analysis was performed in terms of age, site of metastases, spread and co-morbidity. Results: The median age of the patients included in the analysis was 69 years (range 47–85). Progression free survival (PFS) was 17 months in first line setting (overall survival (OS) not reached yet) o, and for the age group >69 and <69 it was 23 and 16 months respectively (p=0.4565). Overall survival for the <69 years old was 36 months. Anemia (all grades) was reported in 90.6% of the patients, while hemorrhage and thrombosis were reported in 28.6% and 14.3% respectively. Conclusions: Multiple line treatment in advanced colorectal cancer, including bevacizumab combined with standard chemotherapy, may improve OS (median: 23+ months) with an acceptable toxicity profile in patients with mCRC. However, further research through well-designed randomized studies is warranted to appraise the beneficial risk- benefit ratio of such an approach.

No significant financial relationships to disclose.
Utility of concomitant chemoradiotherapy with 5-fluorouracil (5-FU) single agent as neoadjuvant treatment regimen in mexican patients with stage III rectal cancer: Experience in the Oncology Hospital
Authors: Gomez Rangel J. , Alvarez Ordorica O. , Villalobos Valencia R. , Silva J. A.
Published: August 2020

e15144

Background: To analyze overall survival, free disease survival, complete and partial pathologic response, effect of stage reduction, toxicity profile and number of anus preservative surgery in patients treated with concurrent chemo radiotherapy with a modified 5-FU single agent regimen as neoadjuvant modality treatment. Methods: Historic Cohort of patients treated in the Oncology Hospital, CMNSXXI between January 1999 to December 2004. The scheme used was a bolus of 5FU 425mg/m2 without leocovorin in three consecutive days each two weeks (days 1–3, 15 -17 and 29–31). Results and Conclusions: There were identified 96 consecutive patients with clinical stage III. The median age was 57.5 years. Ninety and two patients were operated and 51% was candidates to conservative surgery. There were 12.5% of complete pathologic responses and 35% of partial responses. The median of survival has not been reached. The five years of overall survival was 62% and the five-years of disease free survival was 55%. Stage reduction had impact in overall survival with 65% vs 40% at 9.5 years of follow up, and DFS was 58% vs 48% at 9.5 years. We report 16 cases of gastrointestinal toxicity grade 3 and two cases with grade 4. There was reported fourth cases of afebril neutropenia grade 4. Results in OS, DFS and number of complete pathological response were similar to reported by another oncology groups. Stage reduction was traduced in an increased of OS. This schedule can be feasible and applicable in another institutions in develop countries.

No significant financial relationships to disclose.
Phase II study of NGR-hTNF, a selective vascular targeting agent (VTA), in previously treated patients with hepatocellular carcinoma (HCC)
Authors: Santoro A. , Citterio G. , Pressiani T. , De Braud F. G. , Gregorc V. , Rossoni G. , Donadoni G. , Caligaris-Cappio F. , Lambiase A. , Bordignon C.
Published: August 2020

e15500

Background: NGR-hTNF is a VTA exploiting a tumor-homing peptide (NGR) that selectively binds to aminopeptidase N (CD13) overexpressed on tumor blood vessels. In preclinical models, NGR-hTNF has shown potent anti-vascular and antitumor activity, both at low and at high doses. Methods: Patients with recurrent or metastatic HCC were treated with NGR-hTNF given intravenously at 0.8 μg/m2 as 1-hour infusion every 3 weeks (q3w). This phase II trial had a 2-stage design with 16 and a total of 27 patients to be enrolled after first and second stage, respectively. Progression-free survival (PFS) was the primary endpoint with reassessment performed q6w according to WHO criteria. Results: 27 patients with progressive disease following prior loco- regional treatment (59%), systemic therapy (56%), or both (33%) were evaluated over 86 cycles (range, 1 to 14). Patient characteristics were: median age 67 years (range, 53 to 79); M/F 21/6; PS 0/1 18/9; Child-Pugh class A/B: 21/6. No grade 3–4 treatment-related adverse events were observed. Main grade 1–2 toxicities were short-lasting infusion-related constitutional symptoms, including chills (55%). Median PFS was 2.3 months (95% CI, 1.7–2.9 months). One complete response (4%) lasting 9.0+ months was observed in a sorafenib-refractory patient and one partial response (4%) was reported in a Child-Pugh class B patient. Additionally, a 28% tumor shrinkage was detected in one out of six patients (22%) experiencing stable disease. The median PFS duration in stable or responder patients was 4.3 months (95% CI, 2.7–5.8 months). With a median follow-up of 7.6 months, the overall survival rates at 3 and 6 months were 82% and 60%, respectively. Conclusions: NGR-hTNF given at 0.8 μg/m2 every 3 weeks is well tolerated and appears to have promising antitumor activity in previously treated patients with advanced HCC. The drug will be further developed in this setting and, currently, an additional cohort of 12 patients has been enrolled and treated at same dose with a weekly schedule.

