bluuebunny/crossref_metadata_2025 huggingface dataset:
AAV-mediated delivery of interferon-β for the treatment of retinoblastoma in preclinical models
Authors: Shih C. , Laurie N. , Holzmacher J. , Davidoff A. , Dyer M.
Published: March 2020

3565

Background: Interferon-β has anti-tumor properties against a variety of malignancies through direct cytotoxicity as well as immunological effects. In order to circumvent limitations of IFN-β therapy, we have developed an adeno-associated viral gene therapy approach to deliver IFN-β directly to tumors. In this study, we tested the efficacy of AAV mediated delivery of IFN-β in preclinical retinoblastoma models. Retinoblastoma is an ideal candidate for gene-therapy based anti-cancer treatments because viral infection and IFN-β delivery can be contained within the ocular environment thereby minimizing systemic toxicity. Methods: Retinoblastoma cell lines Weri and Y79 were treated in vitro with recombinant human Interferon-β and then subjected to Viacount assays, Nexin apoptosis assays, FACS cell cycle analysis, and immunolabeling for proliferation (BrdU) and apoptosis (caspase and TUNEL). An orthotopic Xenograft retinoblastoma rat model with luciferase reporter were established and treated with single subconjunctival injection of AAV-IFN-β gene therapy. Xenogen in vivo imaging was used to follow tumor volume. Blood and tissue samples (ELISA) were obtained to determine IFN-β levels. Results: Weri and Y79 cells showed maximum reduction in viability at 500 IU/ml and 2500 IU/ml respectively. Weri response was found to be cell death by Caspase and TUNEL assay. Y79 response was found to be due to suppression of proliferation as measured by BrdU incorporation and cell cycle analysis. In the retinoblastoma xenograft model there was no increase in tumor volume by serial in vivo imaging compared to control animals. Stable levels of IFN-β were maintained at 20 ng/ml >6weeks following injection. Plasma levels were undetectable 42 days following treatment. Conclusions: Retinoblastoma cell lines exhibit pleiotropic responses to IFN-β consistent with previous studies. Intravitreal injection of AAV-IFN-β resulted in efficient retinal infection and sustained IFN-β production. Viral spread outside of the eye was not detected. Using our retinoblastoma xenograft model we found that intravitreal injection of AAV-IFN-β had a potent anti-tumor effect in vivo. These data suggest that AAV mediated delivery of IFN-β may provide a complementary approach to systemic chemotherapy.

No significant financial relationships to disclose.
Evaluation of ON 01910.Na, a novel modulator of polo-like kinase 1 (Plk1) pathway, and development of a cyclin-B1-based predictive assay in pancreatic cancer
Authors: Jimeno A. , Chan A. , Zhang X. , Wheelhouse J. , Solomon A. , Cosenza S. C. , Reddy M. , Rudek M. , Kulesza P. , Reddy E. , Hidalgo M.
Published: March 2020

3569

Background: Plk1 is a key mitotic regulator of the transition through the G2/M checkpoint in the cell cycle. This work aimed to evaluate the activity of ON 01910.Na, a Plk1 pathway modulator, in in vitro and in vivo models of pancreatic cancer (PaCa) and to discover biomarkers predictive of efficacy. Methods: ON 01910.Na was tested in 12 PaCa cell lines. Studies assessing Plk1 related markers were conducted to identify biomarkers. For validation a live collection of PaCa xenografts from fresh tumor samples obtained at the time of surgical resection was used (PancXenoBank). The ex vivo assay was based on fine-needle aspirate (FNA) biopsies. Results: ON 01910.Na showed equal activity to gemcitabine against PaCa cell lines. The activity of ON 01910.Na correlated with suppression of two downstream mediators of PLK1, CDC25C and cyclin B1 (by mRNA and protein). ON 01910.Na was tested in xenografts from representative pancreatic cell lines. The selected markers were evaluated in an ex vivo assay, using intra-tumor pharmacokinetics to select the dose of the assay. Cyclin B1 mRNA evaluation yielded the most optimal combination of accuracy and reproducibility. Knockdown of cyclin B1 by siRNA had no effect per se or in the response of the resistant MiaPaca2 to either of the drugs. We next used the ex vivo assay to profile ten patient-derived cases from the PancXenoBank. Two cases were catalogued as potential responders. From each of these ten cases, a group of mice bearing at least 20 tumors received vehicle or ON 01910.Na for 28 days. There was a correlation between the ex vivo cyclin B1 assay and the sensitivity to the tested agent, as the 2 cases prospectively identified as sensitive met pre-specified criteria for response. Of the 8 tumors predicted to be resistant, only one was sensitive. In IHC testing cases showing ex vivo cyclin B1 down-regulation had also decreases in cyclin B1 protein, and there was a correlation between activity and IHC changes in cyclin B1. Conclusions: ON 01910.Na demonstrated significant activity in a preclinical model of PaCa. A rationally designed ex vivo cyclin B1-based assay not only identified cases sensitive to ON 01910.Na, but also replicated the pharmacodynamic events occurring after in vivo exposure.

No significant financial relationships to disclose.
Phase I study of ZEN-008 (AN-152), a targeted cytotoxic LHRH analog, in female patients with cancers expressing LHRH receptors
Authors: Emons G. , Kaufmann M. , Günthert A. , Gründker C. , Loibl S. , Tzekova V. I. , Velikova M. T. , Tomov S. , Sindermann H. , Engel J. , Schally A. V.
Published: March 2020

