bluuebunny/crossref_metadata_2025 huggingface dataset:
Implications of HER family inhibition in targeted therapy of ovarian cancer
Authors: Bull S. L. , Schorge J. O. , Peyton M. J. , Xiang L. , Miller D. S. , Minna J. D. , Lea J. S.
Published: March 2020

13120

Background: The human epidermal receptor (HER) family couples binding of extracellular ligands to intracellular tyrosine kinase (TK) signal transduction pathways, contributing to cellular proliferation. Overexpression of HER family members has been associated with poor prognosis in ovarian cancer. There is growing evidence to support that none of the individual HER members can be considered as the stand-alone target in ovarian cancer and that cooperation between them influences therapeutic response. To evaluate this receptor cooperation in ovarian cancer our goal was to determine HER family expression and to quantify inhibition of HER1 alone compared to inhibition of HER1/HER2 combined. Methods: HER1, HER2, HER3 and HER4 expression was determined by Western blot in 9 ovarian cancer cell lines. Ovarian cancer cell proliferation was determined after inhibition of HER1 using the monoclonal antibody cetuximab, the TK inhibitor gefitinib, or combination of the two. To quantify the combined inhibition of HER1/HER2, 3 cell lines were selected with variable HER1 and HER2 expression. Cell proliferation was then determined in these 3 cell lines after treatment with cetuximab combined with the monoclonal HER2 antibody, trastuzumab. IC50 values were calculated for all treatment arms and compared. A lung cancer cell line (HCC827), with a HER1 TK mutation and sensitivity to gefitinib and cetuximab, was used as a positive control. Results: HER1 was overexpressed in 3/9 ovarian cancer cell lines, HER2 in 1/9, HER3 in 2/9, and HER4 in 4/9. Minimal to no growth inhibition was seen in the 9 cell lines after blocking HER1 with cetuximab, gefitinib, or the combination of both. In the 3 cell lines selected for HER1 and HER2 expression, there was no growth inhibition achieved despite combining cetuximab with trastuzumab. However, this treatment combination increased resistance in 1 of the 3 cell lines (HCC60), noted to overexpress HER1, 2, and 4. Conclusions: Ovarian cancer has variable HER family expression. No correlation was found between HER1 and HER2 overexpression and response to their targeted inhibition. Our findings support the concept the entire HER family plays a role in ovarian cancer growth and suggest an equilibrium shift of HER heterodimerization may play an important role in maintaining cell signaling.

No significant financial relationships to disclose.
Investigation of peptomimetics of GD2 antibodies as targeted therapy against human small cell lung cancer in-vitro
Authors: Wan J. , Saragovi H. U. , Conway H. , Ivanisevic L.
Published: March 2020

13128

Background: GD2 is a well-established target that has been validated for neuroblastoma and small cell lung cancer. The therapeutic and diagnostic use of monoclonal antibodies directed to GD2 in small cell lung cancer is well documented. It has been shown that the binding of GD2 monoclonal antibodies alone can induce growth suppression and cell death of small cell lung cancer cells in-vitro. Our laboratory has developed synthetic small molecule peptomimetics as ligands of GD2. Peptomimetics have favorable in-vivo pharmacological properties compared to antibodies with no immunogenicity, longer half-lives, low toxicity, good tissue penetration, biodistribution and high target selectivity. This study proposed to determine the efficacy of peptomimetics of GD2 antibodies against small cell lung cancer cells in-vitro. Methods: 2 human cell lines were studied. H69 is a classic small cell lung cancer and H82 is a morphological variant small cell lung cancer both of which have been reported in the literature to express GD2. Cell surface expression of ganglioside GD2 was analyzed by flow cytometry (FACScan, BD Biosciences) using GD2 mAB 3F8 and GD2 mAB ME361. Cell proliferation was assessed using standard MTT assays with serum containing medium and cultured for approximately 3 doubling times for each cell line. The cell lines were exposed to increasing doses of GD2 specific peptomimetic to a maximum of 25 uM with controls including serum containing media with and without a GD2 negative peptomimetic and assessed for cell proliferation. Results: GD2 expression was confirmed for both cell lines- H69 and H82 using FACs. Exposure of the GD2 specific peptomimetic clearly caused growth suppression on the range of 35–40% when compared to controls. A dose response relationship was demonstrated with a plateau beyond 10 uM concentrations. Each experiment repeated ≥ 3 occasions. Conclusions: We have shown that attachment of GD2 specific peptomimetics can cause decreased cell proliferation in 2 small cell lung cancer cell lines H69 and H82. We have shown that there is a dose response relationship by which these compounds reduce cell viability. Peptomimetics of GD2 antibodies show promise as a targeted therapy for small cell lung cancer in-vitro and warrant further study.

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The addition of prednisone (Pr) to the combination of docetaxel (T) and perifosine (P) decreases the severity of gastrointestinal (GI) toxicity
Authors: Bernhardt B. , Nemunaitis J. J. , Ebrahimi B. , Cervera A. , Birch R. , Richards D. A. , Smith G. B. , Allerton J. P. , Henderson I. C.
Published: March 2020