[Table: see text]
KRAS and BRAF mutational status as response biomarkers to cetuximab combination therapy in advanced gastric cancer patients
Authors: Stella G. , Rojas Llimpe F. , Barone C. , Falcone A. , Di Fabio F. , Martoni A. , Lamba S. , Ceccarelli C. , Siena S. , Bardelli A. , Pinto C.
Published: August 2020

e15503

Background: The prognosis of advanced gastric cancer (GC) patients (pt) is still poor despite the introduction of new chemotherapy regimens. In colorectal cancer (CRC) it has been demonstrated that KRAS or BRAF mutations are associated with resistance to treatment with the anti-EGFR mAbs. We have assessed whether, and to what extent, the mutational profile of KRAS and BRAF genes affects the response to cetuximab combination therapy in GC. Methods: We have collected 44 tumor samples from pts affected by locally advanced or metastatic GC undergoing cetuximab combination therapy as first-line treatment in two consecutive phase II studies. Thirteen pts received cetuximab plus FOLFIRI (FOLCETUX Study) and 31 pts cetuximab plus cisplatin and docetaxel (DOCETUX Study). Genomic DNA was extracted from paraffin-embedded tumor specimens from all cases. The mutational status of KRAS (exon 2) and BRAF (exon 15) was ascertained by PCR amplification followed by direct sequencing. The objective response was evaluated every 6 weeks by CT according to RECIST criteria. Results: KRAS and BRAF mutations were detected in 5 (11.4%) and 1 (2.3%), respectively, of the 44 tumors analyzed. These frequencies are consistent with those previously reported in GC. In the case of KRAS, 3 cases displayed amino acid substitutions of codon 12 and 1 of codon 13. One case had the A11V variant that had been reported in hematopoietic and lymphoid tissue of the stomach. The only BRAF mutation found in 1 sample was the classic V600E substitution. As a whole, 13.6 % of the analyzed tumors carried a mutation in either KRAS or BRAF genes. K-RAS and BRAF mutations were, as expected, mutually exclusive. In this pt cohort oncogenic activation of KRAS/BRAF-signaling pathways was not significantly associated to objective response (p= 0.757). Also, we found no correlation between KRAS/BRAF mutations and clinical outcome measured as overall survival. Conclusions: In advanced GC the frequency of mutations in KRAS and BRAF is lower as compared with CRC cancer. In our cases, the mutational status of KRAS and BRAF genes does not correlate with the response to cetuximab-based therapy in advanced gastric cancer patients.

No significant financial relationships to disclose.
Preoperative chemoradiation and postoperative adjuvant tetrathiomolybdate for patients with resectable esophageal cancer
Authors: Urba S. , Schneider B. J. , Hayman J. A. , Orringer M. , Chang A. , Pickens A. , Pan C. , Lee J. , Foster J. , Merajver S.
Published: August 2020

e15504

Background: Tetrathiomolybdate (TM) is an oral copper chelator. Copper is necessary for blood vessel growth, and so TM functions as an antiangiogenic agent. Methods: Pts with resectable esophageal cancer were treated at the University of Michigan with chemoradiation followed by surgery, and then 2 years of TM. Chemoradiation was cisplatin 60 mg/m2 on days #1 and 22, paclitaxel 60 mg/m2 on days #1, 8, 15, and 22, and radiation 1.5 Gy fractions b.i.d. x 3 weeks to a total of 45 Gy. Transhiatal esophagectomy was performed on approximately day #50. TM 20 mg p.o. q.d. was started approximately 4 weeks post-op, and continued for 2 years. Doses were adjusted to maintain the ceruloplasmin level between 5 and 15. Results: Between 1/23/02 and 1/24/06, 69 pts were enrolled. Pt characteristics: males - 62 (90%), females - 7 (10%); median age - 60 (range 42–74); adenocarcinoma - 56 (81%), squamous cell carcinoma 13 (19%). The chemoradiation was well tolerated: grade 3 leukopenia in 15 pts (22%), and 17 pts (25%) required feeding tubes. 66 pts went to surgery. 61 pts had a complete resection; 4 pts had metastases discovered at surgery, and 1 pt had extensive positive margins. Histologic complete response rate was 10%. 21 pts never received TM because of metastases noted in the peri-operative period, long post-op recovery time, or pt refusal. 48 pts started TM after surgery and it was well tolerated. Grade 3 toxicities were diarrhea -2 (3%), nausea - 2 (3%), dizziness - 2 (3%). 13 pts completed the full 24 mos of treatment, 12 completed 10–23 mos, 15 completed 2–8 mos, and 8 completed only 1 month or less. 27 pts have had disease recurrence, the majority (23 of the 27) of which was distant. Current status of pts with median follow-up time of 55 months: 25 alive and disease-free, 1 alive with disease, and 43 have died. 3-year survival probability is 47% (95% CI 35%-58.6%). 3-year recurrence-free probability is 51% (95% CI 38%- 62.7%). Conclusions: TM is an antiangiogenic agent which is fairly well tolerated. Prolonged adjuvant treatment over 2 years is difficult but not impossible to complete. Disease-free survival and overall survival are promising when compared to historical controls treated with a very similar chemoradiation regimen without TM in the past at the University of Michigan.

[Table: see text]
A phase I study of gemcitabine plus dasatinib (GD) or gemcitabine plus dasatinib plus cetuximab (GDC) in refractory solid tumors
Authors: Uronis H. E. , Bullock K. , Blobe G. , Hsu S. , Morse M. , Nixon A. , Haley S. , O’Neill M. , Hurwitz H. , Bendell J.
Published: August 2020