3571

Background: Human ovarian, endometrial, and breast cancers commonly express receptors for luteinizing hormone releasing hormone (LHRH-R). LHRH-R can be used for targeted chemotherapy with ZEN-008 (AN-152), in which doxorubicin (DOX) is linked to [D-Lys(6)]- LHRH. Preclinical studies showed a significantly reduced cardiotoxic potential of ZEN-008 compared with DOX, as well as activity in multi-drug resistant tumor models. This study assessed dose limiting toxicities (DLTs), maximum tolerated dose (MTD), and pharmacokinetics (PK) of ZEN- 008 given once every 3 weeks in female patients. Methods: Patients (pts) with tumors proven immunohistochemically to be LHRH- R positive and had progressive disease following chemotherapy were eligible if prior therapy did not exceed 70% of the recommended maximum lifetime dose for DOX. Starting at 10 mg/m2, doses were doubled between pts until side effects of CTCAE grade 2 or higher, then escalation following a modified Fibonacci scheme, with 3–6 pts/group. Safety monitoring included pituitary and cardiac function. Response evaluation followed the RECIST criteria. HPLC with fluorescence detection was used for plasma PK of ZEN-008 and free DOX. Results: Seventeen pts (13 with ovarian, 2 with breast cancer) received ZEN-008 by intravenous infusion over 2 hours at dosages of 10, 20, 40, 80 mg/m2 (1 pt and 2 cycles each). At 160 mg/m2 6 pts had 24 cycles, 1 pt ongoing at 3+ cycles), and at 267 mg/m2 7 pts had a total of 30 cycles, 1 pt ongoing at 4+ cycles). Short-lasting leukopenia/neutropenia of CTCAE Grade 4 was dose limiting in 2 pts at 267 mg/m2. One pt at this dose level had an allergic skin reaction during infusion, subsequent cycles with anti-allergic pre-medication were tolerated. At 160 mg/m2 1 pt with ovarian cancer had CR (lymph node metastasis), at 267 mg/m2 1 pat with ovarian cancer had a transient PR, and 3 pts had stable disease for 5+ cycles. PK analyses showed dose- dependent plasma levels of ZEN-008 and only minor (10–30%) release of DOX. Conclusions: Leukocytopenia was identified as a rapidly reversible DLT in heavily pretreated pts at a ZEN-008 dose of 267 mg/m2, given three-weekly, which is therefore also considered recommended Phase II dosage. Evidence of therapeutic activity was found at 160 and 267 mg/m2.

[Table: see text]
A phase I study of vorinostat (VOR) in combination with capecitabine (CAP) in patients (pts) with advanced solid tumors
Authors: Tang P. , Oza A. , Townsley C. , Siu L. , Pond G. , Sarveswaran P. , Webster S. , Zwiebel J. , Chen E.
Published: March 2020

3576

Background: VOR (suberoylanilide hydroxamic acid; SAHA) is a small molecule inhibitor of histone deacetylase (HDAC) that binds directly to the enzyme’s active site in the presence of a zinc ion. Aberrant HDAC activity has been implicated in a variety of cancers. The combination of 5-fluorouracil and VOR is synergistic in preclinical tumor models. Methods: This phase I study evaluated safety, tolerability, and the recommended phase II dose (RPTD) of VOR and CAP in pts with advanced solid tumors. VOR was administered orally daily while CAP was administered orally bid on days 1–14 of a 21 d cycle. Results: Three dose levels have been evaluated (VOR (mg/d)/CAP (mg/bid)): 300/750, 300/1,000 and 400/1,000. Twenty-three pts have been treated: 6M/17F, median age 59 (range 41–73), ECOG 0:1:2 = 9:13:1, prior therapy 1:2:3 or more = 3:7:13. Pts had colorectal cancer (n=6), nasopharyngeal (n=3) and various other tumors. A total of 104 cycles have been administered, with median = 2 (range 1–15). One dose limiting toxicity (DLT) (grade 3 diarrhea) occurred in 6 patients at dose level 1. No DLT were observed at dose level 2, and 2 DLTs (grade 3 fatigue and grade 3 nausea/vomiting) occurred at dose level 3. RPTD was determined to be VOR 300 mg/d and CAP 1,000 mg/bid. Most common toxicities of any grade and at least possibly attributable (n=22) are: thrombocytopenia (59% of pts), fatigue (55%), nausea (55%), vomiting (50%), hypoalbuminemia (45%), anemia (41%), diarrhea (41%), anorexia (41%), elevated creatinine (36%), lymphopenia (36%), hyponatremia (36%), and hyperglycemia (36%). Common grade 3 toxicities included: hand-foot syndrome (23% of pts), diarrhea (14%), fatigue (14%), and lymphopenia (14%). One pt died on study from ventricular fibrillation due to sotalol and hypocalcemia from pre-existing hypoparathyroidism. Five patients with various tumor types had PR (2 confirmed, 3 unconfirmed) (2 nasopharyngeal, 1 each of ovarian, endometrial and squamous cell carcinoma of head and neck). In addition, disease stabilization was seen in 12 patients. Conclusions: VOR and CAP are well tolerated, and this combination is active in several tumor types. Further evaluations of VOR and CAP are warranted.

No significant financial relationships to disclose.
Final results from an open-label, randomised, phase II study of adecatumumab (MT201), a fully human anti-EpCAM antibody, in patients with metastatic breast cancer
Authors: Awada A. H. , Schmidt M. , Scheulen M. E. , Obrist P. , Marschner N. , Dirix L. , Dittrich C. , Reinhardt C. , Schuler M.
Published: March 2020

3588

Background: High-level expression of the epithelial cell adhesion molecule (EpCAM) has been associated with unfavourable prognosis in various cancers. Adecatumumab was developed as a low-affinity IgG1 antibody targeting EpCAM-positive cancer cells. Methods: EpCAM-positive metastatic breast cancer patients without CNS metastases, with no indication for trastuzumab were eligible; an initial restriction to a maximum of one previous chemotherapy for metastatic disease was subsequently removed. 109 EpCAM- positive patients were enrolled. Patients were stratified into high- and low-level EpCAM expression (n = 74 and 35, respectively) according to immuno-histochemistry testing, and subsequently randomised to receive either high-dose (6 mg/kg/q2w) or low-dose (2 mg/kg/q2w) adecatumumab (n = 54 and 55, respectively). Primary endpoint was clinical benefit rate (CBR = objective response + stable disease) at week 24 with secondary parameters exploring time to progression (TTP) and safety. Results: The primary endpoint (CBR at week 24: >25%) was not met in any of the 4 groups according to central radiological review. Exploratory analyses of the Kaplan-Meier curves, however, showed a lower probability for tumor progression in patients receiving high dose adecatumumab (HR: 0.67 [0.47–0.94]; p=0.047). A similar trend was also observed in patients with high-level EpCAM expression (HR: 0.71 [0.49–1.03]; p=0.116). Further (retrospective) analysis using more stringent criteria for the definition of high-level EpCAM expression indicated an inverse correlation of staining intensity and frequency with probability of progression. An increased incidence of CTC grade 1 and 2 AE was found in the high-dose group with main side effects being gastrointestinal and constitutional symptoms. Conclusions: The observation of dose- and target-dependent activity of adecatumumab warrants further investigation. Definition of the optimum dose and regimen as well as exploration of the predictive value of EpCAM testing will be key in future development.