13142

Background: Miltefosine (M) is an alkophosholipid with activity as a topical treatment for cutaneous breast cancer lesions. Severe GI toxicity limited its development as a systemic anticancer treatment. P is an equipotent derivative of M with less GI toxicity, but nausea,(N), vomiting (V) & diarrhea (D) are still dose limiting. Methods: This phase 1 study evaluated whether the addition of Pr would enhance the tolerability of P & T in combination. Twenty-five patients (pts) were enrolled. The dose of T was 75 mg/m2 on day 8 of a 21 day cycle and half of the pts were randomized to also receive Pr, 5 mg bid. 50 mg of P was given orally 1, 2 or 3 times a day in successive cohorts on days 1 - 14 of each cycle. Results: Disease sites included lung 9, prostate 7, pancreas 3, ovary 2, breast 1 and other 4. The median age was 63 (range 41 - 80). 18 pts were male & median ECOG performance status was 1 (range 0–2). 22 pts had received a median of 2 prior chemotherapy regimens, 15 a prior taxane and 16 prior radiotherapy. Forty-two cycles of T+P were given without Pr (median 3 & range 1 - 18 per pt) and 84 cycles were given with Pr (median 4.5 cycles & range 1 - 17 per pt). The percentage of pts experiencing various grades (Gr) of N, V & D without and with prednisone are shown in the table below: Five of 12 pts not receiving Pr had gr 2 or 3 toxicities compared to 1 of 13 given Pr. (p<0.05) There were 7 pts evaluable for response not receiving Pr of whom 2 patients with prostate cancer had stable disease for 4+ and 10+ months. There were 9 evaluable pts receiving Pr; 3 partial responses (1 lung & 2, prostate pts) were seen and 1 prostate cancer was stable for 10 months. Patients given prednisone increased their average time on treatment by 50%, and this might be the reason that more responses were seen in this group. Conclusions: These data show that Pr decreases the severity of GI toxicity seen with T & P together and provide a rationale for further studies evaluating the effects of Pr on the toxicities of P either alone or in combination with other drugs.

[Table: see text]

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Effect of pan-inhibitory somatostatin analogues, topotecan and bortezomib on the human enterochromaffin neoplastic cell line KRJ-I
Authors: Kidd M. , Eick G. , Pfragner R. , Murren J. , Culler M. , Modlin I. M.
Published: March 2020

13144

Background: Effective therapeutic options to inhibit the growth and limit the spread of carcinoid tumors are limited. Somatostatin (SST) analogs that target specific SST receptors, though often effective at alleviating the symptoms of carcinoid disease, have limited cytostatic effects on carcinoid tumor cells. The anti-proliferative activity of 2 pan-inhibitory SST analogues and lanreotide were evaluated using the human small intestinal carcinoid cell line KRJ-I. The effects of novel cytotoxic agents used in Phase II carcinoid clinical trials, topotecan (topoisomerase-I inhibitor) and bortezomib (proteasomal inhibitor), were also measured. Methods: The SST receptor profile of KRJ-1 cells was determined using hybridization to U133A chips and confirmed by real time PCR with Taqman probes for SSTR1–5. KRJ-1 cells in serum-free medium were treated with 100 pM to 10 μM of the SST pan inhibitory analogs, BIM-23A719 and BIM-23A779, or lanreotide (BIM-23014C) and 1nM to 1 μM of topotecan or bortezomib for 72 hrs. The 3-(4,5-dimethylthiazole-2 yl)-2,5 diphenyltetrazolium bromide (MTT) assay was used to evaluate proliferation which was expressed relative to control cells (no agent added). Results: KRJ-I cells co-express mRNA for SSTR2 and SSTR3 (mean levels ± SEM 0.48 ± 0.13 and 0.73 ± 0.19 copy/copy GAPDH respectively). BIM-23A719 inhibited growth maximally (15 ± 2% of control) at ICmax = 10 pM, whereas BIM-23A779 inhibited growth maximally (11 ± 1% of control) at 100 pM. Lanreotide had no significant inhibitory effect on cell growth and resulted in increased MTT conversion at high concentrations (10 μM). Topotecan and bortezomib inhibited growth maximally at 23 ± 1.5%; ICmax = 50 nM and 32 ± 1.6%; ICmax = 50 nM respectively. Conclusions: Cytotoxic agents are more effective but less sensitive than pan-inhibitory somatostatin analogues for the inhibition of proliferation of the small intestinal carcinoid KRJ-I cell line. The specific SSTR2/3/5 analogue, lanreotide, had no inhibitory effect on KRJ-I proliferation. These results suggest that the KRJ-I cell line is more sensitive to analogues targeting a pan-somatostatin receptor profile than cytotoxic agents. The former may have potential as adjuvant agents for treatment of GI carcinoid tumors.

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Prolonged response to oral gefitinib, topotecan and cyclophosphamide in relapsed/resistant pediatric tumors
Authors: Donfrancesco A.
Published: March 2020

13165

Background: Continuous schedule oral chemotherapy might be a suitable approach for resistant/relapsed pediatric tumors. Gefitinib (G) is an Epidermal Growth Factor Receptor (EGFR, HER1) inhibitor with documented activity in phase I/II adult tumor studies harboring activating mutations in the EGFR gene. Oral topotecan (TPT) and cyclophosphamide (CPM) in association have shown activity in a recent phase I study in pediatric patients (pts). Our study was aimed at evaluating the feasibility of a regimen based on oral G combined with oral TPT and CPM in pretreated pediatric pts. Methods: Pts received oral CPM (50 mg/m2/day) followed by TPT (0.8 mg/m2/day) plus G at the fixed dose of 250 mg/day for 14 consecutive days in an outpatient setting. Courses were repeated every 28 days and response was evaluated every two courses. EGFR mRNA expression in primary tumors was assessed by RT-PCR. Results: 7 pts (5M/2F), median age 8.7 years (range 4.4–22.5) were enrolled: 4 neuroblastoma (NB) pts relapsed after PBSCT and 3 sarcoma pts (1 rhabdomyosarcoma and 2 synovial sarcomas). 5 pts had PD at the time of inclusion, while 2 pts had SD after salvage therapy. Variable levels of EGFR mRNA were detected in 6/7 tumors, the only negative case being the rhabdomyosarcoma. A median of 6 courses (range 1–14) were administered. After a median follow-up of 7 months (range 3–15), 3 pts are DOD (1, 3, 8 months) and 4 pts are alive: 1 with PD, 2 with SD and 1 with CR at 13+, 7+, 7+ and 15+ months since inclusion, respectively. Median PFS was 7 months (range 1–15). Toxicity was mainly hematological (neutropenia), grade 4 according to CTC in 3/7 pts; cutaneous (rash) grade 2 and hepatic (LFT increase) grade 3 toxicity was reported in 1 pt each. 2 episodes of neutropenic fever (1 sepsis) were recorded. Conclusions: This regimen was feasible and well tolerated; a median PFS of 7+ months is encouraging and deserves further evaluation. Of the 4 NB pts, 2 are progression free at 7+ and 15+ months since inclusion (9 and 22 months after relapse). If the preliminary results reported in NB pts will be confirmed, this oral chemotherapy could be evaluated in the setting of minimal residual disease after megatherapy.

