bluuebunny/crossref_metadata_2025_split huggingface dataset:
Feasibility of combining humanized anti-epidermal growth factor receptor monoclonal antibody h-R3 (nimotuzumab) with chemotherapy-A study of toxicity profile and tolerance
Authors: Pendharkar D. , Gupta S. , Pal M. K. , Hakim S. , Rashid T. 
Published: March 2020

14151 Background. Anti-EGFR antibodies have been approved in combination with radiotherapy for the treatment of head and neck squamous cell carcinoma(SCCHN) and being tried in glioblastoma multiforme(GBM). The overall toxicity profile is tolerable. There is no data available on Humanized Anti EGFR antibody in combination with chemotherapeutic agents. Nimotuzumab, the humanized MAb derived from ior EGFR/R3, is a genetically engineered IgG1, with high affinity and specificity to EGFR. This study was undertaken to record the immediate and early toxicity of combining Nimotuzumab with various chemotherapeutic agents. Methods. Patients with SCCHN and GBM, scheduled to receive chemotherapy alone were additionally given 400mg of Nimotuzumab, every three weeks. Two patients with GBM received weekly Nimotuzumab 200 mg along with radiation and chemotherapy. Overall 19 events have been analyzed. The chemoschedules used in combination with Nimotuzumab included-Docetaxel, Carboplatin and Capecitabine in patients with SCCHN and Temozolamide/ Procarbazine in GBM. Antibody infusion was always preceded by antihistaminics and dexamethasone. Results.The combination of Nimotuzumab with chemotherapy was well tolerated. There were no acute infusion related events. No febrile, allergic or anaphylactic episodes were seen. Cutaneous rash classical of other EGFR blockers was not recorded. Two episodes of grade 3 diarrhea, and four events of asthenia were seen. Dryness of the mouth was a complaint in SCCHN patients. None of the patients showed neurological or cardiovascular adverse events. Hematological and biochemical derangements were not observed. Conclusion. Nimotuzumab can safely be combined with various chemotherapeutic agents .There is no unacceptable toxicity associated with combination of chemotherapy and humanized anti-EGFR monoclonal antibody. New schedules combining Nimotuzumab and chemotherapy can be safely explored. No significant financial relationships to disclose.
Cetuximab-induced thrombotic thrombocytopenic purpura in a patient with a resected squamous cell carcinoma of the lip
Authors: Rosen F. , Lad T. , Telfer M. , Catchatourian R. , Yim B. , Griza D. S. , Yogore M. , Jajeh A. , Nathan S. , Ofori-Ntow S. 
Published: March 2020

14155 Background: Chemotherapy-associated thrombotic thrombocytopenic purpura (TTP) has been described in the literature. However Cetuximab, a monoclonal antibody targeted to the EGF receptor, has not yet been associated with TTP. We report a case of an 85 year old woman with a resected squamous cell carcinoma of the lip who developed TTP after receiving cetuximab. Methods: A day after receiving Cetuximab, as part of an adjuvant concurrent cetuximab-radiotherapy regimen, the patient presented with gingival bleeding and confusion without fever but with significant petechial rash and jaundice.. Hemoglobin level was 6.9 g/dL WBC 3.9 k/uL Platelet count 4 k/uL Lactate dehydrogenase 1350 U/L Indirect bilirubin 3.8 mg/dL Haptoglobulin < 6 mg/dL Reticulocyte count 4.4 %. Serum creatinine, ANA, coagulation profile, coomb‘s test were normal. Peripheral blood smear showed 3+ schistocytes. TTP was diagnosed and daily plasmapheresis was initiated. TTP resolved after 8 sessions of plasmapheresis with platelet count increasing to 446 k/uL and sustained. Results: Competing etiologies for our patient’s TTP were cancer and cetuximab. Most reported cases of cancer-associated TTP occurred in patients with metastatic adenocarcinoma. Our patient had a non-metastatic resected squamous cell carcinoma with only residual microscopic disease. Since TTP developed closely following cetuximab administration and resolved with plasmapheresis after stopping cetuximab, we concluded that its development was most likely secondary to cetuximab or to antibody developed to it. Possible mechanisms for cetuximab-induced TTP are direct endothelial damage by cetuximab leading to platelet activation and aggregation or inhibition of metalloproteinase, resulting in accumulation of Ultra-large VWF multimers. Conclusions: Targeted-therapy is emerging as an effective treatment modality in medical-oncology. Further clinical experience is needed to ascertain the full extent of potentially fatal adverse events. To our knowledge this is the first case of cetuximab-induced TTP. No significant financial relationships to disclose.
High rate of TRG1–2 and prolonged RFS with OXA/TOM and FU/LFA during preoperative pelvic RT in patients with poor prognosis locally advanced rectal cancer (LARC)
Authors: Avallone A. , Delrio P. , Guida C. , Tatangelo F. , Petrillo A. , Lastoria S. , Parisi V. , Comella G. , Budillon A. , Comella P. 
Published: March 2020

