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Pancreatic adenocarcinoma has increasingly become one of the leading causes of death in western countries. However, presentation with colonic metastases is far less frequently reported in the literature and may be misdiagnosed as colonic adenocarcinoma. This is a case of a female patient with metastatic pancreatic adenocarcinoma that presented with a sigmoid obstruction.

Purpose: The KRAS proto-oncogene is involved in the RAS/MAPK pathway. KRAS is present in the wild type or mutated forms. The oncogene KRAS is frequently mutated in various cancers. At the time that amino acid glycine is mutated, KRAS protein acquires oncogenic properties that result in the tumor cell growth, proliferation, and cancer progression. There has been limited understanding of the different mutations at codon 12. The consequences of such mutations is not fully understood. Various G12X mutations in pancreatic cancer patients have been examined, with the most common mutations being G12D (40%), G12V (30%), and G12R (15–20%). Now we are understanding that G12X mutations in the KRAS are not all equal. Methods: In a single-arm exploratory study, we accrued 13 KRAS-G12X-mutated pancreatic patients (KRAS G12D, G12V, and G12R). They were divided into two groups: group 1 consisted of seven patients with G12D and G12V and group 2 included six patients with the KRAS G12R mutation. All patients were treated with the combination of gemcitabine at 1250 mg/m2 intravenous weekly for 3 weeks and oral cobimetinib 20 mg b.i.d. for 3 weeks. This was followed by a week of rest before the initiation of the next cycle. Results: In the first cohort, seven patients were on treatment, all of whom progressed and died within the 2 months of the study. In the second cohort, one of six patients achieved partial response, and five achieved stable disease. Median progression-free survival was 6 months (9% confidence interval 3.0–9.3 months) and overall survival has been reached at 8 months. Common adverse reactions included rash, fatigue, nausea, and vomiting (grades 2 and 3). Cancer antigen CA19-9 decreased by >50% in all group 2 patients. Conclusion: Our pancreatic cancer patients were heavily pretreated (all had received FOLFIRINOX and gemcitabine/nab-paclitaxel) before the entry into our trial. Upon entry into our trial, all patients were treated with the combination of gemcitabine and oral cobimetinib. Therefore, this constituted the second exposure of the patients to gemcitabine. This study illustrates a new discovery, which can potentially target 15–20% of pancreatic cancer patients and allow for a significant improvement in their prognosis. We will be conducting randomized phase II trials to substantiate our findings.

735 Background: We have studied the role of KRAS mutations in relation to the prognosis in patients with advanced pancreatic ductal adenocarcinoma (PDAC). KRAS is a well-described oncogenic driver in PDAC, with mutations identified in over 90% of cases, typically involving codon 12. The three predominant missense variants include G12D, G12V and G12R. PDAC has the highest rate of G12R mutations compared to other malignancies, comprising 15-20% of KRAS-mutated tumors. This study presents a new finding in the progression of advanced PDAC utilizing a large clinical and genomic database to further characterize the clinical features of pathogenic KRAS variants in PDAC with a focus on G12R. Methods: PDAC samples were tested using whole transcriptome sequencing (WTS; Illumina NovaSeq) and NextGen DNA sequencing (NextSeq, 592 Genes and NovaSEQ, WES) at Caris Life Sciences (Phoenix, AZ). Transcriptomic signatures including MPAS (MAPK activation score), T-cell inflamed score and tumor micro environment (TME) characterization were calculated on WTS data. Significance was determined by X2 and Fisher-Exact and p adjusted for multiple comparisons (q) was < 0.05 (Benjamini-Hochberg). Real-world overall survival (rwOS) was obtained from insurance claims data and calculated from tissue collection to last contact; time-on-treatment (TOT) was calculated from start to finish of specific treatments; comparison was done by Kaplan-Meier test. Results: A total of 5,555 patients with PDAC harboring either KRAS G12D (n = 2,671), G12V (n = 1,871) G12R (n = 904) or G12C (n = 109) variants were identified. The patients with KRAS G12R mutant tumors had significantly longer median real-world overall survival (mRWOS) compared to G12D (452 vs 358 days, HR 0.82, CI 0.74 – 0.9, p < 0.0001). This difference persisted regardless of treatment with FOLFIRINOX or gemcitabine plus nab-paclitaxel. There was no difference in outcomesbetween patients with KRAS G12R, G12V or G12C. PD-L1 expression was significantly lower in G12R than in G12C or G12D (13% vs 27% vs 19%,) while the prevalence of TMB-H and dMMR was comparable across isoforms. Conclusions: Patients with KRAS G12R variants has improved rwOS compared to G12D irrespective of the chemotherapy regimen administered. Immune profiling suggested that the immune contexture in G12R-driven tumors are distinct from G12D as reflected by reduced PDL1 staining, decreased levels of multiple checkpoint receptors. We aim to further explore the molecular basis for these differences with a focus on PI3K and MAPK pathways. Based on this data, survivorship studies in patients with advanced PDAC should consider reporting KRAS mutational status.