e15506

Background: Dasatinib (D) is a small molecule tyrosine kinase inhibitor with activity against both bcr-abl and src. Cetuximab (C) is a monoclonal antibody that blocks EGFR. Preclinical models suggest D reverses resistance to G. In addition, src and EGFR pathways interact; synergism of dual blockade by D + C is possible. We evaluated two combination regimens, GD and GDC, in a Phase I dose escalation study. Methods: Patients (pts) with advanced solid tumors were enrolled in cohorts of 3–6 to either GD or GDC. G was dosed in mg/m2 weekly for 3 of 4 weeks, D was dosed in mg PO BID, and C was dosed at 250 mg/m2 weekly after loading dose of C=400; cycle length was 28 days. Dose levels were as follows: 1) G 1000 + D 50 ± C; 2) G 1,000 + D 70 ± C; 3) G 1,000 + D 100 ± C. Standard cycle 1 DLT definitions were used. Eligible pts had advanced solid tumors, adequate organ and marrow function, and no co-morbidities that would increase risk of toxicity. Serum, plasma, and skin biopsy biomarkers were obtained pre- and on treatment. Results: 25 pts have been enrolled, including 21 with pancreatic adenocarcinoma, 3 of whom had received prior G. 21 pts were evaluable for toxicity and 18 for efficacy. Four DLT were observed: Gr 3 ANC with infection (GDC1, n=1), Gr 3 ALT (GD2, n=2), and Gr 5 pneumonitis (GDC2, n=1). Possible treatment-related adverse events in later cycles included: Gr3–4 ANC (n=4), Gr4 colitis (n=1), Gr3 bilirubin (n=2), Gr3 Hgb (n=2), Gr3 Plt (n=2), Gr3 edema/fluid retention syndrome (n=1), and Gr3 vomiting (n=2). One previously untreated pt had a partial response. Eight of 18 pts, 3 of whom had received prior G, had stable disease as best response, median duration = 5 months (range 1–7). Biomarker results are pending. Conclusions: The MTD of the GD arm is G1000/D50BID. Stable disease in previous G-refractory pts was noted. Hematologic toxicities were dose-limiting; later toxicities including hematologic, LFT changes, pneumonitis, and fluid retention were seen. To address these toxicities, once daily dosing of D will be explored, followed by an expanded cohort of G + daily D vs G + bid D in pts with treatment-naïve pancreatic cancer.

[Table: see text]
A multicenter randomized phase II study of full-dose gemcitabine and concurrent radiotherapy comparing gemcitabine alone for the unresectable locally advanced pancreatic adenocarcinoma
Authors: Ioka T. , Takakura R. , Nakaizumi A. , Tanaka S. , Iishi H. , Nakamura S. , Nishiyama K. , Oohigashi H. , Ishikawa O. , Watanabe A. , Mukai S.
Published: August 2020

e15512

Background: Some of locally advanced pancreatic cancers (LAPC) are considered to include a potential micro metastasis. We think that full-dose of gemcitabine (GEM) improve the outcome of LAPC. We report the efficacy of full-dose GEM and concurrent radiotherapy, comparing GEM alone for unresectable LAPC. Methods: Patients with histologically or cytologically proven pancreatic adenocarcinoma were eligible for this study. We decide that LAPA which involved a major artery with CT imaging was unresectable. Patients were randomized into a concurrent chemoradiotherapy (CRT) group and a chemotherapy alone (CTX) group. GEM was given intravenously at a dose of 1,000 mg/msq over 30 min on days 1, 8 and 15 of each 28-day cycle and repeated until disease progression in both groups. Patients randomized into CRT group received a limited field irradiation with a total dose of 50 Gy in 25 sessions during first two cycles. The two groups were compared for mean survival, progression free survival and safety. Results: From September 2002 to April 2005, 80 patients were randomized at two institutions into the two arms of the trial (40 patients to CRT group and 40 patients to CTX group). The CRT group had better results than the CTX group as measured by mean survival time (391 vs 372 days, P< 0.02) and progression free survival (237 vs 128 days, P< 0.01). There were no differences in the safety between both groups. Conclusions: The concurrent chemoradiotherapy with full-dose GEM is effective and feasible in patients of LAPC compared with full-dose GEM alone.

No significant financial relationships to disclose.
Response assessment of HCC undergoing chemoembolization by necrosis-adjusted models
Authors: Rosen M. A. , Ruutiainen A. , Siegelman E. , Jones L. , Sun W. , Reddy R. , Shaked A. , Olthoff K. , Soulen M.
Published: August 2020

e15528

Background: Chemoembolization (CE) is an accepted therapy for unresectable HCC. As treated tumors may not shrink in size, response assessment via measurement of the enhancing tumor (EASL) has been proposed as an alternate to whole tumor (RECIST) measures. However, the reliability of this model has not been tested in clinical practice. Methods: We identified 29 HCC patients treated with CE with known overall survival (OS) in whom MRI before and after initial CE therapy was available for review. Three radiologists evaluated the imaging, measuring the largest liver lesion in three dimensions and the largest enhancing region in two dimensions. Readers also assessed percent tumor necrosis and overall tumor response qualitatively. Response models in 1-, 2-, or 3- dimensions, with or without necrosis adjustment, were created to assign patients to CR/PR/SD/PD classes, based on majority classification. Predictive value for OS was assessed for PD vs. other, and for PR/CR vs. SD/PD by the Students’ t-test. Inter-reader concordance was assessed by the Fleiss κ statistic. Results: For non-necrosis adjusted models, OS for progressors vs. non-progressors was statistically significant (p values: 0.0002–0.04), but could not identify early responders. Necrosis adjusted models failed to identify early progressors, but identified responders with improved OS (p values: 0.02–0.12). Inter-reader concordance was higher for necrosis adjusted models (κ range: 0.36–0.52) than for non-necrosis adjusted models (0.16–0.23). Viable tumor response by a two-dimensional product was superior to a one-dimensional diameter for predicting OS (p=0.04 vs. 0.74), and demonstrated higher inter-reader concordance (κ=0.46 vs. 0.30). Qualitative assessment of hepatic tumor could predict differences in OS for both PD vs. others (p=0.0001) and responders vs. non-responders (p=0.04), with acceptable inter-reader concordance (κ=0.34). Conclusions: Two- dimensional, but not one-dimensional, viable tumor measurement can identify response of HCC to chemoembolization and predict OS. Models which incorporate qualitative reader assessment of tumor necrosis may be more flexible than direct measures of viable tumor, and should be considered as alternatives for tumor assessment in chemoembolization.

