bluuebunny/crossref_metadata_2025 huggingface dataset:
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]
Hepatic arterial infusion (HAI) compared to systemic chemotherapy for the treatment of unresectable liver metastases from colorectal carcinoma: A systematic review and meta-analysis of randomized controlled trials
Authors: Mocellin S. , Pilati P. , Lise M. , Nitti D.
Published: March 2020

14519

Background: The treatment of unresectable liver confined metastatic disease from colorectal cancer is a challenging issue. Although locoregional treatments such as HAI claim the advantage of delivering higher doses of anticancer agents directly into the affected organ, the evidence for benefit in terms of overall survival (OS) is conflicting. We aimed to quantitatively summarize the results so far described in randomized trials comparing HAI to systemic chemotherapy. Methods: To date, ten randomized controlled trials (RCT) have been published, for a total of 1,277 patients enrolled. Seven RCT (n=1,098) enrolling at least 50 patients per arm (the minimum sample size required to achieve a type II error lower than 20%) were considered for OS meta-analysis, which was based on the inverse of variance method. For tumor response rates, hazard ratios (HR) and their 95% confidence intervals (CI) were obtained from raw data; for OS, HR and CI were obtained from reported Cox model survival analyses or were calculated from Kaplan-Meier survival curves according to the Parmar method. Results: HAI regimens were based on floxuridine (FUDR) in nine out of ten RCT, while in one case 5-fluorouracil (5FU) + leucovorin (LV) were used. Systemic chemotherapy consisted of FUDR, 5FU, 5FU + LV, or a miscellany of 5FU and best supportive care in three, one, four and two studies, respectively. Tumor response and median OS were better in the HAI arm in eight and three RCT, respectively. At meta-analysis, median tumor response rate was 38.84% and 17.30% for HAI and systemic chemotherapy, respectively (HR: 2.24, CI: 1.80- 2.81; P < 0.0001); on average, median OS was 16.04 and 12.64 months, respectively (HR: 0.83, CI: 0.58–1.19; P value 0.30). Conclusions: Although HAI regimens are followed by significantly higher tumor response rates, no OS advantage can be demonstrated for this locoregional treatment as compared to systemic chemotherapy. Since HAI has been so far compared to systemic chemotherapy regimens not containing modern and more effective antineoplastic agents (e.g. oxaliplatin, irinotecan), these findings do not support the clinical or investigational use of FUDR-based HAI.

No significant financial relationships to disclose.
Preliminary data from a phase II study of cetuximab with irinotecan in heavily pretreated patients with epidermal growth factor (EGFR)-expressing metastatic colorectal cancer (mCRC): LABEL
Authors: Buzaid A. , de Cerqueira Mathias C. , Perazzo F. , Simon S. , Fein L. , Hidalgo J. , Murad A. M. , Esser R. , Loos A. , Lerzo G.
Published: March 2020

14521

Background: Cetuximab (Erbitux) is a monoclonal antibody directed against EGFR that is active in combination with irinotecan in patients (pts) with mCRC, who have progressed during or after a prior irinotecan therapy. Methods: This open, single-arm phase II Latin American study investigated this combination in pts with EGFR-expressing mCRC progressing on or within 3 months of chemotherapy containing at least 6 weeks (w) of irinotecan-based therapy. The primary objective was to assess the best overall confirmed response rate (RR). Sample size calculations were based on an expected rate of 20% (±8%). Planned enrollment was 100 pts. Secondary objectives were to explore the duration of response (DOR), progression-free survival (PFS) time, the 12-week PFS rate, and overall survival time. Pts were treated with cetuximab (initial dose 400 mg/m2 then 250 mg/m2 weekly), plus irinotecan at the same dose and schedule (including dose reductions) as pre-study. Preliminary Results: Of 151 pts from 14 centers screened and in the database, 106 (70%, 3 pts missing) were EGFR-expressing and, of these, 79/106 (75%) were treated on-study. Forty (51%) were male; median age was 59 years [27–82]; 70 (89%) pts had a Karnofsky performance status = 90 and 9 (11%) pts = 80. Nineteen (24%) pts had received = 3 prior treatment regimens, 42 (53%) were previously treated with an oxaliplatin-based regimen for metastatic disease. The confirmed overall RR was 26.6% [17.3–37.7]. Median DOR was 23.9 w [17.1–30], median PFS time was 17.7 w [11.7–18.9], and the 12-week PFS rate was 58% [47–69]. Thirty-three (42%) pts were alive at data cut-off. Median survival was 9.7 months [7.9–13.1]. Treatment was well tolerated with the most common grade 3/4 adverse events including: diarrhea, 20%; neutropenia,10%; acne-like rash, 9%. No grade 3/4 infusion-related reactions were reported. Conclusions: The overall confirmed RRs observed in this heavily pretreated population fully met the expectations for the primary endpoint of this study. LABEL confirmed in a Latin American setting the activity and safety of cetuximab plus irinotecan seen in previous studies.