Introduction and importance Pancreatic adenocarcinoma is one of the leading causes of death. Presentation with colonic metastases is far less frequently reported in the literature and may be misdiagnosed as colonic adenocarcinoma. We report the case of a female patient with metastatic pancreatic adenocarcinoma that presented with a sigmoid obstruction. Case presentation A 66-year-old female presented with constipation and abdominal pain. She was found to have an obstructing sigmoid colon lesion, multiple metastatic lesions in the liver, and a pancreatic tail lesion. She underwent left hemicolectomy and ostomy placement. The gross pathology of the colon and needle biopsy of the liver was consistent of pancreatobiliary origin. Genomic screening performed, patient found to be KRAS G12R mutated. She was given one cycle of chemotherapy, thereafter was referred to hospice care. Clinical discussion Primary metastatic pancreatic cancer is now the 2nd most diagnosed cancer in the United States after lung cancer. The prognosis for the malignancy is poor, patients are usually diagnosed late at the time that the tumor has metastasized to other organs. Colonic metastasis is a rarely seen and far less frequently reported in the literature. Next-generation-sequencing was performed at baseline to further characterize her tumor for any actionable mutations. Conclusion Pancreatic adenocarcinoma is an aggressive malignancy with a poor prognosis. Next-generation-sequencing may offer targeted therapy if an actionable mutation is present such as our patient's, however due to late diagnosis, rapid clinical deterioration, and next-generation sequencing delay we were unable to alter the patient's outcome., Highlights • Colonic obstruction is a rare presentation of metastatic pancreatic adenocarcinoma. • Next-generation sequencing may offer therapies if patient has a targetable mutation. • Pancreas cancer is limited in treatment, NGS may offer better outcome if targetable.