No significant financial relationships to disclose.
A phase I study of triapine in combination with doxorubicin in refractory tumors
Authors: Chang J. E. , Morgan Meadows S. , Traynor A. , Kolesar J. , Marnocha R. , Lee F. , Eickoff J. , Beth E. , Binger K. , Wilding G.
Published: March 2020

13168

Background: Triapine (T) is a novel ribonucleotide reductase inhibitor, affecting the M2 subunit. It has in vitro and in vivo antitumor activity. Hematologic toxicity was dose limiting in single agent phase I trials. Triapine potentiates the activity of DNA damaging agents such as doxorubicin (D), with synergy demonstrated in vivo. Methods: D was administered on day 1 and T was administered on days 1–4 of a 21-day cycle. Patients enrolled in cohorts of three, beginning at D60 mg/m2 and T25 mg/m2. Dose limiting toxicity was defined as grade 3 or 4 leukopenia or thrombocytopenia lasting 7 days, febrile neutropenia or grade 3 or 4 non-hematologic toxicity. Results: Fourteen patients have enrolled in four dose cohorts, receiving 23 courses. At dose level 2 (D60 mg/m2, T45 mg/m2), two patients experienced DLT (febrile neutropenia, grade 4 thrombocytopenia). An additional 3 patients enrolled at dose level one without initial toxicity. Enrollment then resumed at dose level 2a with a decreased dose of doxorubicin (D45 mg/m2, T45 mg/m2). Two patients enrolled on this level had DLT. Enrollment was planned to resume at dose level 1 (D60 mg/m2, T25 mg/m2); however, the sixth patient enrolled to this cohort developed grade 5 heart failure (ejection fraction 20%, pretreatment EF 62%) after the second course. Enrollment has begun at doses of D45 mg/m2 and T25 mg/m2. Hematologic toxicity has predominated, with 52% of courses having grade 3 or 4 neutropenia. Non-hematologic toxicity included grade 2 fatigue in 17% of courses and 1 episode of grade 5 heart failure. Although no objective antitumor responses have been seen, 1 patient with metastatic melanoma had stable disease through 6 cycles of treatment. Another patient with previously rapidly progressive metastatic melanoma had stable disease for over 2 months of treatment. Conclusions: The combination of triapine and doxorubicin appears to have increased toxicity. Enrollment continues.

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Downregulation of PLK1 elevates chemosensitivity of various breast cancer cell lines in vitro and in vivo
Authors: Spaenkuch B. , Heim S. , Kurunci-Csacsko E. , Lindenau C. , Kaufmann M. , Strebhardt K.
Published: March 2020

13169

Background: A central role for polo-like kinases (PLK) in regulating mitosis has been shown in different species. Overexpression of PLK1 is observed in various human tumors, and it is a negative prognostic factor in patients suffering from diverse cancers. In order to reduce side-effects exerted by commonly used anti-neoplastic agents and to enhance chemosensitivity of different breast cancer cell lines, we used phosphorothioate antisense oligonucleotides (ASOs) targeted against PLK1 together with Paclitaxel, Carboplatin and Herceptin. Methods: We used different HER2-positive and -negative breast cancer cell lines (BT-474, MCF-7, MDA-MB-435) to define the role of reduced PLK1 expression for the necessary dose of anti-neoplastic agents. After transfection with PLK1-specific ASOs these agents were added and cell proliferation, cell cycle distribution, and apoptosis were measured. Results: We observed synergistic effects after combination of very low doses of PLK1-specific ASOs with Paclitaxel and Herceptin. Using Carboplatin we could only observe a synergistic effect in MDA-MB-435 cells. Downregulation of PLK1 levels led to an elevated percentage of cells in G2/M. Apoptosis and G2/M arrest were increased after combination of PLK1-specific ASOs with Paclitaxel in MDA-MB-435 cells. In a human Xenograft experiment using MDA-MB-435 cells the combination of PLK1-ASOs with Paclitaxel led to synergistic reduction of tumor growth after three weeks treatment compared to either agent alone. Conclusion: This study suggests that antisense inhibitors against PLK1 at well tolerated doses may be considered as cancer therapeutic agents which elevate chemosensitivity especially against Paclitaxel in very low doses with a significant better outcome than each agent alone.

No significant financial relationships to disclose.
Metastatic Colorectal Cancer Treatment to progression or Not?
Authors: Melosky B. , Lohrisch C. , Kollmansberger C. , Gill S. , Kennecke H. , Shah A. , Coldman A. , Phillips N. , Lim H.
Published: March 2020