No significant financial relationships to disclose.
Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in patients with metastatic colorectal cancer: A sensitivity marker to 5-FU-based therapy
Authors: Castillo Fernandez O. O. , Herrera L. A. , Castro C. , Calderillo G. , Herrera R. , Bauza A.
Published: March 2020

14532

Background: 5-Fluorouracil (5FU) and Folinic Acid (FA) with either oxaliplatin or irinotecan have become the standard chemotherapy used for metastatic colorectal cancer. However, more than 50% of our patients cannot afford it. Moreover, we lack of predictive markers to 5FU/AF therapy. The methylenetetrahydrofolate reductase (MTHFR) is a key enzyme regulating the folate pool and its substrate 5,10-methylenetetrahydrofolate is needed for modulation of 5FU. The C677T MTHFR gene polymorphism is highly prevalent in Mexican population and is linked to altered enzyme activity and increases substrate levels. Many studies have suggested a better response rate to fluoropyrimidine based therapy related with C677T polymorphism. The aim of this study was to evaluate the presence of this polymorphism and its relation with progression free and overall survival in metastatic colon cancer treated with 5FU/FA Methods: Sections of paraffin- embedded healthy colonic mucosa of 29 patients with metastatic unresectable colorectal cancer treated with 5FU/FA as first line chemotherapy between 1998 and 2004 were collected to obtain DNA and determine the polymorphism by PCR and allele specific digestion. Results: We found a highly proportion of at least one mutated allele in our patients (8 homozygous wild type CC, 15 heterozygous CT, 6 mutated homozygous TT). C677T MTHFR gene polymorphism showed statistically significant differences in median progression free survival non polymorphic CC 3.23±0.68 month versus 4.8±0.18 month in polymorphic group CT and TT (p= 0.011 log rank test) and median overall survival in non polymorphic groups 6.7±2.63month versus 13 ±2.51 month in polymorphic group (p= 0.03 Breslow test).No other variable affected progression free or overall survival on univariate analysis. Conclusions: Our findings suggest that C677T polymorphism could play a role on survival in metastatic colorectal cancer treated with 5FU/FA. Futher studies evaluating standard chemotherapy and the analyzed polymorphism are recommended.

No significant financial relationships to disclose.
The impact of metastatic sites in metastatic colorectal cancer at initial diagnosis (MCCID)
Authors: Leone B. A. , Lacava J. A. , Zwenger A. O. , Iturbe J. , Perez J. E. , Machiavelli M. R. , Romero A. O. , Vallejo C. T. , Dominguez M. E. , Rodriguez R.
Published: March 2020