96 Background: In patients with unresectable liver-confined CRLM, regional chemotherapy via HAI in combination with modern systemic chemotherapy (CT) can achieve hepatic disease control and expand surgical resectability. We describe patient selection and early outcomes following implementation of a HAI program at our tertiary referral academic center. Methods: We analyzed demographics, previous systemic treatment, primary tumor location, molecular profiling, extent of hepatic/extrahepatic disease, perioperative HAI outcomes (toxicity, conversion to resection/ablation, radiographic response), and overall survival (OS) in CRLM patients selected for HAI treatment (01/2018—06/2020) after multidisciplinary review. Results: Of 35 patients with unresectable CRLM (primary: colon, n = 24; rectum, n = 11) selected for HAI, 57% were heavily pre-treated (with at least 2 lines of pre-HAI systemic chemotherapy), 71% had a Fong clinical risk score ≥3, 86% presented with synchronous disease, 80% had bilobar metastasis, and 86% had > 5 tumors. All tumors were microsatellite stable, with 20% harboring KRAS/NRAS mutations and none had class I/II BRAF mutations. HAI was initiated at a median 14 (IQR 3, 64) months after CRLM diagnosis, and administered for a median of 7 (range 2, 16) cycles; 91% of patients (31/34) received concurrent HAI and systemic chemotherapy. Although most (69%) patients experienced some degree of hepatic toxicity during HAI therapy resulting in FUDR dose reduction and steroid administration, biliary sclerosis requiring intervention was observed in only 3 (9%) of patients. The overall perioperative morbidity was 17%, and there were no surgical-related 90-day mortalities following HAI pump placement. Excluding patients who initiated HAI treatment within the last 3 months of the study period (n = 3), 13 of 32 patients (41%) were rendered disease-free in the liver following complete resection and/or ablation in combination with HAI/systemic chemotherapy; in the remaining 19 patients (59%), hepatic progression-free survival was 7.3 months (IQR 4, 12). At a median follow-up of 11.2 months, post-HAI median OS for the overall cohort was 12.3 (IQR 7, 20) months. Patients undergoing complete resection/ablation demonstrated improved survival compared with those with progressive disease (median 20 vs 12 months, respectively). Conclusions: Implementation of a HAI program for multimodality liver-directed management of unresectable CRLM is feasible and is associated with meaningful clinical outcomes unlikely to be achieved with systemic therapy alone in heavily pre-treated patients.

4642 Background: he KRAS proto-oncogene is involved in the RAS/MAPK pathway. Various G12X mutations have been examined with the most common mutations being G12D (40%), G12V (30%), and G12R (15-20%) in pancreatic cancer patients. Throughout the course of studying the G12X mutations, we have observed that not all KRAS mutations are equal. Preclinical data shows G12R is impaired in pI3Kα signaling, as compared to KRAS G12V/D. This mechanism is important in PDAC as it allows tumor growth to be sustained. In preclinical studies, PDX derived tumors were transplanted in mice and were treated with a MEK inhibitor plus chemotherapy, which demonstrated a greater tumor regression than either agent alone. Therefore, we have decided to treat patients with Gemcitabine alongside a 2nd generation MEK inhibitor (Cobimetinib). Methods: In our single arm study, 13 KRAS mutated pancreatic patients (KRAS G12D, G12V, and G12R) received the combination of Cobimetinib 20mg BID weekly for three weeks alongside Gemcitabine at 1000mg/m2 weekly, followed by one week of rest. The above constitutes one cycle. Results: Patients were divided into two groups; Group 1 consists of seven patients that were KRAS G12D/G12V mutated, and Group 2 included six KRAS G12R mutated patients. In Group 1, seven patients on treatment progressed and died within two months on the study. In Group 2, one achieved PR and others stable disease. Median progression-free survival was 6.0 months (95% CI 3-9.3 months) and median OS has not been reached. All patients are alive at 8 months. Common adverse reactions include rash, fatigue, nausea, and vomiting. Cancer antigen 19-9 decreased in ≥ 50 of all patients in the latter group. We would like to report our positive study to the society. Moreover, we intend to confirm the study in a larger patient cohort. Conclusions: Pancreatic cancer patients that demonstrate KRAS G12R mutations are treatable with a new active combination chemotherapy.

The metalloid arsenic is a worldwide environmental toxicant, exposure to which is associated with many adverse outcomes. Arsenic is also an effective therapeutic agent in certain disease settings. Arsenic was recently shown to regulate the activity of the Hedgehog (HH) signal transduction pathway, and this regulation of HH signaling was proposed to be responsible for a subset of arsenic’s biologic effects. Surprisingly, these separate reports proposed contradictory activities for arsenic, as either an agonist or antagonist of HH signaling. Here we provide in vitro and in vivo evidence that arsenic acts as a modulator of the activity of the HH effector protein glioma-associated oncogene family zinc finger (GLI), activating or inhibiting GLI activity in a context-dependent manner. This arsenic-induced modulation of HH signaling is observed in cultured cells, patients with colorectal cancer who have received arsenic-based therapy, and a mouse colorectal cancer xenograft model. Our results show that arsenic activates GLI signaling when the intrinsic GLI activity is low but inhibits signaling in the presence of high-level GLI activity. Furthermore, we show that this modulation occurs downstream of primary cilia, evidenced by experiments in suppressor of fused homolog (SUFU) deficient cells. Combining our findings with previous reports, we present an inclusive model in which arsenic plays dual roles in GLI signaling modulation: when GLIs are primarily in their repressor form, arsenic antagonizes their repression capacity, leading to low-level GLI activation, but when GLIs are primarily in their activator form, arsenic attenuates their activity.