13511

Background: Treatment until progression or planned interruption of first line chemotherapy is common in the therapy for metastatic colorectal cancer and are upon the discretion of the oncologist. A retrospective analysis was performed to determine the impact of these differing therapeutic strategies on overall survival. Methods: Eligible patients were treated between 2002 to 2004 in British Columbia. All patients received chemotherapy with both FOLFOX and FOLFIRI, either first or second line. Records were retrospectively reviewed for treatment interruption, efficacy and toxicity. Overall survival was the primary endpoint. Results: 101 patients were identified. Twenty-three patients who progressed before receiving 8 cycles of chemotherapy and 9 patients who stopped their chemotherapy due to toxicity were excluded. The remaining patients were analyzed for survival. Twenty-three patients were treated to progression of whom 6 received first line FOLFIRI and 17 received first line FOLFOX. The mean number of cycles of first line therapy was was 11.5. Forty six patients received a planned break. Of these, 21pateints received first line FOLFIRI and 25 patients received first line FOLFOX. Mean number of cycles of first line therapy was 9.7. Median survival of patients treated to progression was 16 months compared to 22 months for patients with planned break of therapy (p=0.003). The Hazard ratio was 2.3 (p=0.01) in favor of patients who had a planned break. Uni-variate and multivariate analysis showed no significance of sex, age, site (colon versus rectal), sequence and ECOG status as predictive factors. Conclusion: In this study, patients who were treated until progression with first line chemotherapy with either FOLFOX or FOLFIRI had an inferior survival. Possible explanations for the detrimental hazard ratio for patients treated to progression are decreasing reserve for second line therapy when first line therapy is prolonged and increasing resistance to 5-FU based therapy with prolonged exposure. As this is a retrospective, observational study, other variables not captured by the modeled covariates that may have influenced results. This data suggests that treating to best response and then allowing a break does not detrimentally affect survival.

No significant financial relationships to disclose.
Preoperative radiation in combination with uracil/tegafur (UFT) and mitomycin C (MMC) in locally advanced rectal adenocarinoma
Authors: Gemici C. , Mayadagli A. , Salepci T. , Yaprak G. , Seseogullari O. O. , Tugrul F.
Published: March 2020

13512

Background: Preoperative chemoradiation has become the standard treatment approach not only for tumor downstaging, but also for adjuvant treatment of locally advanced rectal adenocarcinomas (Sauer et al. NEJM 2004). The most commonly used chemotherapeutic agent with preoperative radiation is either bolus or infusional 5-fluorouracil (5-FU). These combinations produce pathologic complete responses in the range of 10–30%. Continuous infusion of 5-FU has proven to be superior to bolus 5-FU, when given during radiation. However widespread use of continuous infusion 5-FU has been limited by the need for an indwelling venous catheter and portable infusion pump. UFT acting like infusional 5-FU, offers the advantage of oral administration. Response to preoperative chemoradiation is associated with higher sphincter preservation and survival rates. UFT, MMC (a hypoxic cell cytotoxin) combination during preoperative radiation may improve the response rates. The aim of this study is to assess the efficacy (pCR) and toxicity of this combination. Methods: 26 patients with biopsy proven non metastatic rectal adenocarcinoma were included. Clinical T and N stages, determined by pelvic MRI were; 10/26 cT3, 16/26 cT4, 10/26 cN0, and 16/26 cN+. Pelvic radiotherapy was administered with 6 or 15 MV photons to 46 Gy in 23 fractions over 5 weeks, with four field technique in prone position. During radiotherapy, patients received UFT, 300 mg/m2 divided in two daily doses, five days a week, from Monday to Friday, starting on the first day, ending on the last day of radiation, together with bolus injection of MMC, 10 mg/m2, once in the morning of the first day of radiaton. Surgery was performed 6 or more weeks after the radiation treatment has ended. Results: Acute grade III/IV toxicity was observed in 6 out of 26 patients. Diarrhea, 3 grIII, 1 grIV. Neutropenia, 1 grIII. Dermatitis, 1 grIII. Tumor downstaging was observed in 16 patients out of 26 (62%). Nodal sterilization was obtained in 11 patients out of 16 (69%), with a pathologic complete response in 3 out of 26 patients (11%). Conclusions: Preoperative radiation concurrent with UFT and MMC has a good activity, with manageable acute toxicity.

No significant financial relationships to disclose.
Mortality trends in colorectal cancer (CRC) and influencing factors
Authors: Arrazubi V. , Majem M. , Navarro M. , Pareja L. , Biondo S. , Ribes J. , Cambray M. , Martínez-Villacampa M. , Soler G. , Germà J.
Published: March 2020

13527

Background: A decline in overall cancer death rate was observed in the early 1990s after more than six decades of increase in cancer mortality. Effective prevention, screening and early detection as well as improved treatment strategies may be influencing factors. The aim of this study is to compare the overall survival of patients (pts) with CRC in two different years using our prospective regularly updated register database. Methods: Patients diagnosed of CRC during 1996 and 2000 were included in the study. To analyse the relation between variables the exact Fisher test was used. Survival curves were constructed according to the Kaplan-Meier method and compared by log rank analysis. Analyses were performed using the SPSS package. Results: 289 pts in 1996 and 380 in 2000 were included. Demographic data and tumour characteristics were similar in both groups. 42% of pts in 1996 and 56% in 2000 had received chemotherapy (ChT) (p<0.05). In adjuvant setting, 41.8% of patients with stage II-III colon cancer received ChT in 1996 and 57.5% in 2000 (p=0.019). ChT schedules for advanced CRC included Oxaliplatin and Irinotecan in 23% of ChT in 1996 and in 68% in 2000 (p<0.005). The number of palliative ChT lines was significantly higher in 2000 (p<0.05). Radiotherapy was administered as part of rectal cancer therapy to 48% of pts 1996 and to 60% in 2000 (p=0.05). From those, preoperative radiotherapy was administered to 21% of pts in 1996 and to 66% in 2000 (p<0.05). 4.1% of all pts were lost of follow up. With a median follow up of 104.5 months (m) for 1996 and 56.3 m for 2000, the 5-year overall survival (OS) was 45% and 61.6% respectively (p<0.001). The 5-year disease free survival (DFS) of pts with radical surgery was 73% and 81% respectively (p=0.09). The median survival of pts with radical surgery that relapse during follow up was 13.4 m in 1996 and 17.6 m in 2000 (p<0.04). There were statistical significant differences in OS between 1996 and 2000 in tumour site, stage II-III cancer and males, not in females. DFS for stages II-III was better in 2000, but no significant differences were observed. Conclusions: A positive CRC mortality trend was observed. The influencing factors were related with the use of ChT as an adjuvant treatment and the addition of new drugs in colon cancer therapies as well as preoperative radiotherapy for rectal cancer.