No significant financial relationships to disclose.
Renal atrophy secondary to chemoradiation treatment of abdominal malignancies
Authors: Salerrno May K. S. , Yang G. Y. , Iyer R. V. , Chandrasekhar R. , Wilding G. , Khushalani N. I. , Yendamuri S. S. , Gibbs J. F. , Fakih M.
Published: August 2020

e15532

Background: Information on renal atrophy following abdominal chemoradiation (CRT) is limited. Methods: Patients who received concurrent CRT to the abdomen between 2002 and 2008 were identified for this study to evaluate change in renal size (RS) and function following CRT. Imaging and biochemical data were obtained prior to radiation (RT) and after RT in 6 month intervals. RS was defined by craniocaudal measurement on CT images. Renal function was assessed by serum creatinine and creatinine clearance (CrCl) using the Cockcroft-Gault formula. The primarily irradiated kidney (PK) was defined as the kidney that received the greater mean kidney dose. Results: Median patient age was 64 years (range 31–87), 51.5% of 130 patients were male. Primary disease sites were pancreas (61.5%), periampullary (16.1%), stomach (10.8%), gastroesophageal junction (10%), and retroperitoneum (1.5%). Median follow up was 9.4 months (range 0–55.4 mos). Median radiation dose was 50.4Gy (range 12.6- 55.8Gy). Mean dose to the PK was 18.6 Gy. Compensatory hypertrophy of the non-PK was not seen. Age, gender, hypertension, diabetes, smoking, pre-RT CrCl, and pre-RT RS were not associated with renal atrophy at 12 months post RT. Percent volumes of the PK receiving ≥10Gy (V10), 15Gy (V15), and 20Gy (V20) were significantly associated with renal atrophy at 12 months post RT (p=0.0030, 0.0041, and 0.0046 respectively). Conclusions: Significant detriments in PK size and renal function were seen following abdominal CRT. V10, V15, and V20 were associated with renal atrophy at 12 months post RT. These observations can assist with renal dose constraints in CRT treatment planning for patients at increased risk for renal complications.

[Table: see text]

No significant financial relationships to disclose.
Influence of microscopic malignant peritoneal mesothelioma on posttreatment survival
Authors: Kluger M. D. , Chabot J. A. , Hesdorffer M. , DeRosa C. M. , Taub R. N.
Published: August 2020

e15534

Background: Progression of malignant peritoneal mesothelioma to clinically evident disease is poorly understood. Operative cytoreduction and post-operative intraperitoneal chemotherapy, followed by a second operative cytoreduction with heated intraoperative intraperitoneal chemotherapy is protocol at Columbia University. Our ability to assess presence of microscopic disease at a unique second operation provides in vivo insight into disease progression. Methods: Operative, pathology and oncologist records were reviewed for 98 consecutive patients with peritoneal mesothelioma treated between 5/95 and 1/08. Microscopic disease was defined as positive pathology on random biopsies in the absence of gross disease at second operation, and disease-free as absence of gross and microscopic disease. Survival was defined as time from first operation to death or last follow-up. Survival and recurrence were compared using the Kaplan Meier and log-rank methods, and correlations by Fisher's exact method. Results: 98 first and 69 second operations were performed. Patients were 59% male, 88% Caucasian and mean age was 52. At the second operation, 38 had gross disease, 23 were disease-free and 8 had microscopic disease. Median follow-up was 21 months, median overall survival was 48 months, and median survival for the epithelial subtype was 64 months. There was no significant difference in survival between disease- free and microscopic pathologies (log-rank p<0.69). 72% of disease-free (SE 11%) and 80% (SE 18%) of those with microscopic disease were alive at 96 months. 16% of disease-free and 7% of patients with microscopic disease had a recurrence (p<0.4). The time to clinical recurrence for both disease-free and microscopic disease was not significantly different (log-rank p<0.88). Conclusions: Survival and clinical recurrence in those with microscopic disease, none of whom were treated for this entity, were not significantly different from those who were disease-free at the second operation. These in vivo after treatment findings suggest that malignant peritoneal mesothelioma may progress slowly from microscopic to clinical disease and can be closely monitored rather than aggressively treated after initial cytoreduction and intraperitoneal chemotherapy.

No significant financial relationships to disclose.
Neoadjuvant paclitaxel poliglumex, cisplatin, and radiation for esophageal cancer: A phase II trial
Authors: Ng T. , DiPetrillo T. , Suntharalingam M. , Fontaine J. , McNulty B. , Akerman P. , Chen W. , Horiba M. N. , Burrows W. , Safran H.
Published: August 2020