A 32-year-old female with stage IV colorectal cancer and metastasis to the liver experienced cardiotoxic reactions after treatment with 5-fluorouracil and its oral prodrug capecitabine even at two-thirds the recommended dose. After careful considerations, the decision was made to attempt capecitabine retrial at a further suboptimal dose with combination chemotherapy where she no longer experienced cardiac events. As a result, the liver tumour shrank and rectal mass stabilised, tumour markers dropped and she underwent surgical resection of both masses. Later there was local recurrence of disease near the previous liver tumour, so the suboptimal capecitabine therapy was restarted without complaint. The patient became a candidate for a NanoKnife procedure, offering a potentially curative therapy. This case report summarises a novel treatment strategy for those patients with advanced colorectal cancer who experience cardiotoxic reactions to fluoropyrimidines, the active agent of gold standard treatment.

In the past decade, the therapeutic potential of arsenic trioxide (ATO) in the treatment of acute promyelocytic leukemia (APL) was recognized. This encouraged other investigators to test the efficacy of ATO in the management of other hematological and solid tumor malignancies. Notably, as a single agent, arsenic trioxide did not benefit patients diagnosed with solid tumors. However, when it was combined with other agents, treatment benefit emerged. In this article, we have summarized the outcome of clinical trials that used arsenic trioxide as a single agent as well as in combination settings in patients diagnosed with solid tumors. We have also reviewed possible additional mechanisms by which ATO may be useful as a chemosensitizer in combination therapy. We hope that our review will encourage clinical investigators to rationally combine ATO with additional chemotherapeutic agents in treating patients diagnosed with solid tumors.

There is no consensus on the most effective modality for the treatment of resectable esophageal adenocarcinomas (EAC). We theorized that treatment modality may influence survival differently depending on the stage of disease. A single-institution, retrospective examination of resectable EAC between 2000 and 2008 was performed. Resectable EAC were stratified into early disease (stage 2a or less) and late disease (stage 2b or more) based on pretreatment endoscopic ultrasound (EUS). Patients with T4, >N2, and/or distant disease were excluded. A total of 156 patients were included in this study. Most patients were white (97 %), male (83 %), and over 60 years of age (51 %). Patients with early disease on pretreatment EUS exhibited improved overall survival compared to patients with late disease (P

Achyranthes aspera(familyAmaranthaceae) is known for its anticancer properties. We have systematically validated thein vitroandin vivoanticancer properties of this plant. However, we do not know its mode of action. Global gene expression analyses may help decipher its mode of action. In the absence of identified active molecules, we believe this is the best approach to discover the mode of action of natural products with known medicinal properties. We exposed human pancreatic cancer cell line MiaPaCa-2 (CRL-1420) to 34 μg/mL of LE for 24, 48, and 72 hours. Gene expression analyses were performed using whole human genome microarrays (Agilent Technologies, USA). In our analyses, 82 (54/28) genes passed the quality control parameter, set at FDR ≤ 0.01 and FC of ≥±2. LE predominantly affected pathways of immune response, metabolism, development, gene expression regulation, cell adhesion, cystic fibrosis transmembrane conductance regulation (CFTR), and chemotaxis (MetaCore tool (Thomson Reuters, NY)). Disease biomarker enrichment analysis identified LE regulated genes involved in Vasculitis—inflammation of blood vessels. Arthritis and pancreatitis are two of many etiologies for vasculitis. The outcome of disease network analysis supports the medicinal use ofA. aspera, viz, to stop bleeding, as a cure for pancreatic cancer, as an antiarthritic medication, and so forth.