No significant financial relationships to disclose.
Trends in rectal cancer survival in relation to the local control strategy
Authors: Latosinsky S. , Demers A. A. , Sun X. , Turner D.
Published: March 2020

13536

Background: The Swedish Rectal Cancer Trial showed improved survival with improved local control due to adjuvant radiotherapy. Improved survival in several population-based studies, credited to improved local control due to quality assurance programs involving surgery, ± radiotherapy, has also been reported. In Manitoba (Canada) local control in rectal cancer was suboptimal in the mid 1990’s (local recurrence >18% in stage I-III) despite adopting the 1991 NIH chemo-radiotherapy guidelines. There continues to be no quality assurance program. We were interested in exploring trends in survival in Manitoba, particularly in the subset of patients where local control is an issue. Methods: All patients diagnosed with rectum and rectosigmoid adenocarcinoma from 1985 to 1999 were identified from the Manitoba Cancer Registry. Demographic, peri-operative and operative treatment information, and death dates were abstracted from the Registry. Manitoba population and death counts used in the calculation of age-specific relative survival probabilities were obtained from Statistics Canada. Survival was examined for all patients for the time periods of 1985–89, 1990–94 and 1995–99 and subsequently limited to those that underwent major rectal cancer surgery (Hartmann’s, anterior, and abdominal perineal resection). The Ederer II method was used in the estimation of survival probabilities. Results: A total of 3021 rectal cancer patients were identified with 1723 (57.0%) having major surgery. Five-year relative survival for all patients was 48.7%, 49.6% and 56.2% for the three periods respectively. The major surgery group results were 56.9%, 58.1% and 59.7%. Peri-operative radiotherapy was used in 38% of the 1995–99 major surgery group, twice the rate of 1985–89; peri-operative chemotherapy 41%, a ten-fold increase. Conclusions: Consistent with other studies, overall rectal cancer five-year survival in Manitoba has improved since 1985. Smaller survival improvements in the major surgery subgroup, despite increased radiotherapy use (as well as chemotherapy), suggests that better local control was not the major factor in the overall survival improvement, as has been suggested in other studies. Future work should include review of the local control strategy and factors to explain the improved survival.

No significant financial relationships to disclose.
FOLFOX-4 vs. FOLFIRI vs. IROX as first line chemotherapy for metastatic colon cancer: efficacy and toxicity
Authors: Stanculeanu D. L. , Matache R. , Minea L. , Cringeanu A. , Anghel R.
Published: March 2020

13541

Background: The combination of OXA or IRI with 5FU-LV are accepted as standard treatment for metastatic colorectal cancer. However, the right sequence in first or second line is still under debate. We developed a non-randomised prospective study in first line metastatic colorectal cancer comparing the efficacy and the toxicity of three different chemotherapy regimens - FOLFOX-4 vs. FOLFIRI vs. IROX. Methods: From January 2004 to January 2005 we included in the study 57 patients with metastatic non-resectable colon cancer - 22 in FOLFOX arm, 18 in FOLFIRI arm and 17 in IROX arm. In the FOLFOX arm patients received OXA 85 mg/m2 d1, LV 200 mg/m2 d1,2, 5FU 400 mg/m2 bolus d1,2, 5FU 600 mg/m2 as 22 hours CI d1,2 q15d; in the FOLFIRI arm - IRI 180 mg/m2, LV 400 mg/m2, 5FU 400 mg/m2 bolus and 5FU 2400 mg/m2 as 46 hours CI, q15d; in the IROX arm - IRI 300 mg/m2 d1, OXA 85 mg/m2 d2, q3w. The main patients characteristics were: median age 60 vs 62 vs 59; number of metastatic sites ≥ 2: 41% vs 33.33% vs 35.3%; performance status ECOG 0–1: 86.3% vs 83.3% vs 88.2%. The primary end-point was the objective response rate (CR + PR) and the secondary end-points was the toxicity. The objective response was evaluated every 3 months; at disease progression patients were offered to switch to a comparator regimen. Results: The objective response was 63.6% in FOLFOX arm (with a CR of 9%), 44% in FOLFIRI arm (CR - 5.5%) and 53% in IROX arm (CR - 11,7%); the stable disease rate - 27.3% in FOLFOX arm, 44.4% in FOLFIRI arm, 35.3% in IROX arm and the disease control rate - 91% in FOLFOX arm, 88.8% in FOLFIRI arm and 88.2% in IROX arm. The main grade 3–4 toxicities were: neutropenia - 22.7% vs 16.66% vs 29.4%; febrile neutropenia - 4.5% vs 5.5% vs 11.76%; diarrhea - 9% vs 22.2% vs 23.5%; nausea/vomiting - 4.5% vs 5.5% vs. 11.76%; neuropathy - 18.18% vs 0% vs 17.6%. No patients stoped the treatment because of side effects. Conclusions: All three regimens were well tolerated, with comparable results - with a slightly better disease control rate in the FOLFOX arm and a tendance of a better complete response rate in the IROX arm. The FOLFOX regimen had lower rates of nausea, vomiting, diarrhea; sensitive neuropathy and neutropenia were more common with regimens containing oxaliplatine. The IROX regimen had a higer incidence of adverse effects.