No significant financial relationships to disclose.
A phase I dose escalation study of sunitinib plus capecitabine in patients with advanced solid tumors
Authors: Sweeney C. , Verschraegen C. , Chiorean G. , Lee F. , Jones S. , Tye L. , Bello A. , Chao R. , Burris H.
Published: March 2020

3592

Background: Sunitinib malate (SU) is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, RET, and FLT3, approved internationally for the treatment of advanced RCC and imatinib-resistant or -intolerant GIST. This phase I study assesses the safety, tolerability and pharmacokinetics (PK) of SU in combination with capecitabine (C). Methods: Pts with advanced solid tumors not amenable to curative therapy, previously treated with =2 prior chemotherapy regimens, and ECOG PS =1 were eligible. Prior antiangiogenic therapy was not permitted. Three SU schedules were evaluated: 4 wks on treatment followed by 2 wks off in 6-wk cycles (4/2 schedule); 2 wks on followed by 1 wk off in 3-wk cycles (2/1 schedule), and continuous dosing (CD schedule). In all cases C was administered orally bid on days 1–14. SU and C doses were alternately escalated in serial pt cohorts to determine the maximum tolerated dose (MTD) of SU for all schedules using a standard 3 + 3 design. PK and antitumor efficacy were also assessed. Results: A total of 50 pts have been enrolled; 28 pts have been treated on the 4/2 schedule: SU 50 mg + C 1,000 mg/m2, and SU 37.5 mg + C 1,250 mg/m2 were not tolerated. Dose limiting toxicities (DLTs) included: grade 3 myalgia (n=1), grade 3 fatigue (n=2), and grade 3 hand- foot syndrome (n=2). The MTD for the 4/2 schedule was SU 37.5 mg/day + C 1,000 mg/m2. No DLTs nor dose reductions were observed among 9 pts treated at the MTD. Preliminary PK data do not indicate drug-drug interactions between SU and C. 3 pts (1 each with breast cancer, neuroendocrine carcinoma, and thyroid carcinoma) achieved confirmed partial responses. On the 2/1 schedule patients are being accrued to SU 37.5 or 50 mg + C 1,000 mg/m2 and doses of SU 37.5 mg + C 1,000 mg/m2 or SU 25 mg + C 1,250 mg/m2 are being explored on the CD schedule. Conclusions: The combination of SU 37.5 mg/day (4/2 schedule) with C 1,000 mg/m2 in pts with advanced solid tumors appears tolerable. SU may be administered in combination with C with no apparent drug-drug interaction. Subsequent cohorts will define the MTD of SU administered on the 2/1 and CD schedules. Further studies of this combination in breast cancer are warranted.

No significant financial relationships to disclose.
A phase I study of lapatinib and topotecan in patients with solid tumors
Authors: Molina J. R. , Erlichman C. , Kaufmann S. , Adjei A. , Rubin S. , Friedman R. , Reid J. , Qin R. , Felten S.
Published: March 2020

3598

Background: Drug resistance to topotecan can be the result of BCRP/ABCG2 expression. BCRP is a member of the ABC transporter family that pumps anticancer drugs out of the cell. Lapatinib is a potent and selective dual inhibitor of epidermal growth factor receptor (EGFR or ErbB1) and ErbB2 (Her2/Neu). 4-aminoquinazoline tyrosine kinase inhibitors have been shown to enhance the cytotoxicity of topotecan through inhibition of BCRP-mediated drug efflux in cancer cells. Methods: Thirty-seven patients with advanced stage cancers were enrolled at escalating dose levels of lapatinib and topotecan in cohorts IA, IB and IIB (MTD). Treatment schedule included lapatinib (750 - 1500 mg/d) daily for 21 (cohort IA) or 28 days (cohort IB) and topotecan (2.4 - 4.0 mg/ m2), days 1, 8 and 15; cycles were repeated every 28 days. Three patients were treated at each dose level, 18 on cohort IA, 9 on cohort IB and 10 at MTD (cohort IIB). Assessments of toxicity were performed with each cycle and clinical response was determined per RECIST criteria every other cycle. Results: The MTD for cohorts IA and IB was reached at a dose of 1250 mg of lapatinib and 3.2 mg/m2 of IV topotecan on days 1, 8 and 15. No DLT were seen during the dose escalation stage of cohorts IA and IB. Ten patients were enrolled at the MTD. There were no grade 4+ events. Thirteen grade 3+ events, considered to be related to treatment, were seen in 6 patients. The most common grade 3+ toxicities included dehydration (2) diarrhea (2), nausea (3), vomiting (2), neutropenia (1), thrombocytopenia (1), and fatigue (1). No abnormalities in left ventricular ejection fraction were noted. Stable disease was seen in 46% of the 37 patients. Conclusions: The combination of lapatinib and topotecan is a well-tolerated regimen. The MTD for the combination is lapatinib 1,250 mg orally once daily for 21 or 28 days and topotecan 3.2 mg/m2 on days 1, 8 and 15. Pharmacokinetic analysis for drug interaction will be available for presentation at the meeting. Supported in part by GSK and Mayo Clinic