14500 Background: We have previously reported that 3 cycles of Oxaliplatin (OXA), Raltitrexed (TOM) and 5-Fluorouracile (FU) + levo-folinic acid (LFA) during pelvic RT had an acceptable toxicity and produced a complete (TRG1, 42%) or subtotal (TRG2, 29%) pathologic tumor regression in 71% of 31 pts with poor prognosis LARC (Avallone et al, Br J Cancer 2006). Here we report an expanded experience on such treatment. Methods: We enrolled 62 eligible pts (M, 33; F, 29), with median age of 58 (27–79) yrs, and adenocarcinoma of the extraperitoneal rectum, with at least one of the following characteristics: cT4 (N pts), cN+ (N), cT3N0 with tumor location = 5 cm from the anal verge and/or CRM +ve (assessed by MRI) (N). Pts received 3 biweekly courses of OXA 100 mg/sqm + TOM 2.5 mg/sqm on day 1, and LFA 250 mg/sqm + FU 900 mg/sqm (31 pts) or 800 mg/sqm (31 pts) on day 2, and concomitant pelvic RT (1.8 Gy/day, total dose 45 Gy). TME was planned 8 weeks after the end of treatment. Pathologic response was evaluated by tumor regression grading (TRG) according to Mandard’s modified classification. Pts with cT4, pN+ and pCRM +ve received also 4 months of weekly FU/FA. Results: All pts received full dose of RT, and 98% of the planned CT cycles. Neutropenia was the most common grade = 3 toxicity (40%), while grade 3 diarrhea was seen in 19% of pts with FU 900 mg/sqm, and in only 6% of pts with FU 800 mg/sqm. All but 2 pts had a TME with R0 resection, and no treatment-related or perioperative death occurred. Median number of sampled lymph nodes was 36 (range, 10–80). 28 (45%) pts obtained a TRG1, and 17 (27%) pts a TRG2. Activity of the treatment was similar in all risk groups, regardless of FU dosage. 1 pt suffered a local recurrence (after 9 months), and 3 pts had distant metastases (after 22, 33, and 47 months). After a median follow-up of 34 (range 6–54) months, all pts are alive, and the estimated 34-month RFS was 95%. All pts achieving a TRG1, and all but one with TRG2 (pCRM +ve), were recurrence-free. Conclusions: These data confirm the feasibility and activity of the whole treatment. A slight reduction of FU dosage appeared to improve the safety of this combination. Currently, we are now evaluating the addition of bevacizumab 5 mg/kg every 2 weeks before and during this concurrent treatment. No significant financial relationships to disclose.
Is neoadjuvant (neoadj) treatment necessary prior to liver resection in patients with resectable liver metastases (mets) from colorectal carcinoma (CRC) treated with post-resection hepatic arterial infusion (HAI) plus systemic (SYS) chemotherapy
Authors: Kemeny N. E. , Capanu M. , Huitzil-Melendez F. , Haviland D. , Fong Y. , Jarnagin W. , Blumgart L. , DeMatteo R. , D’Angelica M. 
Published: March 2020