No significant financial relationships to disclose.
Analysis of response pattern for patients with recurrent or metastatic colorectal cancer treated with Irinotecan, 5-FU, and low dose leucovorin (modified FOLFIRI) as 1st line chemotherapy
Authors: Lee M. A. , Kang J. H. , Hong Y. S. , Lee K. S. , Park S. M. , Kang W. K. , Park S. M.
Published: March 2020

13546

Background: Irinotecan in combination with 5-fluorouracil (5-FU) and high dose leucovorin (LV), known as FOLFIRI regimen, has shown activity in recurrent or metastatic colorectal cancer. We analyzed the response pattern of irinotecan, 5-FU and low dose LV (modified FOLFIRI) as a first line therapy for patients with relapsed or metastatic colorectal cancer. Methods: Between September 2002 and November 2005, 46 patients with histologically confirmed recurrent or metastatic colorectal cancer were enrolled. The chemotherapy schedule consisted of irinotecan 180 mg/m2 intravenous (i.v) on day 1, 5-FU 400 mg/m2 as i.v bolus with 600 mg/m2 as a 22hr continuous infusion on day 1 and 2, leucovorin 20 mg/m2 on day 1 and 2, repeated every two weeks.We investigated the pattern of response to chemotherapy according to clinical parameters. Results: The overall response rate was 47.8%. There was no difference according to disease status and location of primary cancer, but Each metastatic lesions showed different response to chemotherapy. The response rate for metastatic lesions in liver was 54.2%, but only 7.7% for lung lesion. Most peritoneal lesions and lymphadenopathies showed stable disease (60.0% and 55.6%, respectively). 27 patients received 2nd line chemotherapy with oxaliplatin, 5-FU and leucovorin (FOLFOX regimen) after progressive disease. The overall response rate with FOLFOX was 15.2%. With 2nd line chemotherapy, response rate for lesions in liver was 23.5%, but 11.1% for lung lesions. For peritoneal seeding, no response was observed (72.7% stable disease). If the lesion did not achieve response to 1st line chemotherapy, it did not showed response to 2nd line treatment. Conclusions: The response to chemotherapy may be different according to metastatic site within same cancer. The lesions in liver may respond better than those in lung. If the lesion is classified ‘refractory‘ with 1st line treatment, or stage IV cancer with lung or peritoneal seeding only, we may consider more aggressive treatment to achieve better response.

No significant financial relationships to disclose.
Does body mass index affect lymph node retrieval in colon resection for cancer?
Authors: Pimiento J. M. , Cristancho M. A. , Aboulhosn K. , Fancher T. , Palesty J. A. , Dudrick S. J.
Published: March 2020

13571

Background: The management of colon cancer is a multidisciplinary effort that begins with adequate staging centered around the assessment of lymphatic spread. Multiple research groups have studied the number of lymph nodes retrieved and its relation with the outcome of patients with colon cancer, reporting better outcome in patients with a higher number of nodes retrieved. It has been well established that fatty tissue makes lymph node recovery difficult.Our objective was to evaluate if Body Mass Index (BMI) is associated with the number of lymph nodes retrieved, age, stage or location of the tumor. Methods: Retrospective chart review of patient who underwent colon resection for cancer between January 2001 to January 2005. Demographics, BMI and pathologic findings were recorded. Results: 395 patients had diagnosis of colon cancer, 140 underwent surgical procedures for these malignancies. Only 127 patients had complete records. The average age was 72 years. The average lymph node retrieval was 11.4. There was a significant relation between nodes harvested and specimen length (p 0.0028), age (p 0.0011), and stage IV cancer (p 0.002). There was no significant relationship between lymph node retrieval and BMI (p 0.1), location of the tumor (p 0.6) or stage I, II or III. Conclusion: We did not find any statistically significant correlation between BMI and lymph node retrieval, confirming reports that indicate the necessity of adequate lymph node harvest in patients with colon cancer for adequate staging and treatment. This may be because this study was done at a non-specialized center and because the operations were done by a number of different surgeons and the histopathology by numerous pathologists. The relation of improved lymph node harvest with greater specimen length supports other studies that point toward surgical and pathologic techniques as the most important factors in the appropriate staging of colon cancers. Hence, standardized surgical and histopathologic techniques need to be employed for harvesting adequate numbers of lymph nodes in resection specimens because number of nodes is critical to therapy, and an insufficient numbers of nodes may have a detrimental impact on colon cancer patient outcome. A prospective study should be performed in order to confirm the results of this study.

No significant financial relationships to disclose.
Postoperative chemoradiotherapy in patients with rectal cancer, prognostic factors for disease control and survival
Authors: Hetnal M. , Malecki K. , Korzeniowski S. , Zemelka T.
Published: March 2020

13575

Background: The aim of this paper is an assessment of results of adjuvant chemoradiotherapy in patients with rectal cancer with respect to prognostic factors, causes of treatment failures and treatment tolerance. Methods: 178 pts with Dukes’ stage B or C rectal cancer received postoperative chemoradiotherapy between 1993 and 2002. Median age was 62; 110 patients were males, 68 were females. Median follow-up time was 45 months. Main endpoints of the analysis were locoregional recurrence-free survival (LRRFS), distant relapse free survival (DRFS), disease free survival (DFS) and overall survival (OS). Kaplan-Meier method was used to calculate survival rates. Univariate and multivariate analyses of prognostic factors were performed using log rank and Cox’s proportional hazard method. Results: The 5-year LRRFS was 73%, DRFS was 80%, DFS was 61% and OS was 65%. Lymph node involvement and method of resection (AR favoured) were the only independent prognostic factors for LRRFS. Lymph node involvement, in particular when four or more are involved, was independent prognostic factors for DFS. For DRFS are histological grade, lymph node involvement and extracapsular extension of the lymph node metastases. For OS, the independent prognostic factors were infiltration of the pararectal fatty tissue, lymph node involvement in particular when four or more are involved, total number of chemotherapy cycles (at least six favoured). The 5-year LRRFS was 73%, DRFS was 80%, DFS was 61% and OS was 65%. Radiation therapy was well tolerated in 45% of patients. Most common early reactions were diarrhoea, nausea/vomiting and leucopoenia. Conclusions: Involvement of lymph nodes and method of resection were the only independent prognostic factors for LRRFS. Prognostic factors for OS were infiltration of the pararectal fatty tissue, lymph node metastases, four or more involved lymph nodes, total number of chemotherapy cycles.