No significant financial relationships to disclose.
The dual specific Src/Abl kinase inhibitor AZD0530 inhibits the formation and activity of human osteoclasts
Authors: Klein-Nulend J. , van Duin M. A. , Green T. P. , Everts V. , de Vries T. J.
Published: March 2020

3602

Background: Gene knockout studies have demonstrated the critical importance of the non-receptor TK Src to osteoclast bone resorptive function. Deregulated Src TK activity is also reported as a hallmark of the invasive cancer cell. Bone metastatic cancer cells interact with and activate osteoclasts in a destructive cycle of bone degradation and stimulation of tumor cell growth. Therefore targeting Src activity would appear to be a rational therapeutic approach in treating metastatic bone disease. We have reported previously (AACR 2005) on the activity of the dual Src/Abl kinase inhibitor AZD0530 in inhibiting the bone resorptive activity of mature rabbit osteoclasts in a bone slice model. Here we tested the effect of AZD0530 in a human co-culture system, examining its activity on i) osteoclast formation by peripheral blood mononuclear cells (PBMCs) co-cultured with osteoblasts, and ii) osteoclastic bone resorption. Methods and Results: PBMC adhesion to osteoblasts and osteoblast morphology was not affected by AZD0530 (0.1–10 μM). However, AZD0530 inhibited the formation of multinucleated osteoclast-like cells dose dependently. PBMC-osteoblast co-cultures were then exposed to 1 μM AZD0530 for different time intervals. AZD0530 was most effective in inhibiting the formation of osteoclast-like cells when added at the onset of osteoclastogenesis, suggesting that Src activity is important during the initial induction of osteoclast formation. Formation of actin rings, to which c-Src co-localizes, is a prerequisite for osteoclastic bone resorption. The effect of AZD0530 on formation of actin rings was analyzed using the co-culture system on cortical bone slices. AZD0530 prevented migration of osteoclast precursors to the bone surface, and the subsequent formation of actin rings. On withdrawal of the drug, this process was reversible. Conclusions: Our data suggest that Src activity is pivotal for the formation, migration and activity of osteoclasts. Data reported elsewhere suggest AZD0530 will also impact on tumor cells directly. AZD0530 is a promising new anti-cancer drug with potential to additionally treat metastatic bone disease through its inhibition of both osteoclast activity and tumor cell invasion into and within the bone micro-environment.

No significant financial relationships to disclose.
A randomized trial of prophylactic cranial irradiation (PCI) versus no PCI in extensive disease small cell lung cancer after a response to chemotherapy (EORTC 08993–22993)
Authors: Slotman B. , Faivre-Finn C. , Kramer G. , Rankin E. , Snee M. , Hatton M. , de Schaetzen G. , Collette L. , Senan S.
Published: March 2020

4

Background: Prophylactic cranial irradiation (PCI) significantly reduces the risk of brain metastases (BM) and improves survival in patients with limited disease small cell lung cancer. Development of BM is often accompanied by deterioration of physical and psychological functioning and response to therapy is poor. Patients with extensive disease (ED SCLC) are at high risk for BM. This randomized study assesses PCI in patients with ED SCLC. Methods: Patients (18–75 years; WHO=2) with confirmed ED SCLC and any response to 4–6 cycles of chemotherapy, were randomized to receive PCI (doses ranging from 20 Gy/5 fr to 30 Gy/12 fr) or no PCI. The primary endpoint was the cumulative incidence of symptomatic BM. CT or MRI of the brain was performed whenever any of the pre-defined “key-symptoms” was present at baseline or during follow-up. The study was sized to detect a hazard ratio of 0.44 with 80% power and 2-sided 5% significance (52 events, 287 patients). Results: Between Feb ’01 and Mar ’06, 286 patients entered the trial, 76% with residual disease in the thorax and 71% at distant sites. Baseline characteristics were well balanced. Only 6% of patients in the PCI arm were not treated and 3% interrupted treatment. Acute toxicity was mild: nausea/vomiting was reported by about 30% of PCI-treated cases and about 30% reported late reactions (mostly mild headache). PCI significantly reduced the risk of symptomatic brain metastases (Gray P<0.0001, HR=0.27, CI: 0.16–0.44). The 1-year cumulative incidence of symptomatic BM was 14.6% on PCI (CI 8.3–20.9) versus 40.4% in controls (CI 32.1–48.6). PCI had no impact on extra-cranial progression rates (Gray P>0.1), but it significantly prolonged progression-free survival time (P=0.0218, HR=0.76, CI: 0.59–0.96) and overall survival (P=0.0033, HR=0.68, CI: 0.52–0.88). The 1-year survival rate was 27.1% for the PCI and 13.3% for the control arm. Conclusions: PCI significantly reduces the risk of symptomatic brain metastases, and significantly improves both disease-free and overall survival in patients with ED SCLC. PCI should be offered to all ED patients showing a response to initial chemotherapy.

No significant financial relationships to disclose.
Impact on quality of life of adding cetuximab to irinotecan in patients who have failed prior oxaliplatin-based therapy: The EPIC trial
Authors: Eng C. , Maurel J. , Scheithauer W. , Wong L. , Lutz M. , Middleton G. , Stoller R. , Zubel A. , Lu H. , Sobrero A. F.
Published: March 2020