e15542

Background: Paclitaxel poliglumex (PPX) is a drug conjugate that links paclitaxel to poly-L-glutamic acid thereby increasing its radiation enhancement factor to 4.0 to 8.0 compared to 1.5–2.0 for paclitaxel. The Brown University Oncology Group previously performed a phase I study establishing the dose of single agent PPX with radiation, and the combination of PPX, cisplatin and radiation for esophagogastric cancer. A phase II study was therefore initiated to evaluate the pathologic response rate of neoadjuvant PPX, cisplatin and radiation for patients with esophageal cancer. Methods: Eligible patients had pathologically confirmed adenocarcinoma or squamous cell carcinoma of the esophagus or GE junction with no evidence of distant metastasis. Celiac nodal disease was allowed. Patients received weekly PPX 50mg/m2 and cisplatin 25mg/m2 for 6 weeks with concurrent with 50.4Gy of radiation. Six to eight weeks after completion of chemoradiotherapy, patients underwent surgical resection. Results: Twenty-three eligible patients have been enrolled. The median age is 63 years. Grade 3/4 treatment related toxicities in the first 15 patients include dehydration (n=5), anorexia (n=5), esophagitis/dysphagia (n=4), electrolyte abnormalities (n=3), nausea (n=2), hypersensitivity (n=2), weight loss (n=1), and anemia (n=1). One patient developed carcinomatous meningitis during treatment. Five of the first 11 patients (45%) undergoing resection had a pathologic complete response. Conclusions: This preliminary data suggests that PPX may provide enhanced radiosensitization as compared to standard paclitaxel, consistent with the preclinical data of PPX and radiation.

No significant financial relationships to disclose.
Adjuvant sunitinib following chemoradiotherapy (CRT) and surgery for esophageal cancer: A phase II trial
Authors: Horgan A. M. , Darling G. , Wong R. , Visbal A. , Guindi M. , Jonker D. , Liu G. , Hornby J. , Xu W. , Knox J. J.
Published: August 2020

e15550

Background: Locally advanced esophageal cancer (LAEC) has a 5-year survival of < 30 %. Most patients (pts) fail after curative intent tri-modality treatment with distant metastatic disease. This phase II trial aims to determine if adjuvant targeted therapy, after neoadjuvant CRT plus surgery for resectable LAEC, may impact on systemic disease without significant toxicity. Methods: Pts with LAEC of the thoracic esophagus or gastroesophageal junction, ECOG PS 0,1 and surgical candidates treated with: preoperative Irinotecan (65mg/m2 initially, ammended to 50mg/m2) + Cisplatin (30mg/m2) on weeks 1,2,4,5,7,8 + concurrent conformal radiotherapy (50Gy/25 fractions) on weeks 4–8. Esophagectomy during weeks 15–18. Sunitinib 37.5mg daily (escalating to 50mg daily if tolerated) commenced 4–12 weeks post surgery, for 1 year. Primary endpoint is feasibility and efficacy of adjuvant sunitinib. Planned sample size 36pts. Results: 30pts enrolled from 11/06 to 12/08. Median age 64 yr (43–71), male: 22, adenocarcinoma: squamous 22:6; 10 pts stage IIA, 5 IIB and 13 III. 2 pts excluded with positive PET scan. 28 pts completed CRT - 18 pts (64%) received ≥80% of planned chemotherapy dose, 23 pts (82%) received full radiation dose. Grade 3/4 toxicity included: neutropenia (17/28), diarrhea (7/28), dehydration (4/28), febrile neutropenia (FN) (3/28) and nausea (2/28). 2 deaths on chemotherapy (1 bacterial meningitis, 1 FN) leading to irinotecan dose- reduction. Dysphagia improved in 14/23 pts during CRT. 18 pts have undergone esophagectomy. Complete pathological response in 4 (22%), downstaging in 3 (17%), stable disease in 11 (61%). 2 pts unresectable (metastases at laparotomy). 1 post-operative death due to pulmonary embolus. 9 pts have commenced sunitinib, 6 maintained at starting dose of 37.5mg; 2 dose reductions; 1 discontinued with poor wound healing. Grade 3 toxicity included: leukopenia (2/9), hand-foot reaction (1/9) and depression (1/9). Conclusions: In LAEC, induction Irinotecan/Cisplatin and radiotherapy followed by esophagectomy is associated with a significant but manageable toxicity profile. Early initiation of sunitinib is feasible and well-tolerated. Updated results to be presented.

No significant financial relationships to disclose.
Perioperative morbidity and mortality after radical lymphadenectomy for operable esophageal cancer
Authors: Pramesh C. S. , Mistry R. C.
Published: August 2020

e15554

Background: The role of radical lymphadenectomy in localized resectable esophageal cancer is controversial. Radical lymphadenectomy confers more accurate staging, and improves locoregional control rates. However, there is no convincing evidence yet for a definite improvement in overall survival. Higher morbidity and mortality rates with radical lymphadenectomy are often quoted as reasons to avoid these procedures during esophageal resection. Methods: We retrieved data from October 2003 to December 2008 from a prospective surgical database maintained at a single tertiary cancer centre. Demographic data, operative details and postoperative morbidity and mortality were analysed. Postoperative complications analysed included need for prolonged ventilation, pulmonary complications, recurrent laryngeal nerve (RLN) paresis, cardiac ischemia and arrhythmias, and anastomotic leaks. Results: Six hundred and forty five patients (453 men, 192 women, mean age 53.6 years, range 19–76 years) were operated by transthoracic total esophagectomy for esophageal cancer between October 2003 and December 2007. Three hundred and ninety eight patients underwent two-field lymphadenectomy and 247 underwent three field radical lymphadenectomy. There was a higher incidence of prolonged ventilation (13.4% vs 6.6%, p=0.003), RLN paresis (61.4% vs 32.5%, p=0.000), and pulmonary complications (38.5% vs 24.4%, p=0.000) with radical three field lymphadenectomy compared to two field lymphadenectomy. The incidence of cardiac events (1.6% vs 2.6%, p=0.230), cardiac arrhythmias (5.8% vs 7.1%, p=0.640), anastomotic leaks (6.7% vs 8.2%, p=0.258) and postoperative mortality (5% vs 5.3%, p=0.80) were similar in the two groups. Conclusions: Radical three field lymphadenectomy increases pulmonary complication rates but has no impact on cardiac complications, anastomotic leaks, or operative mortality.