Neoadjuvant treatment is standard for locally advanced esophageal cancer. However, whether the addition of radiation to neoadjuvant regimen improves survival remains unclear. The aim of this study was to compare survival in locally advanced esophageal cancer treated with neoadjuvant chemotherapy versus chemoradiation.A prospectively maintained database of esophagectomies (1999-2012) was analyzed. We identified 297 patients with locally advanced esophageal cancer that underwent either neoadjuvant chemotherapy (n = 231) or chemoradiation (n = 66) followed by esophagectomy. Pretreatment and pathologic staging were compared to assess response. Overall survival was recorded.Most patients in the chemotherapy and chemoradiation groups had pretreatment stage III disease (66.7% versus 65.2%; P = 0.44). Median follow-up was 79.3 and 64.9 mo for chemotherapy and chemoradiation cohorts, respectively. Complete response rate was higher in chemoradiation than chemotherapy groups (30.3% versus 13.8%; P 0.001). Overall survival was similar between complete responders in both groups (median not reached versus 121.1 mo; chemotherapy versus chemoradiation). However, partial responders in the chemotherapy cohort had improved median survival (147.2 mo) versus those in the chemoradiation cohort (83.7 mo, P 0.03). Within the chemotherapy-only group, partial responders had improved survival compared with nonresponders (P = 0.041); however, there was no difference in survival between partial and complete responders (P = 0.36).In patients undergoing esophagectomy for locally advanced esophageal cancer, neoadjuvant chemotherapy was associated with an equivalent overall survival, when compared with neoadjuvant chemoradiotherapy. Adding neoadjuvant radiation may enhance complete response rates but does not appear to be associated with improved survival.

Achyranthes aspera (Family Amaranthacea) is used for cancer therapy by ayurvedic medical practitioners in India. However, due to the non formal nature of its use, there are no systematic studies validating its medicinal properties. Thus, it's utility as an anti cancer agent remains anecdotal. Earlier, we demonstrated A. aspera to exhibit time and dose-dependent preferential cytotoxicity to cultured human pancreatic cancer cells. In this report we validate in vivo anti tumor properties of A. aspera.The in vivo anti tumor activity of leaf extract (LE) was tested by intraperitoneal (IP) injections into athymic mice harboring human pancreatic tumor subcutaneous xenograft. Toxicity was monitored by recording changes in behavioral, histological, hematological and body weight parameters.Dosing LE to athymic mice by I.P. injection for 32 days showed no adverse reactions in treated mice. Compared to the control set, IP administration of LE to tumor bearing mice significantly reduced both tumor weight and volume. Gene expression analysis using Real time PCR methods revealed that LE significantly induced caspase-3 mRNA (p0.001) and suppressed expression of the pro survival kinase Akt-1 (p0.05). TUNEL assay and immunohistochemistry confirmed apoptosis induction by activation of caspase-3 and inhibiting Akt phosphorylation in treated sets. These results are in agreement with RT PCR data.Taken together, these data suggest A. aspera to have potent anti cancer property.

Thymidylate synthase (TS; TYMS) is a pivotal enzyme in the DNA synthesis pathway. The 5’UTR of TYMS gene has a polymorphic 28 bp segment. Presence of two or three repeats of this unique 28 bp sequence is common. A distinct population distribution pattern for this polymorphic trait among different racial groups had been reported. We analyzed TYMS genotype in the peripheral blood mononucleocytes (PBMC) of 74 individuals in the South Florida region of the United States of America. The number of 28 bp repeats in the 5’ UTR was determined by PCR followed by agarose gel electrophoresis. The distribution of the three different genotypes was found to be 35.1% for 2R/2R, 39.2% for 2R/3R and 24.3% for 3R/3R. One individual was detected with 3R/4R genotype. Functional analyses associated homozygous for three repeats (3R/3R) to higher TYMS expression and therefore poor prognosis to chemotherapy. The other possible genotypes viz 2R/2R or 2R/3R is proposed to have better prognosis. However, there are reports that challenge this observation.