4003

Background: EPIC, a multinational phase III clinical trial examined the impact of cetuximab on survival in pretreated EGFR- expressing metastatic colorectal (MCRC) patients (pts). Pts were randomized to either cetuximab 400 mg/m2 followed by 250 mg/m2 weekly and irinotecan 350 mg/m2 q 3 weeks or irinotecan alone. The primary endpoint was overall survival (OS) with quality of life being one of the secondary endpoints. Methods: Health Related Quality of life (HRQoL) of pts in this trial was assessed through the EORTC QLQ-C30 questionnaire, version 3.0. Pts completed the questionnaire pretreatment, every second cycle, and at first follow-up visit. HRQoL was compared between treatment arms using a Wei-Lachin test. Results: Baseline demographics were balanced between the arms. Cetuximab plus irinotecan (n=648) was superior to irinotecan alone (n=650) in progression-free survival (HR 0.69, p<.0001) and response rate (16.4 vs 4.2%, p<.0001). OS was comparable between the arms, but may have been influenced by subsequent therapy: 46% of subjects in the irinotecan alone arm received cetuximab, 89% of them in combination with irinotecan. Baseline HRQoL scores did not significantly differ between treatment arms for 11 of the 15 scales. For 4 scales (Social Functioning, Fatigue, Dyspnea, and Appetite Loss), there were statistically significant differences in baseline scores, in favor of the cetuximab plus irinotecan arm. Non- compliance rates (missing questionnaires) were similar between the arms. A statistically significant difference was noted for pts in the cetuximab plus irinotecan arm in HRQoL on 10 of the 15 scales as compared to patients in the irinotecan arm, with the scores of the cetuximab plus irinotecan arm consistently higher, as noted by the scales of Global Health Status (p=.047), pain (p< .0001), and nausea (p<.0001). Conclusions: In addition to statistically significant improvements in PFS and RR in patients receiving cetuximab plus irinotecan compared with irinotecan alone, HRQoL was better preserved on the combination arm with less deterioration in symptom scores (pain, nausea, insomnia), as well as global health status scores.

No significant financial relationships to disclose.
Ratio of metastatic to examined lymph nodes is a powerful predictor of overall survival in rectal cancer: An analysis of Intergroup 0114
Authors: Meyers M. O. , Hollis D. R. , Mayer R. J. , Benson A. B. , Goldberg R. M. , Cummings B. , Gunderson L. L. , Martenson J. A. , Macdonald J. S. , O’Connell M. , Tepper J. E.
Published: March 2020

4006

Background: Lymph node (LN) metastasis is associated with decreased survival in rectal cancer. It has been suggested that at least 14 LN be evaluated for adequate staging. However, a large percentage of patients have fewer than the recommended number of LN examined. We hypothesized that LN ratio would be predictive of overall survival in rectal cancer. Methods: Data was analyzed from Intergroup 0114, a mature trial of postoperative adjuvant chemotherapy and radiation in T3/4 and/or LN positive rectal cancer. Survival was the same for all arms allowing the entire group to be considered as one. The primary endpoint evaluated was overall survival. A proportional hazards model was used to determine the relative prognostic impact of LN ratio compared to number of LN examined, number of positive LN, number of negative LN and AJCC nodal stage. LN ratio was defined as the number of positive LN divided by the total number of LN examined. Four groups were analyzed based on proportion of positive LN: =0.25, >0.25–0.50, >0.50–0.75 and >0.75. Results: 1,648 patients were evaluable. There were 251 T1/2, 1,251 T3 and 146 T4 tumors. 513 patients were N0, 743 N1 and 392 N2. Median number of LN was 9. LN ratio was predictive of 5-year overall survival with rates of 0.71, 0.56, 0.50 and 0.43 respectively when analyzed by quartile (p<0.0001). LN ratio remained significant when overall survival was analyzed by number of LN examined and grouped into <10, <15 and >15 nodes evaluated (p<0.0001 for all). LN ratio also predicted overall survival in N1 (p=0.04) and N2 (p=0.0002) disease. When comparing LN ratio (χ2=79.5, p<0.0001) to number of LN examined (χ2=4.7, p=0.03), number of positive LN (χ2=38, p<0.0001), number of negative LN (χ2=32, p<0.0001) and AJCC nodal stage (χ2=55.5, p<0.0001), LN ratio appears to be the strongest predictor of overall survival. Conclusion: LN ratio predicts overall survival in patients with resected rectal cancer. Importantly, this is true in patients who have had a small number of LN evaluated, in addition to those with a large number of LN examined. LN ratio also appears to be a stronger predictor of overall survival than other described LN prognostic factors. LN ratio may be a useful variable to stratify outcome in patients with node-positive rectal cancer.

No significant financial relationships to disclose.
Assessing 12 or more lymph nodes increases the proportion of stage III disease in colorectal cancer (CRC): Evidence from the Surveillance, Epidemiology and End Results (SEER) cancer registry
Authors: Cai Q. , Sullivan P. A. , Yeh Y. , Russell M.
Published: March 2020

4016

Background: NCCN guidelines (2001) recommend assessment of ≥12 lymph nodes (LN) to improve accuracy of CRC staging. The impact of aggressive LN sampling on CRC staging has not been explored rigorously to date. This study examines variations in CRC staging by number of LN assessed. Methods: 299,242 patients from SEER aged ≥18 years diagnosed with CRC during 1990–2003 were included. Multivariate logistic regression was used to assess the association between sampling ≥12 LN (vs. <12) and staging, adjusting for age, sex, race, region, tumor size and grade, and year of SEER entry. Results: Patients who had ≥12 LN sampled were 1.3 times more likely to be diagnosed with stage III than stage II CRC [95% CI 1.28–1.34, p< .01]. The odds of being staged as III versus II increased over time [OR=1.01, 95% CI 1.01–1.02, p< .01]. However, the introduction of the NCCN guidelines was not associated with nodal sampling. Conclusion: The proportion of CRC patients who received appropriate sampling with most recent data available is unacceptably low. The significant increase in stage III patients who had ≥12 LN sampled may increase the proportion of patients considered for aggressive treatments. Because accuracy of staging is improved with nodal sampling, clinicians will be better positioned to treat patients if LN sampling recommendations are followed.