14536

Background: The role of metastatic site in MCCID is unclear. The goal of this study is to evaluate if metastatic site influence survival in this setting of patients (P). Methods: Analyses were based on individual data of 300 P with MCCID treated with biochemical modulation of 5- Fluorouracil by Methotrexate regimens in different prospective trials conducted at GOCS Institutions since May 1984 to Aug 2000. P with surgical resection of liver metastases were not included in the analyses. 38 P were excluded for incomplete data. P were grouped according to metastatic sites into group A= Liver metastases only (n=161), group B= Liver and other metastatic sites (n=61) and group C= Non liver metastases (n=40) (lung, peritoneal, others). Different prognostic variables were considered: age, sex, PS, weight loss, size of liver metastases, unilateral or bilateral liver involvement, number of liver metastases, histologic differentiation of primary tumor, location of primary tumor, lactate dehydrogenase, alkaline phosphatase, ALT, AST and hemoglobin. Overall survival (OS) was analyzed since date of diagnosis by means of Kaplan-Meier and the Log-rank test was used to assess the differences. Results: The average follow-up time was 14.4 months (0–73.4). Clinical, laboratory and tumor characteristics were similar among groups A, B and C respectively. However P in group A had bigger size of liver metastases, higher number of them and more bilateral liver involvement respect to group B (p=0.02, p=0.03, p=0.05 respectively). Median OS in group A=21.0 months, group B=13.1 months and group C=15 months (p= 0.02). Statistical difference in OS was observed between group A and group B (p= 0.015). No difference was observed between groups A plus B vs the heterogeneous group C (p= 0.83) Conclusions: P with liver only metastatic site had better prognosis respect to those with other coexisting site of metastases despite presenting higher tumor burden in the liver. No factors analysed in the study explaine this difference. The subset of P with liver only metastatic site would be considered as a distinctive group and deserve further molecular studies.

No significant financial relationships to disclose.
Complications and effectiveness of combination chemotherapy in metastatic colorectal cancer (MCRC) with unresected primary (UP)
Authors: Abdal Raheem S. , Gupta B. , Tan W. , Wilding G. , Smith J. , Yang G. , Rajput A. , Bullard Dunn K. , Fakih M. G.
Published: March 2020

14537

Background: The outcome of patients (pts) with MCRC and unresected primary (UP) has not been studied systematically in the modern era of targeted and combination chemotherapy. We conducted a single institute retrospective study to determine the rate and nature of complications in this population. Methods: MCRC-UP pts treated at Roswell Park Cancer Institute between 2002 and 2006 were identified. Demographic, toxicity, efficacy, and palliative intervention data were collected. Primary tumor related complications including obstructive symptoms, bleeding, perforation, and fistulas were assessed. Results: 24 pts with colonic UP were identified. 14/24 were treated with bevacizumab-based chemotherapy (11 FOLFOX, 3 capecitabine), 7/24 with FOLFOX, 2 with capecitabine, and 1 with FOLFIRI. No perforations, hemorrhagic events, or arterial events were noted. None of the 24 pts required palliative surgical intervention secondary to the UP. Only 2 pts developed obstructive symptoms and 1 pt developed an entero-cutaneous fistula; all 3 events were attributed to peritoneal carcinomatosis. 10 pts with rectal UP were identified. 1 pt received upfront chemoradiation followed by 5-FU/bevacizumab. 9/10 pts were treated with upfront systemic chemotherapy (6 bevacizumab-based [5 FOLFOX, 1 capecitabine], 3 FOLFOX). Of these 9 pts, 4 required subsequent palliative radiation therapy for obstructive symptoms (3 pts) or pain (1pt) while 5 continue on systemic chemotherapy (median 1st line chemotherapy duration > 7 months). No perforations, bleeding requiring transfusion, or arterial events were noted among the rectal cancer population. 1 pt required a diverting colostomy for obstruction despite palliative CRT. Median time to progression on first line chemotherapy was 7.4 months for colon cancer and 8 months for rectal cancer. The median overall survival was 13.6 months for colon cancer and has not been reached for rectal cancer (exceeded 13 months). Conclusion: Treatment of MCRC with UP is feasible and is rarely associated with complications related to the primary tumor. Rectal cancer with UP can be managed with upfront chemotherapy. Subsequent palliative RT is needed in about 50% of these pts.