No significant financial relationships to disclose.
5-fluorouracil (5FU) pharmacokinetic and hormonal status in female colorectal cancer patients
Authors: Bononi A. , Gusella M. , Crepaldi G. , Padrini R. , Ferrazzi E.
Published: March 2020

13576

Background: It is well known that females present a significantly reduced clearance of 5FU compared to males treated with the same doses.We tested the hypothesis that it may depend on the hormonal status, so that pre-menopausal women would have different 5FU pharmacokinetics compared with both postmenopausal women and elderly women. Methods: 48 colorectal cancer patients were prospectively studied: all of them were on adjuvant treatment based on 5FU repeated boluses. On the second day of the first cycle peripheral blood was drawn after drug administration. Plasma level were detected by HPLC analysis and pharmacokinetic parameters were calculated trough a one phase exponential decay model. Results: All patients had 100–90 Karnosky Performance status score. 12 were in pre-menopausal phase (age range : 40–55 years); among the others we distinguished a younger 19 people group (age lower than 70 years old) and an elderly 17 patient group (age equal or higher than 70 years old). They received a 5FU mean dose of 406 ± 15 mg/mq, not significantly different among the three groups. After intravenous bolus injection a high interindividual variability of 5-FU pharmacokinetics was detected: AUC0-∞ (area under the curve of drug plasma levels versus time) ranged between 368 and 1236 mg × min/L and the highest values (>1000) were found in two elderly patients, considered fit; anyway there was no significant difference among AUC of the three groups. 5FU total clearance ranged between 0.53 and 1.9 L/min and means were 1.07 ± 0.3, 1.02 ± 0.3 and 0.98 ± 0.3 L/min in pre-menopausal, postmenopausal and elderly women respectively; again 5FU clearance/ BSA (body surface area), half live elimination times and peak concentration plasma levels were not significantly different among the three groups. Conclusions: It seems that sexual hormonal status do not influence 5FU total body elimination capability, and that pharmacokinetic differences between genders should be related to other factors,as for example Body Composition. Funded by AIRC-Veneto

No significant financial relationships to disclose.
Phase I study of pemetrexed plus cisplatin in unresectable, advanced gastric carcinoma in Taiwan
Authors: Chen J. , Chao Y. , Chen L. , Li C. , Reece W. , Khan R. , Pope E. , Otero J. C.
Published: March 2020

14009

Background: Phase I of this Phase I/II study (H3E-AA-S038) was conducted to determine the recommended dose of pemetrexed (PT) when given with cisplatin (Cis) to patients with unresectable, advanced gastric carcinoma. Methods: Patients 18 to 70 years of age, with stage IV disease or post-surgery recurrence, no prior palliative chemotherapy, and an ECOG performance status of 0 or 1 were included. Patients received PT and Cis on Day 1 every 21 days. Cis was dosed at 75 mg/m2. PT dosage was planned at 600, 700, 800, and 900 mg/m2. Vitamin B12 and folic acid supplementation, and dexamethasone (or equivalent corticosteroid) prophylaxis were required. The initial number of patients to be enrolled per dose level (DL) was 3. If 0/3 patients had dose-limiting toxicity (DLT), PT dose was escalated. If 1/3 patients had DLT, 3 more patients were enrolled at that DL. If ≥2 patients had DLT, the dose was not escalated further. The recommended dose of PT for Phase II was the highest dose at which <2/6 patients experienced DLT. The following toxicities were defined as DLT: death due to toxicity; neutropenia [<0/5 × 109/L for ≥5 days, or <1.0 × 109/L with fever (≥38.5 ºC)]; thrombocytopenia (<10.0 × 109/L, or <50.0 × 109/L with bleeding); AST or ALT >20 × ULN; and non-hematological toxicities of CTC grade 3 or 4 (except nausea and vomiting). Intra-patient dose escalation was not permitted. Results: Sixteen patients were enrolled. The mean (±SD) age of enrolled patients was 52.8 (±10.0) years, and the majority were male (62.5%). At DL1, 0/3 patients experienced DLT. At DL2, 1/6 patients had DLT. At DL3, 3/7 patients had DLT, and so PT dose was not escalated. All DLTs occurred in cycle 1; 2 involved neutropenia, 1 tumor hemorrhage, and 1 hypokalemia. Grade 3/4 toxicities were experienced by 12/16 (75%) patients, including 9 (56%) hematological and 10 (63%) non-hematological events. Five out of thirteen (38%) patients with measurable disease had a RECIST response (2 had a complete response, 1 each at DL1 and DL2; 3 had a partial response, 2 at DL2 and 1 at DL3). At this interim analysis, 2 patients were still on therapy. Conclusions: The recommended dose of PT is 700 mg/m2. Phase II will examine response and safety of PT plus Cis in advanced gastric carcinoma.

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Targeted tumor therapy with the TGF-beta2 antisense compound AP 12009 for the treatment of advanced solid tumors
Authors: Oettle H. , Seufferlein T. , Schmid R. , Luger T. , Ludwig S. , Schmaus S. , Beyer M. , Fischer D. , Hafner M. , Schlingensiepen K.
Published: March 2020