[Table: see text]

[Table: see text]
Outcomes in white (W) patients (pts) and those of African (A) descent receiving adjuvant therapy for colon cancer (CC)
Authors: Yothers G. , Blackstock W. , Wolmark N. , Goldberg R. M. , O’Connell M. J. , Benedetti J. , Dignam J. , Sargent D. J.
Published: March 2020

4017

Background: Published reports suggest that CC pts of A descent have inferior survival compared to W pts. Whether these differences are explained by clinical factors at diagnosis, socioeconomic factors impacting access to care, or intrinsic differences in the biology of the tumors or the response to therapy is unclear. Pts in clinical trials have data collected for important baseline clinical factors and should receive comparable oncologic care regardless of socioeconomic factors. Methods: We analyzed data from 13,435 individual pts on 11 phase III adjuvant CC trials accrued from 1977 to 2002. Analysis was restricted to stage II and III pts, with race reported as black or white. Endpoints were overall survival (OS - time to death), recurrence-free survival (RFS - time to recurrence or death), and recurrence-free interval (RFI - time to recurrence censoring for death). Cox models stratified by study controlled for gender, stage, age, and treatment type (rx) to determine the effect of race. Kaplan-Meier estimates (KM) were adjusted (adj) by the Xie-Liu method for study, gender, stage, age, and rx. Results: A pts (n=1134, 8.4%) were younger than W (median 58 vs 61, p<0.001) and more likely female (55 vs 45%, p<0.001). A pts had poorer OS than W pts ( table ). OS results were consistent in subsets defined by gender, stage, and age. RFS results were attenuated compared to OS, but still favored improved RFS in W pts ( table ). RFI results were further attenuated and not significantly different by race ( table ). Conclusions: Even with identical rx for CC in controlled clinical trials, A pts have poorer OS and RFS than W pts. The OS deficit was consistent across subgroups, and neither deficit was explained by differences in gender, stage, age, or rx. RFI was similar for both races, suggesting that the OS and RFS differences may be largely due to deaths unrelated to CC.

[Table: see text]

[Table: see text]
Tissue biomarkers (BIOM) in colon cancer (COC): The translational study on the randomized phase III trial comparing infused irinotecan/5-fluorouracil (5-FU)/folinic acid (FA) to 5-FU/FA in stage II-III COC patients (pts)
Authors: Roth A. D. , Tejpar S. , Yan P. , Fiocca R. , Dietrich D. , Bodoky G. , Labianca R. , Cunningham D. , Van Cutsem E. , Bosman F.
Published: March 2020

4022

Background and Aims: PETACC 3 is a large adjuvant trial with 3,005 COC pts. The value of BIOM in COC in adjuvant setting is still a matter of debate because of lack of large data sets. We took advantage of PETACC 3 to assess P53, SMAD4, thymidylate synthetase (TS), telomerase (HTERT) expressions, UGT1A1 genotype, KRAS and BRAF mutations, microsatellite instability (MSI), 18q and 8p LOH with regard to their prognostic and predictive value and their individual interactions on a very large homogeneous cohort of COC pts. In addition we investigated the association between UGT1A1 genotype and occurrence of diarrhoea and Gd 4 neutropenia. Methods: 1,564 formalin fixed paraffin embedded (FFPE) tissue blocks of PETACC 3 pts were prospectively collected and 5–20μ sections cut. DNA from normal (Nor) and tumoral (Tu) tissue was extracted after section microdissection. P53, SMAD4, TS and HTERT were assessed by immunohistochemistry (IHC); MSI was typed with 10 markers, KRAS exon 2 and BRAF exon 15 mutations by allele specific real time PCR on Tu DNA; 18q and 8p LOH by typing multiple SNPs by pyrosequencing on Nor/Tu DNA; UGT1A1 genotypes by PCR and fragment sizing on Nor DNA. Prognostic/predictive value of each BIOM is analysed by Cox regression for disease free survival and by logistic regression for specific toxicity. Associations between any 2 categorized BIOM and between each BIOM and each known prognostic variable are tested by chi-square tests. Results: DNA of 1405 pts was extracted and successfully analyzed in 97.1% for KRAS, 98.6% for BRAF, 94% for 18q LOH, 93.6% for MSI, 86% for UGT1A1, 8p LOH is still ongoing. Of 1530 pts slides IHC analysis was successful in 94.5% for P53, 94.2% for SMAD4, 82.9% for TS, 53.9% for HTERT. The clinical database was made available in Nov 06 and statistical analysis started on Dec 11th 2006. Conclusion: This is the largest multicenter centrally coordinated tissue BIOM study performed in COC to date. The high success rate of analysis shows that large prospective BIOM studies can be performed on routine FFPE material. Final results on the prognostic/predictive value of each molecular BIOM will be available at the meeting.

No significant financial relationships to disclose.
A prospective study of oxaliplatin and capecitabine (CapOx) in metastatic colorectal cancer (MCRC) with baseline stratification according to resectability status
Authors: Watkins D. J. , Jackson C. , Chua Y. , Chong G. , Norman A. R. , Brown G. , Mudan S. , Karanjia N. , Cunningham D.
Published: March 2020

4024

Background: Consideration of metastasectomy is now standard practice in the management of selected patients (pts) with stage IV MCRC. As a result, modification to the current staging system has been suggested to more clearly define subgroups of stage IV pts. As yet, there are no prospective data comparing the outcomes of pts according to resectability status. This phase II study evaluates the outcomes of pts according to baseline resectability status, and examines the utility of CapOx chemotherapy as a neoadjuvant treatment strategy. Methods: Eligible pts had received no prior chemotherapy for MCRC. At study entry imaging review was undertaken and pts stratified into 3 groups according to resectability status; non-resectable (group 1), potentially resectable liver disease (group 2), resectable liver disease (group 3). All pts received identical chemotherapy; capecitabine 2,000mg/m2 d1–14 and oxaliplatin 130mg/m2 d 1 repeated every 3 weeks. Repeat imaging was undertaken every 4 cycles. For pts in groups 2 & 3, all imaging was reviewed by a specialist hepatic MDT, where feasible metastasectomy was undertaken following 4 or 8 cycles of chemotherapy. Planned enrolment was 130 pts, with study endpoints including; response rate, PFS & OS. Results: 129 pts are enrolled. Median age 62 (range 29–78). Median number of cycles delivered 8 (range 1–12). Grade III/IV toxicities; diarrhoea 14%, neutropenia 7.8%, peripheral neuropathy 2%. 60 day all cause mortality 3.1%. There have been no post operative deaths following liver resection. Median follow up is 19.3 months. Outcome data for each group is summarised below. Conclusion: CapOx chemotherapy is safe and well tolerated when used as a neoadjuvant treatment strategy. This prospective study clearly demonstrates the wide variation in outcomes according to baseline resectability status, and highlights the need for modification to the staging system to account for these patient subgroups in future studies.