14503 Background: Neoadjuvant therapy in patients (pts) with resectable liver mets has been reported to be associated with improved survival. We evaluated the clinical benefit of neoadj therapy in our pts receiving HAI + SYS after liver resection. Methods: In 4 studies of HAI + SYS after resection of CRC mets, data on neoadj, age, gender, clinical risk score (CRS), number of mets, primary site, resection margin status, presence of synchronous primary and/or bilobar disease were analyzed. Univariate and multivariate Cox proportional hazards models were used to examine differences in overall survival, hepatic or extrahepatic disease-free survival (DFS) between pts who received vs pts who did not receive neoadj. Differences among subgroups were compared using the log-rank test. Results: 234 pts from 4 post-liver resection trials using HAI + SYS were included. Each trial used HAI floxuridine/dexamethasone, with differing SYS regimens: FU/LV (n = 74); CPT11 (n = 98); FOLFOX (n = 31); and FOLFOX or FOLFIRI, ± bevacizumab (n = 31). Neoadj was given to 28% of the pts. Median followup was 4.6 years. No differences in terms of survival, hepatic or extrahepatic DFS were noted between pts who did or did not receive neoadj. Multivariate analyses showed no survival advantage for pts who received neoadj (Y vs N) (HR 0.997, 95% CI, 0.56–1.78). No subsets of pts were identified that showed an improvement in survival from neoadj (table), including pts who responded to neoadj prior to liver resection. Conclusions: Our results do not appear to support the use of neoadj in pts with resectable liver mets from CRC, if they are to be treated with postoperative HAI and SYS chemotherapy. [Table: see text] No significant financial relationships to disclose.
Safety and efficacy of repeated anti-CEA radioimmunotherapy (RAIT) with 131I-labetuzumab post salvage resection of colorectal liver metastases
Authors: Liersch T. , Meller J. , Lorf T. , Sahlmann C. , Niessner M. , Langer C. , Ghadimi B. M. , Wegener W. A. , Becker H. , Goldenberg D. M. 
Published: March 2020

14507 Background: As shown recently (JCO 2005; 23:6763–70), a single application of RAIT improved both, median overall survival (OS), and 5-year survival rates of colorectal cancer (CRC) patients (pts) post salvage resection of liver metastases (LM) compared to controls without RAIT (P=0.004). In an ongoing phase II trial we are evaluating the safety and efficacy of repeated RAIT at doses of 2x 40–50 mCi/m2 (3 mos apart) post salvage resection of LM. Methods: To date, 26 pts (8x f, 18x m; age: 63 ± 9 ys) who underwent surgery for CRC-LM have received the first dose of 131I-labetuzumab (Immunomedics, In., NJ, USA), a humanized monoclonal antibody against CEA, within 2 months of LM surgery. Three months after the first RAIT, a second infusion of 40–50 mCi/m2 has been applied to all pts after completion of standardized re-staging procedures. Results: The primary tumor sites were 17 colonic and 9 rectal cancers; primary tumor stages were 5x UICC-II, 7x UICC-III, 14x UICC-IV. 13 pts received adjuvant therapy. In 11 pts preoperative chemotherapy (FOLFOX or FOLFIRI) was given to achieve resectability of bilobular LM. After resection of LM (y)mTNM tumor stages were 1x mTNM-I, 6x mTNM-II, 6x mTNM-III and 4x mTNM-IV, respectively. After first RAIT, hematologic Grade 3 and 4, toxicity (WBC/platelet count) occurred in 8/14 and 5/3 pts, respectively. No cumulative toxicity was seen after repeated RAIT, with complete bone marrow recovery observed in all cases so far. To date, all pts are alive. Of the total, 17 pts received RAIT with adjuvant intention (as classified by FDG-PET and CT scans at pre-RAIT re-staging). In these, DFS was 70% post salvage resection of LM during ongoing follow-up of 15 months (median; range: 4–23 mos). As of Dec. 20, 2006, cancer recurrence was detected in 5/17 pts (3x pulmonary, 1x intrahepatic, 1x both) and in 4 pts R0-resection of distant metastases was done. 1 patient with pulmonary and intrahepatic relapses receives polychemotherapy with palliative intention. The pts‘ compliance to repeated RAIT has been 100%. Conclusion: RAIT re-treatment to date appears to be safe, feasible, and well accepted. Extended follow-up of the encouraging survival data will be presented. No significant financial relationships to disclose.
Phase 1 study of picoplatin (pico) in combination with 5-fluorouracil (FU) and leucovorin (LV) as initial therapy in subjects with metastatic colorectal cancer (CRC)
Authors: Gladkov O. , Manikhas G. , Biakhov M. , Tjulandin S. , Karlin D. 
Published: March 2020