No significant financial relationships to disclose.
Apoptosis inducing factor is decreased in metastatic colon cancer in ex-vivo models of colon carcinogenesis by tissue microarray
Authors: Huerta S. , Amirkhan R. H. , Siddiqui A. A. , Livingston E. H. , Huerta-Yepez S.
Published: March 2020

14539

Background: In vitro studies suggest that apoptosis inducing factor (AIF) expression is decreased in metastatic cells relative to those derived from primary tumors. This study was undertaken to determine AIF expression patterns in patients with stage I/II vs. stage III/IV colorectal cancers. Methods: Colon cancer specimens were prospectively collected (11/05–6/06) from 12 patients from 3 different sites: tumor, adjacent to tumor, and tissue 2 cm from the tumor. Paraffin-embedded specimens were examined by tissue microarray with AIF-specific antibodies. Total AIF expression as well as cytoplasmic and nuclear expression was assessed by an investigator blinded to the tissue site and patient stage. Staining was assessed as: 1=absent, 2=mild, 3=moderate, 4=high and 5=very high. The clinical characteristics and tumor stage of all patients were analyzed. Results: All patients were male. Eight patients had non-metastatic disease at the time of laparotomy, four had metastasis to: lymph nodes (n=3) and liver (n=1). Stage I/II patients (n=8) were of similar age compared to stage III/IV patients (n=4) [61.3±4.2 vs. 54.4±6.0 y.o.; p=0.6] had similar tumor size (3.81±0.7 vs. 4.08±1.4 cm; p=0.4). There was no difference in the level of expression of AIF in normal tissue collected 2-cm away from the tumor site in stage I/II vs. stage III/IV colon cancers in the cytoplasm (3.81±0.17 vs. 3.30±0.38; p=0.4), nucleus (3.19±0.43 vs. 2.49±0.46; p=0.8) or overall (4.06±0.27 vs. 3.37±0.8). A significant decrease in AIF expression was observed in stage III/IV tumors compared to stage I/II tumors in tissue collected adjacent to the tumor in the cytoplasm (3.12±0.22 vs. 4.46±0.25; p=0.03), the nucleus (2.10±0.44 vs. 3.63±0.32; p=0.03) and overall (3.12±0.22 vs. 4.46±0.25; p=0.03). There was a trend towards a decrease in AIF expression between stage III/IV vs. I/II tumors in tissue collected directly from the tumor in the cytoplasm (2.55±0.24 vs. 3.56±0.26; p=0.12), the nucleus (1.39±0.25 vs. 2.73±0.63; p=0.14) and overall (2.79±0.38 vs. 3.90±0.37; p=0.22). Conclusion: AIF expression is decreased in metastatic colon cancer. The main differences occur in the normal mucosa adjacent to the tumor.

No significant financial relationships to disclose.
Nigro regimen treatment of squamous cell cancer of the anus
Authors: Kalmadi S. R. , Pelley R. J. , Kay E. , Saxton J. P. , Bukowski R. M. , Kim R. D. , Lavery I. C. , Fazio V. W.
Published: March 2020

14545

Background: To identify prognostic factors for patients with squamous cell cancer (SCC) of the anus treated with Nigro Regimen chemo/radiation therapy. Methods: Survival data of 61 patients with SCC of the anal canal were reviewed who were treated with definitive radiochemotherapy (RCT) between 9/83 and 3/06. All patients received RCT at the Cleveland Clinic Foundation. Results: Patient characteristics were typical of other studies. Median age was 57 years (34–82), women: men (42:19), PS 0–1 (95%), smokers 52%, and clinically lymph node positive tumors 27%. T3–4 tumors were 50%, high for most series. The median follow-up time was 52 mos (7–246 mos). The median disease free survival (DFS) and overall survival (OS) have not been reached. 5-year DFS was 76% (95% C.I. 62–88%) and 5-year OS was 76% (95% C.I. 60–86%). Colostomy free survival at 5-years was 41/61 (67%). Log rank analyses showed that female sex (5-yr DFS 82 vs 55%, p=0.03), and clinical stage (5-yr DFS, stage 1 100%, stage 2 80%, stage 3a 65%, stage 3b 0%) correlated with better disease free survival. Patient age (less than 60 or greater), time of diagnosis (before 1996 or later), and smoking status did not correlate with better disease free survival. There were 14 recurrences, 7 systemic, 7 local with APR salvaging 4 patients with local relapse. There were 2 cases of treatment related hemolytic uremic syndrome, with one death. Conclusions: The Nigro regimen is successful in curing anal cancer in a significant majority of patients. We appear to have reached a therapeutic plateau and have not had any significant improvement in cure rates over the last two decades. Identification of subsets more prone to relapse is crucial, to target with more intense treatment in future trials. In the current series, male sex and advanced clinical stage correlated with poor disease free survival, when anal cancer patients were treated with the Nigro regimen RCT. Future studies should investigate whether more intensive treatment is needed in males, and patients with more advanced disease.