To the Editor,5-Fluorouracil (5-FU) has been the most active chemotherapeutic agent for metastatic colorectal cancer (CRC), and the mainstay of treatment for the last 40 years. The reported respons...

Aims of the study Achyranthes aspera (Family: Amaranthacea ) is a medicinal plant used as an anti-cancer agent in ayurveda, a traditional system of medicine practiced in subcontinental India. The aim of the study was to systematically investigate the anti-proliferative properties of Achyranthes aspera leaves extracted in methanol (LE) on human cancer cells in vitro . Materials and methods We tested time, dose dependent and specific anti-proliferative activity of LE by clonogenic cell survival assay on human cancer and normal epithelial cell lines in vitro . We further investigated its effect on the expression of metastatic and angiogenic genes by real time polymerase chain reaction. On silica gel column, we carried out initial fractionation analysis. Results LE exhibited time and dose dependent cytotoxicity on several tumor cells. Compared to cancer cells of colon, breast, lung and prostate origin, pancreatic cancer cells were significantly more sensitive to LE. Preliminary mechanistic studies suggested that LE selectively suppressed the transcription of metalloproteases (MMP-1 and -2), inhibitors of MMPs (TIMP-2) and angiogenic factors (VEGF-A and VEGF-B). Fractionation of LE on methanol equilibrated silica gel column resolved into three fractions of which fraction (F 3) was found to be enriched with anti-proliferative activity. Conclusion Methanolic extract of Achyranthes aspera contains potent anti-proliferative compound with specific activity against pancreatic cancer. Further studies are needed to confirm the in vivo anti-tumorigenicity and subsequent chemical characterization of the active molecule(s).

Purpose: This Phase I study was designed to determine a safe combination dose of 5-fluorouracil (5-FU) and arsenic trioxide (ATO) to treat 5-FU–resistant relapsed/refractory colorectal cancer patients. We studied the effect of ATO in the downregulation of thymidylate synthase (TS) in peripheral blood mononuclear cells and in tumor biopsies. Experimental Design: ATO was administered for 5 consecutive days during the first week and twice during weeks 2 to 3 and once on week 4. 5-FU/leucovorin (LV) was administered on days 8, 15, and 22. A modified accelerated titration design was used. 5-FU was dose escalated first followed by a planned dose increase for ATO. Results: No dose-limiting toxicities were seen in seven patients who received 0.15 mg/kg ATO; grade 3 toxicities were as follows: neutropenia 1, diarrhea 1, and bowel obstruction 1. In patients receiving 0.20 mg/kg ATO, grade 3 toxicities were QTc prolongation 1, fatigue 4, alkaline phosphatase elevation 2, diarrhea 2, and peripheral edema 1. TS gene expression in peripheral blood mononuclear cell decreased in all patients. Eight tumors were biopsied, four showed TS downregulation, three showed upregulations, and one did not change. Estimated median progression-free survival and overall survival were 3.1 and 13.9 months, respectively. In patients who showed TS increase or no change versus TS reduction, estimated median progression-free survival was 2.6 versus 7.9 months (P = 0.188) and overall survival was 8.6 versus 11.7 months (P = 0.44), respectively. Conclusions: Thus, we determined 0.20 mg/kg ATO, 2,600 mg/m2 5-FU, and 500 mg/m2 leucovorin (LV) to be the recommended phase II dose. Clin Cancer Res; 16(11); 3019–27. ©2010 AACR.