No significant financial relationships to disclose.
Correlation between FDG PET/CT and the expression of Ki-67, MMP-2, micro-vessel density (MVD), and pathological grading in squamous cell carcinoma of the esophagus
Authors: Liu L. , Huang Y. , Guo J. , Wang Z. H. , Song D. G.
Published: August 2020

e15556

Background: Variable uptake of 18FDG has been noticed in positron emission tomography (PET) studies of patients with esophageal squamous cell carcinoma (ESCC). The aim of the present study was to determine if 18F-FDG PET/CT standardized uptake value (SUV) could quantitatively reflect tumor proliferation, invasion and angiogenesis, and to reveal the relationship between SUV and pathological grading of ESCC. Methods: Preoperative PET scans were performed in 47 patients with histologically proven ESCC. 18FDG uptake was semiquantitatively measured by SUV.Tumour sections were HE stained to determine the pathological grading,and were stained by immunohistochemistry for proliferation marker (Ki67), invasion marker (MMP-2), and angiogenic marker (CD34). The correlations between FDG SUVmax and Ki67 expression, MMP-2 expression, corresponding MVD were statistically analysed respectively. Results: Among all the 47 cases,there were 13 well- differentiated squamous cell tumors, 16 moderately differentiated tumors and 18 poorly differentiated tumors,45 of 47 tumors revealed FDG. accumulation in primary tumor foci confirmed by subsequently histopathologically. The mean FDG SUVmax value was 12.504 ± 6.805. Average Ki-67 index was (7.837±29.798) %, average MMP-2 index was (71.551%±27.126) % and average MVD was (18.429±9.603) accordingly. The SUV and Ki-67 index, MMP-2 index were positively correlated (r=0.581,0.594), and it was not correlated with MVD(P>0.05). The mean SUV of well-differentiated, moderately differentiated and poorly differentiated tumors were 9.787±1.477, 12.313±0.479, 15.053±2.147 respectively, and a significant difference could be determined between them by statistical analysis(P=0.000). Conclusions: A significant positive correlation is demonstrated between FDG PET/CT SUV and Ki-67 index, MMP-2 index of the primary ESCC. SUV could reflect proliferation and invasion potential of tumor. However, there is no significant correlation between SUV and MVD, thus it could not reflect tumor angiogenesis in ESCC. To some extent, SUV could reflect pathologic grading of ESCC.

No significant financial relationships to disclose.
Mortality rate with irinotecan/cisplatin plus concomitant radiation therapy in patients with locally advanced esophageal squamous cell carcinoma
Authors: Geib G. , Machado M. W. , Pozzi B. , Lazaretti N. S. , Dutra C. , Pereira Lima M. N. , Ferreira P. R. , Azevedo S. J. , Schwartsmann G.
Published: August 2020

e15560

Background: The cisplatin/irinotecan doublet plus concomitant radiation therapy has been tested in phase II studies as a non-infusional alternative for the treatment of locally advanced esophageal squamous cell carcinoma (ESCC), showing good antitumoral activity and acceptable safety profile. Here, we describe our institutional experience with this combination, specially regarding its toxicity profile. Methods: A series of 26 patients with locally advanced, unresectable ESCC patients treated at our institution between September/2006-January/2008 is reported. Treatment consisted of cisplatin 30 mg/m2 and irinotecan 65 mg/m2 on weeks 1, 2, 4, 5, 8, 9, 11 and 12, and radiation therapy (50,4 Gy, 1,8 Gy/day) on weeks 8–12. Study endpoints were tumor response rate (RECIST), safety profile (CTCAE v3), overall and one year survival. Results: The mean age of patients was 61 years, with stage III disease in 88% of cases and performance status (ECOG) 0–1 in 90% of them. Twenty patients (77%) were available for response, with complete response, partial response/stable disease and progressive disease seen in 40%, 45% in 15% of cases, respectively. With a median follow up of 20 months, the overall survival was 9,2 months and the one-year survival 34,6%. All patients were evaluable for toxicity, with severe (grade 3–4) nausea/vomiting, diarrhea, neutropenia and thrombocytopenia documented in 45%, 33%, 18% and 13% of cases, respectively. Notably, treatment related deaths were observed in 5 cases (19%), mainly due to infectious complications, which led to the closured of this protocol due to excessive toxicity. Conclusions: In spite of its promising antitumor activity, this treatment regimen cannot be recommended for routine use due to its unacceptable treatment-related mortality.

No significant financial relationships to disclose.
Pretreatment serum TIMP-1 levels and survival in advanced pancreatic cancer
Authors: Vargas R. , Shrivastava V. , Leitzel K. , Ali S. M. , Carney W. , Hamer P. , Brown-Shimer S. , Linnartz R. , Mietlowski B. , Lipton A.
Published: August 2020