No significant financial relationships to disclose.
Prospective control trial of cancer ultrastaging in the left colon with sentinel lymph node
Authors: Hernando R. , Serra X. , Bombardó J. , Casalots A. , Mena E. , Martín J. , Junquera F. , Pericay C. , Navarro S.
Published: March 2020

14547

Background: The use of the sentinel node lymph (SNL) in connection with colorectal cancer is a subject in which there has been some controversy. Methods: Prospective control trial of 60 patients with left colon cancer stage II. Methylene Blue® or Nanocoll® had been used to identify the SNL. The standard pathologic examination with hematoxylin and eosin (H&E) had been compared with the study of SNL with H&E and Cytokeratine CAM 5.2. Results: Identification of the SNL: 100%, 2.4 SNL detected in each patient. Nodal disease (N+) was found in 19 patients (31.7%), and 41 patients (68.3%) were classified as node-negative (N0). Hidden micrometastasis in the SNL were found in 9.7% (4/41) patients considered as N0 by conventional histopathology. However, in 17.7% (7/41) patients considered as N0 we found large cell clusters, contatining up to 10 tumor cells, falling short of the AJCC on cancer criteria, and were considered to have high- risk disease. Having applied both the SNL study and the standard pathologic examination the number of patients N+ has increased to 38.3% (23 patients), ultrastaging: 6.6% (p= ns). If the patients with large cell clusters in the SNL had been considered as N+ the number of N+ patients would have increased to 50%(30 patients), ultrastaging 18,3%(p=0,001). Conclusions: The combined nodal study (H&E + SNL) increased 6.6% the staging in our group, and it let to identify a group of patietnts N0 with high-risk tumor progression. If the large cell clusters in the SNL were considered as micrometastases disease the ultrastaging would have been 18.3%.The implications of large cell clusters prognosis is yet, unknown.

No significant financial relationships to disclose.
Dermatological toxicities of panitumumab in the treatment of patients with metastatic colorectal cancer (mCRC) from three clinical studies
Authors: Drelich D. A. , Rose L. , Ramirez M. , Jacobs M. , Mitchell E.
Published: March 2020

14551

Introduction: Epidermal growth factor receptor (EGFr) expression in CRC is associated with metastatic potential and poor prognosis. Panitumumab, a fully human monoclonal antibody against EGFr, was approved for the treatment of patients with refractory mCRC. The main side effects of panitumumab include dermatological manifestations that have been termed “rash”. However, classification of the dermatological manifestations has not been clearly described. Methods: We summarized the dermatological manifestations of 19 patients from 3 clinical studies investigating the the safety and efficacy of panitumumab monotherapy in mCRC in a single institution. Two of these studies were open lable, phase 2 in design which enrolled patients with documented disease progression (PD) during or after adequate doses of fluoropyrimidine, irinotecan, and oxaliplatin chemotherapy. In the other panitumumab was given in combination with irinotecan or oxaliplatin with bevacuzumab, 5FU, and leucovorin. Pts received panitumumab at 6mg/kg Q2W until PD or intolerability. Skin assessments were made q2w. Results: Five patients were men (26%) and 14 (73%) women; 12 were Caucasian (63%) and 7 (36%) African American. The median age was 53 (Range 38–80). Tumor response, disease control, and skin manifestations did not correlate with tumor EGFr levels as assessed by immunohisxtochemistry (Dako EGFR pharmDxtm). No enhancement of skin toxicity was observed when panitumumab was combined with chemotherapy. The median number of cycles received was 11 (Range 3–20). All pts experienced erythema; 17 macular/papular; 13 pustular; 18 acneiform rash; 15 pruritis; 3 honey crusting; 15 dry/flaking; 11 paronychia; 9 hirsuitism; 9 trichomegaly; and all 7 African American patients had significant hyperpigmentation. Photograph illustrations of each category and severity will be presented. Conclusion: Rash associated with panitumumab is common and can be classified according to the clinical dermatological manifestations; specific treatment strategies should be developed and evaluated accordingly. This is the first report of hirsuitism in women and hyperpigmentation in African Americans.