14510 Background: Pico is a platinum analogue designed to overcome platinum resistance with improved safety and efficacy compared with conventional platinum agents. FOLFOX (FU, LV, oxaliplatin) has emerged as the standard of care in first and second-line therapy of advanced -stage CRC but significant neurotoxicity limits long-term use of oxaliplatin in this regimen. Pico has been well tolerated in >600 patients with rare clinically significant nephro-, oto-, or neurotoxicity (∼2% grade 3 and 0% grade 4), even in platinum pretreated patients. Pico has demonstrated synergy with FU in vitro and is thus an attractive candidate to replace oxaliplatin in the FOLFOX regimen. The objective of this Phase 1 study is to identify the maximum tolerated dose (MTD) of pico administered either every 2 wks or every 4 wks with FU and LV administered every 2 wks. Methods: Each patient receives q 2 wk FU and LV: LV, 400 mg/m2, 2-hr infusion, followed by 5- FU bolus, 400 mg/m2 and then 5-FU, 2,400 mg/m2, 46 hr continuous infusion. Subjects are randomized to pico administered either every 2 or every 4 wks. Starting dose of pico for q 2 weekly regimen was 45 mg/m2 and in subsequent cohorts pico increases by 15 mg/m2. Starting dose of pico for q 4 wk regimen was 60 mg/m2 and in subsequent cohorts pico increases by 30 mg/m2 until dose limiting toxicity (DLT) establishes the MTD. Results: 23 pts have been treated to date, the first have received 32 wks of therapy. Therapy has been well tolerated, with infrequent dose delays from non-cumulative platelet and ANC toxicity and 1 episode of mild diarrhea. No DLT has been seen through the first 3 cohorts, i.e. with picoplatin, 75 mg/m2 with every dose of FU-LV or120 mg/m2 with every other dose of FU-LV. Dose escalation continues. Response assessments for 12 patients in the first 2 cohorts (6 on each pico schedule, all below the MTD) after 16 wks show 4 partial responses, 5 stable disease and 3 progressive disease. Conclusions: Picoplatin can be safely administered with 5FU and LV. A phase 2 study of FU, LV and pico will begin as soon as the MTD is identified and a safe dose and schedule are defined. No significant financial relationships to disclose.
Long-term maintenance capecitabine and celecoxib improved clinical outcomes by targeting colorectal cancer micrometastasis
Authors: Zhang M. , Curley S. , Ng C. , Kurland B. , Krishnan S. , Rodriguez-Bigas M. , Janjan N. , Feig B. , Hamilton S. , Lin E. 
Published: March 2020

14513 Background: Role of mainteance therapy after achieving complete response (CR) remain undefined for patients with metasatic colorectal cancer. We studied prognostic and treatment factors including maintenance capecitabine and celecoxib (XCEL) in all 19 unresectable metastatic colorectal cancer patients (pts) who had CR from the prior XCEL study. Methods: Event charts are used to summarize the timeline of the various treatments. Kaplan-Meier survival estimates and univariate log-rank tests were used to evaluate RFS and OS as time from CR. Prognostic and treatment factors included: tumor size, metastasis number (9 solitary disease), site (13 being extrahepatic), stage on diagnosis (stage II versus III/IV), disease free interval prior to stage IV disease, surgery (5 R0, 3 R1–2 resections), lactate dehydrogenase levels, first-line irinotecan chemotherapy, radiation (9 pts ≥ 45 Gy, 3 Pts < 45 Gy), and maintenance XCEL (duration 0–50.3 months). Results: Nine of 19 patients experienced recurrence (median 13 months after CR), and 4 died during the follow-up period (median 31 months after CR). The 2-year RFS for the unresected and R1–2 resected patients was 71% versus 20% for the R0 resected patients (p = 0.07). This paradoxical RFS pattern corresponded to a RFS advantage for maintenance XCEL (p = 0.002), but not any other prognostic or treatment factors. All relapses occurred in situ following discontinuation of XCEL except for the surgical cases. Patients undergoing maintenance XCEL also benefited in OS (p = 0.04). The median OS from XCEL and from onset of metastasis reached 51.9 months (95% CI, 45 months- not reached [NR]) and 73.3 months (95% CI, NR-NR months) respectively. Conclusions: Maintenance XCEL targets colorectal micrometastases and produces a paradoxical RFS and OS advantage among the high-risk unresected/R1–2 resected patients than R0 resected patients. Prospective studies are warranted to validate roles of maintenance XCEL in the treatment of colorectal micrometastases. No significant financial relationships to disclose.
Isolation and characterization of spontaneous spheroid aggregates within human colon carcinomas
Authors: Dangles-Marie V. , Validire P. , Richon S. , Weiswald L. , Briffod M. , Pecking A. , Gayet B. , Bellet D. 
Published: March 2020