e15568

Background: Tissue inhibitor of metalloproteinase-1 (TIMP-1) has been shown to have diverse multifunctional roles in tumorigenesis such as inhibition of the catalytic activity of MMPs, growth promotion, inhibition of apoptosis and regulation of angiogenesis. Elevated TIMP-1 has been associated with an unfavorable prognosis in many cancers including breast, colorectal, gastric, head and neck, lung, and lymphoma. VEGF is also intimately associated with angiogenesis. Methods: This study determined serum TIMP-1 and VEGF levels in a phase III clinical trial of 157 patients with advanced pancreatic cancer. ELISAs for TIMP-1 and VEGF (Oncogene Science / Siemens HealthCare Diagnostics, Cambridge, MA) were employed to measure pretreatment serum TIMP-1 levels in 157 pancreatic cancer patients enrolled in a randomized, double-blind, placebo-controlled phase III trial. Statistical analysis was performed with TIMP-1 and VEGF on a continuous and cutpoint basis. Serum biomarker levels were then correlated with patient survival using Kaplan -Meier life table analysis. Results: Serum TIMP-1 levels in 157 pancreatic patients had a median of 409.9 ng/mL, and ranged from 144 to 1078 ng/mL. Patients with higher serum TIMP-1 had significantly shorter survival on a continuous basis (p = 0.001), on quartile analysis (p = 0.004), and on a dichotomous cutpoint analysis of upper 25 % vs lower 75 % (median survival 101 days vs. 197 days)(p< 0.001). Serum VEGF level was not associated with survival on a continuous (p = 0.57) or cutpoint analysis (p= 0.93). Conclusions: Pancreatic cancer patients with higher serum TIMP-1 levels had significantly shorter overall survival. Serum TIMP-1 level should be evaluated as a predictive factor for response to novel treatment regimens.

[Table: see text]
Effect of N-cadherin knock-down on invasiveness of esophageal squamous cell carcinoma
Authors: Ke L. , Wei H. , Na L. , Na L. , Xin W. , Qing-Xia F.
Published: August 2020

e15571

Background: Cell adhesion molecules are of crucial importance in cancer invasion and metastasis. Epithelial to mesenchymal transition, characterized by reduced E-cadherin and increased N-cadherin expression, has been recognized as a feature of aggressive tumors, but the importance of this phenotype has not been settled in esophageal squamous cell carcinoma. Aim: To examine the expressions of N-cadherin and E-cadherin in 62 normal esophageal epithelium specimens, 31 adjacent atypical hyperplasia epithelium specimens and 62 esophageal squamous cell carcinoma specimens, and to investigate the roles of N-cadherin in the invasiveness of esophageal squamous cell carcinoma cell line EC9706 transfected by N-cadherin shRNA.. Methods: PV immunohistochemistry was used to detect the expression pattern of N-cadherin and E-cadherin in 62 normal esophageal epithelium specimens, 31 adjacent atypical hyperplasia epithelium specimens and 62 esophageal squamous cell carcinoma specimens. The invasiveness of esophageal squamous cell carcinoma cell line EC9706 in vitro and in vivo was determined by transwell assay and nude mice experiments after EC9706 was transfected by N-cadherin shRNA. Results: The positive rates of N-cadherin decreased in the sequence of carcinoma, adjacent atypical hyperplasia and normal esophageal tissue, which were 75.8%, 61.3%, 29.0% (P < 0.05), respectively, while those of E-cadherin increased in sequence, which were 40.3%, 71.0% and 95.2% (P < 0.05). The increased expression of N-cadherin and decreased expression of E-cadherin were related to the invasion, differentiation, and lymph node metastasis (P < 0.05). The expression level of N-cadherin decreased in the N- cadherin knocked down cells, and the invasiveness of those cells decreased significantly as well in vitro and in vivo. Conclusions: These results suggest that N-cadherin is an important factor in the invasiveness of esophageal squamous cell carcinoma and N-cadherin may serves as a potential molecular target for biotherapy of esophageal squamous cell carcinoma.

No significant financial relationships to disclose.
Survival predictors in second-line chemotherapy for metastatic gastric cancer
Authors: Bohanes P. O. , Courvoisier D. , Perneger T. , Morel P. , Huber O. , Roth A. D.
Published: August 2020

e15575

Background: Many patients (pts) with metastatic gastric cancer (MGC) are in good condition after first line chemotherapy (chemo) and are offered further treatment. However there is no established predictor to select pts who will most likely benefit from second line chemotherapy (SLC). Methods: We conducted a retrospective review of all patients with metastatic gastric or gastro-oesophageal junction adenocarcinoma who were treated until death at our institution and died between 01.1994 and 06.2008. Prognostic values of the tumour characteristics, pts characteristics at SLC, previous curative surgery (PCS) and sensitivity to previous chemo were analysed by Cox univariate and multivariate regression for overall survival (OS). Results: 65 pts with MGC were treated at our institution up to their death. Of these, 43 pts (65%) received SLC. 24 pts (55.8%) received CPT-11 based SLC. 4 pts (9.3%) docetaxel-platin, anthracyclines and fluoropyrimidine based SLC. 3 pts (7%) oxaliplatin and 3 pts (9.3 %) other chemo. Median OS from the start of SLC was 30.1 weeks. 25 pts (58.1%) had disease control (response and stable disease) lasting at least 12 weeks under SLC. Potential prognostic variables with their frequencies and prognostic values are listed in the Table . Multivariate analysis showed that PCS was significant predictor for OS (HR=0.46, p<.05). PFS1 of more than 26 weeks was a strong significant OS predictor (HR=0.41, p<.05). Interaction test between PFS1 and PCS was not significant (p=0.48). Conclusions: Benefit from a SLC in MGC is highly related to former sensitivity to first line chemo. This is of major importance in the design of trials in MGC in a second line setting. [Table: see text]