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Measures of oxaliplatin-induced neutrotoxicity in 187 patients with FOLFOX4
Authors: Matsusaka S. , Mizunuma N. , Matsuda M. , Suenaga M. , Ogura M. , Ichimura T. , Shoji D. , Oya M. , Muto T. , Hatake K.
Published: March 2020

14552

Background: Oxaliplatin-based regimen (FOLFOX regimen) for patients with colorectal cancer have improved survival. Neurotoxicity is the most frequent dose-limiting toxicity of oxaliplatin. Various strategies and pharmacologic agents are currently under investigation to prevent or treat oxaliplatin-induced neurotoxicity. One of them is Stop-and-Go strategy based on the observation of reversibility of the neurotoxic symptoms after discontinuation of oxaliplatin. Stop-and-Go concept will prolong the time of oxaliplatin-based therapy as long as antitumor efficacy is still maintained. Methods: Patients with a histologically verified advanced colorectal carcinoma were eligible for the study. From April 2005 to March 2006 at Cancer Institute Hospital, 187 patients whom treated with bimonthly oxaliplatin-based regimen (FOLFOX4) were enrolled. An oxaliplatin specific neurotoxicity scale are distinct from the National Cancer Institute common toxicity criteria classification (CTC-AE vol. 3). This study was performed to carefully assess the onset and duration to recovery of oxaliplatin neurotoxicity and resumption rate of FOLFOX4. Results: Neurotoxicity was observed in 72 patients with Grade 1, 56 patients with Grade 2 and 33 patients with Grade 3. Oxaliplatin-induced cumulative neurotoxicity develops progressively. The median cumulative doses of oxaliplatin were 170 mg/m2 with Gr. 1; 845.8 mg/m2 with Gr. 2; and 850 mg/m2 with Gr. 3. The median time to onset were 16 days with Gr. 1; 174 days with Gr. 2; and 177 days with Gr. 3. The median time to recovery after stopping the therapy and the median time to progression during the discontinuation of oxaliplatin were 56 and 59 days, respectively, in patients allocated to Gr. 2 compared with 106 and 73 days, respectively, in patients allocated to Gr. 3. The recovery time during the discontinuation showed a statistically significant reduction of the values in the Gr. 2 but not in Gr. 3 (p = 0.0024). The resumption rates of oxaliplatin were 73.7% with Gr. 2 and 46.4% with Gr. 3. Conclusions: Our results may focus to manage time course of Stop-and-Go strategy in clinical practice.

No significant financial relationships to disclose.
Phase I trial of neoadjuvant chemoradiotherapy with capecitabine and weekly irinotecan followed by laparoscopic mesorectal excision
Authors: Ugidos L. , Conill C. , Delgado S. , Gines A. , Gallego R. , Ayuso J. R. , Miquel R. , Lacy A. M. , Castells A. , Maurel J.
Published: March 2020