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XELOX compared to FOLFOX4: Survival and response results from XELOX-1/ NO16966, a randomized phase III trial of first-line treatment for patients with metastatic colorectal cancer (MCRC)
Authors: Cassidy J. , Clarke S. , Diaz-Rubio E. , Scheithauer W. , Figer A. , Wong R. , Koski S. , Lichinitser M. , Yang T. , Saltz L.
Published: March 2020

4030

Background: In a phase II study in untreated MCRC patients, XELOX (capecitabine + oxaliplatin) appeared to have similar efficacy compared with previously published FOLFOX4 data [1]. We therefore started a phase III 2-arm open-label non-inferiority study comparing XELOX with FOLFOX4. In 2003 the addition of bevacizumab (Bev) to irinotecan/5-FU/LV was shown to improve progression-free survival (PFS) and overall survival [2]. We then amended our trial to a 2x2 partially blinded study to assess the addition of Bev. Methods: Original 2-arm study: XELOX (oxaliplatin 130 mg/m2 iv, capecitabine 1,000 mg/m2 bid oral d1- 14, q3w) vs. FOLFOX4 (oxaliplatin, 5-FU, leucovorin as described previously) [3]. In August 2003, amended to 2x2 partially blinded study: by adding Bev 7.5 mg/kg iv q3w or placebo (Pla) to XELOX and Bev 5 mg/kg iv q2w or Pla to FOLFOX4. Results: The original 2-arm study recruited 634 pts; after transition to 2x2, an additional 1400 patients were recruited. We previously reported non-inferiority in terms of PFS of XELOX vs. FOLFOX4 for the whole study population [4]. With 404 events, the overall survival data from the original 2-arm study are mature and show a HR for XELOX vs. FOLFOX4 of 0.93 (97.5% CI, 0.74–1.16). The response rates by investigator and independent review for the whole study population are shown in the table . Conclusions: XELOX is non-inferior to FOLFOX4. Overall survival data for the whole 2034 patient study population will be presented at the meeting. *no response assessment. 1. Cassidy J et al. J Clin Oncol 2004;22:2084–91. 2. Hurwitz H et al. N Eng J Med 2004;350:2335–42 3. De Gramont A et al. J Clin Oncol 2000;18:2938–47. 4. Cassidy J et al. Ann Oncol 2006;17(Suppl. 9):LBA3.

[Table: see text]

[Table: see text]
Comparable safety and response rate with bevacizumab in combination with capecitabine/oxaliplatin (CapOx/Bev) versus capecitabine/irinotecan (CapIri/Bev) in advanced CRC (mCRC): A randomized phase II study of the AIO GI tumor study group
Authors: Schmiegel W. H. , Reinacher-Schick A. , Freier W. , Dietrich G. , Arnold D. , Kanzler S. , Geissler M. , Graeven U. , Hegewisch-Becker S. , Schmoll H.
Published: March 2020

4034

Background: Bevacizumab (Bev) combined with 5-FU/FA and both, irinotecan or oxaliplatin are standard regimens for mCRC. Recently, a phase III trial has demonstrated that infusional 5-FU can be substituted by capecitabine (cape) when combined with oxaliplatin and Bev whereas conflicting data are available for feasibility and efficacy of cape/irinotecan combinations. This randomized phase II trial was to compare safety and efficacy of Bev with either CapOx or CapIri in untreated mCRC. Methods: Eligibility criteria: untreated mCRC pts, ECOG PS <= 2, measurable lesion(s), adequate hematologic and organ function. Primary endpoint was % of pts progression-free after 6 months. Treatment plan: Bev 7.5 mg/kg day (d)1 with either oxaliplatin (130 mg/m2 d1)/cape (1,000 mg/m2 bid d1–14; CapOx/Bev, arm A) or irinotecan (200 mg/m2 d1)/cape (800 mg/m2 bid d 1–14; CapIri/Bev, arm B), all q d22. Arm B doses were 20% lower for both, cape and irinotecan, compared to previous trials reporting an unacceptable toxicity profile (Köhne, ASCO 2005). Treatment was continued until progression or unacceptable toxicity. Results: So far, toxicity data are available on 228 (118/110 pts arm A/B) of total 240 pts. Baseline characteristics (arm A/B): median age 64/65 yrs, male 67%/68%. A total of 684/719 cycles (median 6/6 cycles) have been administered. Most common CTC grade 3/4 toxicities (% of pts): Diarrhea 17.0/15.5, hand-foot-syndrome 5.9/2.7, peripheral neuropathy 15.3/0.0. Specific AE′s such as thrombosis, 3° hypertension and GI perforation occurred in 3.4/4.5%, 3.4/0.9% and 0.9/0.9% of pts, respectively. Among 185 evaluable pts (96/89), tumor control rates (CR+PR+SD) in arm A/B were 81.4%/82.8%, overall response rates (CR+PR) were 49.0%/52.7%. Conclusions: Both regimens, CapOx/Bev and CapIri/Bev, are well tolerated without differences in toxicity (except neuropathy). Interestingly, despite the protocol defined dose reduction of CapIri there is seemingly no difference in efficacy as measured by tumor control and response rate. Meanwhile, the trial has finished accrual and data including PFS rate will be presented at the meeting.