14515 Background: In vitro spheroid model using cancer cell lines is widely admitted to mimic in vivo micro tumors, including micrometastases. Floating spheroid cell cluster culture has been recently used for normal and cancer stem cell expansion. Spontaneously spheroids generated in vivo have been only studied in ovarian cancer ascites while organoid aggregates have been sometimes observed in the establishment of human colon cancer cell lines. In this study, we investigated whether spontaneous spheroid aggregates from colon cancer could be isolated and characterized. Methods: 127 colorectal primary tumor specimens have been collected and mechanically dissociated into small fragments, which were then shortly cultured on cell plastic flask. Production of spheroid- like structures, referred to as colospheres, was examined at Day 1 and colospheres were gathered for phenotypic characterization. Results: Colospheres were successfully generated from 67 surgical specimens (53%). The capacity to form colospheres was strictly restricted to tumor tissue: dissociated normal colon mucosa never generated colospheres and colospheres were formed exclusively by cancer cells. The ability to generate colospheres was demonstrated to be significantly related to tumor aggressiveness, according to nodal status and AJCC’s stages (Chi-2 test, p<0.05). Immunohistochemical studies showed that cells forming colospheres were frequently positive for Ki67, and displayed often a disturbed expression of the epithelial caretaker E-cadherin. Peripheral cells of colospheres were able to migrate into Matrigel in absence of any chemoattractant. Conclusions: Collectively, the morphology of these colospheres derived directly from tumoral tissues and made up exclusively of cancer cells, their potential capacity to acquire an epithelial-to-mesenchymal transition phenotype and their in vitro migration ability could be aligned with the collective migration properties of carcinomas. Consequently, these ex vivo spherical structures might form an in vitro cell system for micrometastasis studies, at the very time when mortality among colorectal cancer patients continues to be attributed to metastasis development. No significant financial relationships to disclose.
Phase II study of the clinical and biological activity of cetuximab and celecoxib in patients (pts) with refractory colorectal cancer (CRC)
Authors: Chan E. , Merchant N. B. , LaFleur B. J. , Rothenberg M. L. , Coffey R. J. , Morrow J. D. , Milne G. L. , Trivedi B. L. , Lockhart A. C. , Berlin J. D. 
Published: March 2020

14516 Background: The epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) pathways play key roles in colon carcinogenesis. EGFR and COX-2 signaling can be mutually reinforcing. Celecoxib, a selective COX-2 inhibitor, inhibits the EGFR pathway through inhibition of PI3/Akt and NF-κB pathways. This study explores the clinical and biological effects of blockade of complementary pathways of the EGFR by combining cetuximab with celecoxib. Methods: Cetuximab-naive pts with refractory CRC were treated with cetuximab (400 mg/m2 loading dose followed by weekly cetuximab at 250 mg/m2) and celecoxib (200 mg orally twice daily). Patients were assessed for response every 8 weeks. Urinary PGE-M, a metabolite of PGE-2 which correlates with in vivo COX-2 activity, and serum TGF-a, a ligand that binds to EGFR, were measured to assess the biological effect of COX-2 and EGFR blockade. Results: Seventeen of a planned 40 pts accrued to this study. Currently, data is available on 12 of these patients. Three pts had to stop treatment on 1st infusion due to a grade 3 cetuximab infusion reaction. One pt had a mild infusion reaction and was successfully rechallenged after pre-medication and a slower infusion rate. By RECIST criteria, 1 pt (8.3%) achieved a partial response (PR) and 4 pts (33%) had a best response of stable disease (SD). The mean time on study for the 9 pts without grade 3 infusion reaction was 95.7 days (range 28- 175). Pts with SD or PR were on study for a mean of 135 days (range 107–175 days) and pts with progressive disease (PD) were on study for a mean of 47 days (range 28–56 days). Baseline urinary PGE-M levels in pts with SD or PR were higher than in pts with PD (30.5+17.6 vs 18.1+9.4 ng/mg Cr). Baseline serum TGF-a levels were similar between the two groups (27.1+9.6 vs 25.4+10.3 pg/ml respectively). Conclusions: In preliminary analysis, this regimen resulted in response rates similar to published response rates for single agent cetuximab. Pts with at least SD had higher baseline urinary PGE-M levels, which may serve as a marker for efficacy of this combined therapy. Data on serial TGF-a and PGE-M levels will be presented. Response data on all 17 pts will be presented. Supported by P50 CA95103 and Bristol-Myers Squibb. Celecoxib provided by Pfizer. [Table: see text]