14556

Background: To establish the feasibility and efficacy of capecitabine with weekly irinotecan (CAPIRI) and concurrent radiotherapy (RT) in patients with locally advanced and resectable metastatic rectal cancer, followed by LAME. Methods: Eligible criteria included adenocarcinoma of the rectum staged by endoscopic ultrasonography (us), spiral abdominal and pelvic CT and chest X-ray. Patients received weekly irinotecan 50 mg/m2 (days 1,8,15,22,29) and two doses of capecitabine (days 1 through 5 for 5 weeks); dose level; (DL) I 250 mg/m2 bid; DL II 375 mg/m2 bid; DL III 500 mg/m2 bid, according to phase I methodology. Conformal radiotherapy was administered up to a total dose of 45 Gy/1.8 Gy per fraction. LAME was planned 5–7 weeks after CRT. Results: From January 2003 to March 2006, 22 patients (three with potentially resectable metastatic disease) were included. Median age was 62 (range 48 to 78). 6 pts were usT3N0 and 16 pts usT3–4N1. Seven patients were treated at DL I, six at DL II and nine at DL III. Grade 3 or 4 adverse events were observed in all levels; DL I asthenia (1p); DL II diarrhea (2p) and DL III asthenia and neutropenia (1p), diarrhea (1p) and hyperbilirrubinaemia (1p). All patients except one who refused treatment after 1 week therapy (DL I), completed CRT and underwent surgical resection (R0 81%, R2 19%). Abdominoperineal resection was done in two cases (9%). Conversion rate to open surgery was 5%. Median hospital stay was 7.9 days. The overall postoperative morbidity was 4.7%. Median excised nodes were 11 (range 4–21). Pathological complete response was observed in two patients (9%), both of them in DL III. With a median follow-up of 25 months (range 9–46), disease free survival and overall survival was 67% and 95% respectively. Conclusions: Preoperative CRT with CAPIRI is feasible, but severe adverse events were found in all levels despite the use of lower dose of capecitabine than previously published. LAME after CAPIRI had short oncologic outcomes comparable with open mesorectal excision.

No significant financial relationships to disclose.
Individualizing the interval between neoadjuvant chemoradiation with uracil-tegafur (UFT) and total mesorectal excision in magnetic resonance imaging (MRI) defined poor-risk rectal cancer
Authors: Sizer B. , Arulampalam T. , Austin R. , Basu D. , Lacey N. , Menzies D. , Motson R.
Published: March 2020

14557

Background: The importance of achieving negative circumferential resection margins (CRM) for patients (pts) with MRI - defined poor - risk rectal cancer (PRRC) has led to an increase in the use of pre-operative chemoradiotherapy (CRT) employing long fractionation schedules, usually with an interval of 4 to 6 weeks before surgery. We report our experience of using serial MRI post CRT to optimise the timing of total mesorectal excision (TME) surgery at maximal radiological response for each pt. Methods: Data was collected prospectively from 4/03 to 10/06 on toxicity and response for 50 consecutive patients ( 36 male; median age 64 years, range 39 - 76 years), 47 with biopsy - proven PRRC by MRI criteria (threatened / definite CRM involvement, T3 > 5mm into perirectal fat, T4 tumours, and / or multiple nodes) and 3 pts with localised recurrence after previous anterior resection. Pts received 2 phase, conformal external beam radiotherapy ( 45 - 50.4 Gy / 25 - 28 fractions / 5 weeks), concurrently with their choice of either oral UFT (n = 44, 88%), 240mg/m2/d d 1 - 28 with Leucovorin (LV) 90mg/d or iv bolus 5 FU (n= 6) 300mg/m2 d 1,8,15,22,29 with LV 20 mg/m2). Clinical re-assessment q 2 wkly from 4 weeks post CRT, with serial MRIs 4-weekly, from 6 wks. Results: 48 pts (96%) completed CRT, worst toxicity, diarrhoea Grade 3, 6%. Mean number of MRI scans per pt post CRT 1.48, with response seen in 46 pts (92%), of whom 43 (86%) underwent resection, 27 (63%) of which were performed laparoscopically. Median time to surgery was 11 weeks (range 8 to 15 wks). 37pts (86% of those undergoing surgery) achieved R0 resection, mean CRM 6.1mm, mean no. of identifiable lymph nodes 6.4, most frequent pathology ypT3 pN0 26%, pCR 16%, Tmic, 21%. Surgical morbidities included small bowel adhesions requiring laparotomy 8%, infection/abscess 14%. Post-operative mortality 5%. 1 PRRC pt developed liver metastases prior to surgery. Conclusions: CRT with UFT/LV is well tolerated and effective in achieving substantial tumour regression pre-operatively for PRRC. The optimal timing of surgery post CRT at maximal response can be documented with serial MRI, resulting in a high rate of R0 resections. Laparoscopic TME is feasible in this group of pts.

[Table: see text]