[Table: see text]
Adjuvant chemotherapy with uracil-tegafur (UFT) for stage III colorectal cancer: Final results of randomized trials by the National Surgical Adjuvant Study of Colorectal Cancer (NSAS-CC)
Authors: Hamaguchi T. , Shirao K. , Moriya Y. , Yoshida S. , Kodaira S. , Ohashi Y.
Published: March 2020

4049

Background: In the latter 1990s, no consensus was reached as to whether adjuvant chemotherapy was standard treatment for completely resected stage III colorectal cancer in Japan. At that time, we started two randomized controlled trials to clarify the role of adjuvant chemotherapy of stage III colon and rectal cancer in the same time. Methods: Patients with completely resected stage III cancer of the colon or rectum (PS, 0 to 2; age, 20 to 75 years; no other adjuvant therapy) were eligible for these trials. Patients were registered within 6 weeks after surgery and were randomly assigned to receive surgery alone (control group) or surgery followed by treatment with UFT (400 mg/m2/day), given for 5 consecutive days per week for 1 year (UFT group). The target number of patients was 500 for colon cancer and 400 for rectal cancer (hazard ratio = 0.67, one-sided a= 0.05, β= 0.2). The primary endpoint was relapse-free survival (RFS), and the secondary end point was overall survival (OS). Results: Between October 1996 and April 2001, a total of 334 patients with colon cancer and 276 with rectal cancer were enrolled. Four ineligible patients were excluded; data from the remaining 332 patients with colon cancer and 274 with rectal cancer were analyzed. The patients’ characteristics were similar in the groups. Analysis of the results of follow-up until March 2006, at least 5 years after surgery in all patients (median follow-up period, 6.2 years), showed no significant difference in RFS or OS in colon cancer. In rectal cancer, however, RFS and OS were significantly better in the UFT group than in the control group. The only grade 4 toxicity was diarrhea, occurring in 1 patient with colon cancer and 1 patient with rectal cancer. Conclusions: Postoperative adjuvant chemotherapy with UFT is well tolerated and improved RFS and OS in patients with stage III rectal cancer. In colon cancer, the expected benefits were not obtained (hazard ratio = 0.67). [Table: see text]

No significant financial relationships to disclose.
Adherence to surveillance guidelines following curative resection for stage II and III colorectal cancer
Authors: Cheung W. Y. , Pond G. R. , Rother M. , Krzyzanowska M. , Brierley J. , Swallow C. , Kaizer L. , Myers J. , Phillips S. , Siu L. L.
Published: March 2020

4051

Background: The risk of disease recurrence in stage II and III colorectal cancer (CRC) patients (pts) following curative resection underscores the need for post-operative surveillance. However, there is continual controversy as to whether an intensive or conservative strategy is more appropriate. Our aims were to determine adherence in the ‘real world‘ to ASCO guidelines on CRC surveillance and to evaluate differences in practice patterns and outcomes between an academic instituation, Princess Margaret Hospital (PMH), and a community cancer center, Credit Valley Hospital (CVH). Methods: Stage II and III CRC pts diagnosed between 1999 and 2001 were identified from hospital cancer registries. Surveillance practices and outcomes in the first 5 years of follow-up were retrospectively reviewed. Results: A total of 244 and 97 pts were identified at PMH and CVH, respectively: 80 stage II and 119 stage III colon cancers (CC), and 66 stage II and 76 stage III rectal cancers (RC). Median age at diagnosis was 61.8 years. Surveillance patterns over a 5-year period, adherence to ASCO guidelines and comparisons between hospitals were tabulated (see table ). There were a total of 70 CRC recurrences: 53/244 (22%) at PMH and 17/97 (18%) at CVH. Among them, 53 (76%) were detected by surveillance (44 PMH, 9 CVH) and 17 (24%) by symptoms (9 PMH, 8 CVH). For recurrences detected by surveillance, 20/53 (38%) were resectable, whereas only 3/17 (18%) of those detected by symptoms were resectable. Of the 20 resectable recurrences detected by surveillance, 40% were CC and 60% were RC; CT scan was the method of detection in 55% of cases, and sites of recurrence included liver (7), lung (6), local (5), and nodes (2). Conclusions: CRC surveillance revealed significant departures from ASCO guidelines with a large academic institution employing a more intensive surveillance strategy with imaging than a community cancer center. Surveillance was associated with a higher proportion of resectable tumor recurrences than detection by symptoms.

[Table: see text]

No significant financial relationships to disclose.
Impact of timing of initiation of adjuvant chemotherapy on survival after resection of colorectal cancer
Authors: Ahmad I. , Anan G. , Alvi R. , Haider K. , Sami A. , Yadav S. , Arnold F. , McLeann L. , Popkin S. , Ahmed S.
Published: March 2020

4054

Background: Based on the results of intergroup trials, adjuvant chemotherapy has become the standard of care for patients with Duke stage C colon and Duke stages B and C rectal cancer. Although initiation of adjuvant chemotherapy soon after recovery from surgery is desirable, only few studies have examined whether a delay in starting adjuvant chemotherapy affect clinical outcomes. Our objective in this study is to determine the impact of timing of adjuvant chemotherapy on survival after resection of Duke stage C colon and Duke stages B and C rectal cancer. Methods: Study involves use of the information available from patients chart review in the province of Saskatchewan, Canada. Patients 18 years of age and older (median age 66 years), diagnosed with Duke Stage C colon and Duke stages B and C rectal cancer between 1993 and 2000 were included. Median followup was 54.8 months. All patients with rectal cancer received radiation treatment as per institution policy. Cox proportional hazards models were used to analyze the impact of timing of adjuvant chemotherapy on survival. Results: Among 701 patients eligible for study, 453 (64.6%) patients received adjuvant chemotherapy within 56 days of surgery (group I) and 248 patients (35.3 %) received adjuvant chemotherapy after 56 days of surgery (group II). Median time interval between surgery and the initiation of adjuvant chemotherapy in group I, and II were 41 days and 70 days respectively. Five year DFS for group I was 39% as compared to 37% for group II (HR 0.94, CI 0.76–1.16, p = 0.58). Median OS for group I was 97.5 months as compared to 68.9 months (HR 1.08, CI 0.85–1.37, p= 0.54). Age, histology and number of lymph nodes analyzed, were identified as independent prognostic factors in multivariate analysis. Conclusions: In this study, patients with Duke stage C colon and Duke stages B and C rectal cancer who received adjuvant chemotherapy within 56 days of resection has similar outcomes as compared to patients who received adjuvant chemotherapy after 56 days of resection.

[Table: see text]