14012

Background: TGF-β overexpression in advanced tumors is correlated with tumor-induced immunosuppression, proliferation and angiogenesis. Furthermore, it is a key factor for induction of epithelial to mesenchymal transition (EMT), thus promoting invasion and metastasis. Targeted tumor therapy by an antisense oligonucleotide has already been proven to be successful in tumor therapy: AP 12009, a TGF-β2-mRNA-specific antisense oligodeoxynucleotide, has shown strong clinical indication of efficacy including complete and lasting remissions in malignant glioma. Methods: Spurred by the highly encouraging clinical data in malignant glioma and strong anti-tumor activity in a wide variety of preclinical assays, clinical studies in further indications were initiated. A multi-center dose-escalation phase I/II trial with AP 12009 in patients suffering from advanced solid tumors was started in 2005. Primary endpoint is to assess the maximum tolerated dose (MTD) as well as the dose-limiting toxicity (DLT). AP 12009 is administered i.v. in 14-day cycles. Results: Preclinically, in human pancreatic cancer and melanoma cell cultures AP 12009 significantly reduced the TGF-β2 secretion of cancer cells, inhibited tumor cell proliferation, and blocked migration of cancer cells. Additionally, AP 12009 reversed TGF-β2 mediated immunosuppression induced by pancreatic carcinoma cells. In the ongoing clinical phase I/II dose-escalation study, two cohorts of tumor patients have already been treated intravenously with AP 12009 as of Dec 2005. Further dose escalations are ongoing. So far, no DLT, no possibly related SAEs and only seven possibly related AEs were observed. MTD is not yet reached. The majority of patients received more than the minimum number of two cycles, one of them received ten full cycles. First signs of efficacy could also be observed. Conclusions: In conclusion, the preclinical results with pancreatic cancer and malignant melanoma cell cultures as well as the successful clinical application of AP 12009 in the lead indication malignant glioma form a rational basis for the use of the antisense compound AP 12009 as targeted therapy of advanced, TGF-β2 overexpressing tumors.

[Table: see text]
Assessment of 18FDG PET and pathological response following neoadjuvant chemotherapy for oesophageal cancer
Authors: Harrison C. , Park R. M. , O’Neill C. , McManus D. , Hughes S. , Carey D. , Kennedy A. , McGuigan J. , McManus K. , Eatock M.
Published: March 2020

14026

Background: Response to chemoradiation for oesophageal carcinoma on PET scanning is associated with pathological response and survival. Recent trials suggest that neoadjuvant chemotherapy for oesophageal cancer improves disease free and overall survival. We have examined the relationship between PET and histopathological response in those who have undergone surgical resection following preoperative chemotherapy in Northern Ireland. Methods: We assessed 20 consecutive patients with resectable oesophageal cancer. Staging in all patients included an endoscopic ultrasound scan and PET scan before and after preoperative chemotherapy and a PET scan after pre-operative chemotherapy. PET response (≥50% decrease in SUVmax) and pathological response were assessed independently by a Nuclear Medicine specialist and two histopathologists. Evidence of histopathological response was assessed using the Mandard criteria and by determining the proportion of the total blocks of tumour with evidence of viable disease. Results: 20 have been treated, 15 males and 5 females with a median age of 68 (range 39–76). Clinical staging suggested stage III disease in 12 patients (60%), stage IIa in 6 (30%), stage IIb and IVa disease 1 in each group. 16 patients with adenocarcinoma received 3 cycles of ECF chemotherapy and 4 with squamous cell carcinoma received 2 cycles of Cisplatin/5FU chemotherapy. The median time to surgery from first chemotherapy was 101 days (range 84–165). Final pathological stage was less than predicted by pre-treatment staging in 9 patients (45%). PET response was seen in 10 patients (50%), of these, 9 had a Mandard score of ≤3. With median followup of 8 months (range 3–21 months), 18 patients (81.9%) are alive disease free, 3 (13.6%) have died from disease, 1 (4.5%) died postoperatively. Conclusions: In this small series evidence of response to pre-operative chemotherapy assessed by reduction in SUVmax on 18FDG PET scanning is associated with pathological response. We suggest that this association is worthy of further evaluation and prospective investigation.

No significant financial relationships to disclose.
Phase II study of S-1 and biweekly docetaxel combination in advanced or recurrent gastric cancer
Authors: Kakeji Y. , Oki E. , Nishida K. , Koga T. , Tokunaga E. , Morita M. , Emi Y. , Maehara Y.
Published: March 2020

14031

Background: Docetaxel (TXT) and S-1 are active agents against gastric cancer. A synergistic antitumor effect has been shown in a preclinical study (Takahashi et al., Oncology 2005), and our previous phase I trial demonstrated the safety and tolerability of the combination, and its potent activity. To prospectively evaluate toxicity and efficacy of S-1/ biweekly TXT, we conducted the current phase II study in patients with advanced and recurrent gastric cancer. Methods: Patients (pts) with advanced or recurrent gastric cancer, who have not received any chemotherapy except postoperative chemotherapy (not including S-1 or TXT), were eligible for the trial, and were treated with docetaxel 35 mg/m2 one hour iv infusion on day 1 and 15, and S-1 at a full dose of 80 mg/m2/day for two weeks every four weeks. Results: Thirty-five pts with measurable lesions (RECIST) (10 females, 25 males; performance status [PS] 0/1/2: 23/8/4, age 27–74, differentiated/undifferentiated adenocarcinoma: 19/16) have been enrolled. A total of 113 cycles were administered (median 3, range 1–6), and all pts were assessable for toxicity and efficacy. Grade 3–4 toxicities were: neutropenia in 20.0% (grade 4: 11.4%) of patients, leukocytopenia in 11.4% (grade 4: 0%), anemia in 5.7%, appetite loss in 8.6%, stomatitis in 8.6%, fever in 2.9%, and fatigue in 2.9%. All treatment related toxicities resolved, and no toxic death was reported. Thirteen partial responses (PR) were obtained, resulting in an overall response (OR) rate of 37.1% (95% CI: 0.22–0.55). Thirteen pts (37.5%) had stable disease, and 4 pts (12.5%) progressed. The tumor control rate was 74.3% (95% CI: 0.57–0.88). The median survival time (MST) and time to treatment failure (TTF) were 326 and 75 days, respectively. Conclusions: The combination of S-1/ biweekly TXT is active in advanced or recurrent gastric cancer, and can be given safely with proper management of adverse events even in outpatient clinic. S-1/ biweekly TXT is one of the most effective regimen to control metastatic gastric cancer with less toxicity.

No significant financial relationships to disclose.