No significant financial relationships to disclose.
Tolerability of sorafenib in the treatment of hepatocellular carcinoma (HCC) in patients with Child A and B liver cirrhosis
Authors: Schuette K. , Zimmermann L. , Bornschein J. , Huster D. , Csepregi A. , Malfertheiner P.
Published: August 2020

e15593

Background: Sorafenib (S) is the only drug that prolongs overall survival in patients (pts) with advanced HCC by nearly 3 months in pts with Child A liver cirrhosis (LC). This study aims to evaluate tolerability of S in pts with Child B LC. Methods: Pts with HCC not suitable for curative therapy were treated with S since it became available for clinical use. 50 of 139 consecutive patients diagnosed with HCC were treated with S (8 f, 42 m; median age 67 (18–86) yrs). Initial dose was 400 mg/day and increased in case of good tolerability stepwise up to 800mg/day. Pts were stratified according to the stage of LC and analyzed for treatment toxicity based on the National Cancer Institute Common Toxicity System. Results: 41 pts with HCC had LC, 17 in Child A and 24 in Child B stadium. Due to side effects a dose escalation to 800mg was possible in 9 pts (22.0%) only, 3 with Child A and 6 with Child B LC. Grade 1/2 toxicity was observed in 15 pts with initial Child A (88.2%) and in 11 pts with initial Child B LC (45.8%), grade 3/4 toxicity occurred in 2 pts with Child A (11.8%) and 3 pts with Child B LC (12.5%). After 12 weeks of follow-up, 12 pts with Child A (70.6%) and 10 pts with Child B LC (41.7%) at entry were still under treatment. A deterioration of liver function from Child A to Child B was observed in 5 of 17 pts (29.4%) and from Child B to Child C in 1 patient (4.2%). In 5 pts (29.4%) with Child A LC and 14 pts with Child B LC at entry treatment had been discontinued in advance. Survival in patients with LC Child A was better than in patients with LC Child B (median overall survival 327 (60–495) vs 138 (10–560) days resp., ns). Conclusions: Systemic therapy of advanced HCC with S appears to be a safe treatment option in pts with Child B LC. However, tolerability is an important limitation in the use of S independently of the stage of LC. Whether pts with advanced HCC benefit from a systemic treatment with smaller doses than 800mg/day needs to be addressed in further studies.

[Table: see text]
Reconsenting patients with cancer on clinical trials: Does added risk influence continued participation?
Authors: Elegbede A. , Andrei A. , Andrei A. , Holen K. D.
Published: August 2020

e15610

Background: The general policy endorsed by multiple professional societies and cooperative groups regarding patients on cancer clinical trials states that subjects should be informed of new adverse events or significant developments during study participation and re-consented to continue on study. However, no information is known as to the effect of re-consenting on a patients’ decision to continue study participation. Our research question addresses how the severity of reported risk to other study participants will impact the subjects’ decision to continue participation in a clinical trial. Methods: We surveyed 34 patients with gastrointestinal (GI) tumors all of whom were currently enrolled in a clinical trial. The survey portrayed hypothetical adverse reactions affecting another study participant ranging from Grade 1 to Grade 5 according to the National Cancer Institutes Common Terminology Criteria for Adverse Effects v. 3.0. The survey asked about subjects’ opinions of the theoretical adverse event categorized as “would not be concerned,” “would be concerned, but would continue the study,” and “would discontinue the study.” Results: Patients willingness to continue the study was highest at Grade 1 with 97% of all participants. However, willingness to continue participation progressively declined as the severity of adverse events increased such that only 44% of participants would continue participation with a reported Grade 5 adverse event. Conclusions: Among surveyed GI cancer patients, willingness to continue participation in a clinical trial declined significantly as the severity of adverse events increased from Grade 1 to Grade 3 - 5 (p-value < 0.001. This could be due to multiple factors, including the terminal nature of the patients’ cancer, the side effects of study therapy and the patients’ response to study treatment. This data could produce a reasonable adverse event grade cut-off for re-consenting patients regarding new side effects.

No significant financial relationships to disclose.
High-risk factors affecting survival after transcatheter therapy with doxorubicin-eluting beads for unresectable hepatocellular carcinoma
Authors: West J. K. , Dhanasekaran R. , Kooby D. A. , Staley C. A. , Kauh J. , Kim H. S.
Published: August 2020

e15614

Background: Transcatheter therapy with drug eluting beads (DEB) with Doxorubicin is a relatively new modality of palliative treatment of patients with unresectable HCC. It is important to identify prognostic factors which affect survival after treatment with DEB to enable optimal patient selection and to ensure maximal survival benefit. Methods: Fifty consecutive patients with unresectable HCC who were treated with transcatheter therapy with DEB between the period of 2005 and 2008 were studied. Kaplan Meier test was used to study survival. Categorical variables were compared with Log rank test and continuous variable with Cox proportional hazards method. Results: The survival rates at one year from first transcatheter therapy in patients belonging to Okuda stage I, II and III were 67%, 35% and 27% (p=0.043). The survival rates at one year from the first transcatheter therapy in Child Pugh Class A, B and C were 60%, 39% and 13% (p=0.003). Portal vein thrombosis was present in 24%(12/50). Median survivals in patients with and without portal vein thrombosis were 335 days(31–638) and 610 days(482–738)(p=0.285). The median survival in patients with tumor thrombus and bland thrombus were 169 days and 335 days(p=0.69). The median survival in patients with main portal vein thrombosis and branch portal vein thromboses were 316 days(135–497) and 550 days(202–897)(p=0.89).Pre- procedure albumin, bilirubin and MELD score were found to be prognostic factors on univariate analysis ( Table 1 ).On multivariate analysis, pre-procedure serum albumin and Okuda staging were found to be independent prognostic factors. Conclusions: On multivariate analysis, serum albumin and Okuda staging were found to independently influence survival of patients treated with Doxorubicin eluting beads for unresectable hepatocellular carcinoma. The presence of portal vein thrombosis did not affect the long term survival. [Table: see text]

No significant financial relationships to disclose.