Our objectives were to determine response rate, time to progression, overall survival and tolerability of novel combination chemotherapy, consisting of irinotecan, high-dose 24-h continuous intravenous infusion of floxuridine and leucovorin in advanced previously untreated colorectal cancer. Thirty-eight patients with advanced colorectal cancer were treated at Sylvester Comprehensive Cancer Center, University of Miami, from 2000 to 2004, and received weekly intravenous infusion of irinotecan at 110 mg/m 2 with a combination of 120 mg/kg floxuridine and 500mg/m 2 leucovorin administered as a 24-h continuous intravenous infusion. The treatment cycle consisted of 4 weeks of consecutive therapy followed by 2 weeks of rest Five (13%) patients achieved complete response, 10 (26%) patients achieved partial response, 17 (45%) patients attained stable disease and six (16%) patients progressed. The overall response rate was 39% in this study. This chemotherapy regiment was well tolerated; the most common grade 3 toxicities were neutropenia (16%), anemia (16%), vomiting (24%), diarrhea (16%), and hand-and-foot syndrome (26%). The median time to progression was 11.5 months (347.5 days) with 95% confidence intervals of 6.8-12.9 months (206-389 days). The time to progression ranged from 1.8 to 34 months. The median survival of the patients in this trial was 31.28 months (952 days) with a confidence interval of 20.9-38.0 months (629-1141 days). Intravenous infusion of floxuridine and leucovorin is beneficial as first-line therapy in advanced colorectal cancer, demonstrating a prolonged time to progression and overall survival with acceptable tolerability and manageable toxicity profile.

Arsenic trioxide (As2O3) has demonstrated effectiveness in treating acute promyelocytic leukemia (APL). Therefore the FDA has approved it to treat APL. In patients with refractory metastatic colorectal carcinoma (CRC), we assessed the efficacy and toxicity of As2O3/AA (ascorbic acid) as the outcome of this trial. Five patients with refractory metastatic CRC who failed all previous standard chemotherapy were enrolled in this study. They were treated with 0.25 mg/kg body weight/day As2O3 and 1000 mg/day of ascorbic acid for 5 days a week for 5 weeks. Each treatment cycle extended for 7 weeks with 5 weeks of treatment and 2 weeks of rest. All the patients developed moderate to severe toxic side effects to arsenic trioxide/AA therapy and therefore the study was discontinued. No CR (complete remission) or PR (partial remission) was observed. CT scans demonstrated stable or progressive disease. Three of the five patients died within 2 to 5 months after cessation of the therapy. None of the deaths could be related to this clinical trial. Two years of follow-up study showed that two patients were alive with stable disease. Under the current treatment regimen all patients developed moderate to severe side effects with no clinically measurable activity. As an alternate, efforts may be made to reduce the dose and arsenic trioxide may be combined with other standard regimen in reversing the chemo resistance.

Background Alopecia is a common side-effect of cancer chemotherapy. Although this complication has been known for many decades, little progress has been made in its prevention or treatment. Previously, we made the following observations: (a) treatment of 8-day-old rats with 1-0-n-arabinofuranosylcytosine (ara-C), doxorubicin, and cyclophosphamide (CYC) produced either total body alopecia (ara-C and CYC) or alopecia confined to the head and proximal part of the neck (doxorubicin); (b) Imuvert, a biological response modifier, and interleukin-1 protected against alopecia-induced by ara-C; and (c) neither Imuvert or interleukin-1 protected against CYC-induced alopecia. Objective Experiments were designed to test for agents to protect against CYC-induced alopecia. Methods Agents were tested in the 8-day-old rats as a model for chemotherapy-induced alopecia. Results Mesna and S-2-(3-aminopropylamino)-ethylphospnorothioic acid (WR-2721) did not offer any protection against chemotherapy-induced alopecia. N-Acetylcysterine offered very good protection against alopecia induced by CYC but not that produced by ara-C in the newborn rate animal model. ConclusionN-Acetylcysteine may prove to be important in the prevention of CYC-induced alopecia, but this needs to be tested in the clinical setting.

BACKGROUND: The role of endoscopic ultrasound (EUS) to evaluate treatment response postneoadjuvant therapy for restaging esophageal cancer prior to surgical resection is uncertain. Accuracy of EUS is lower but potential to predict response to chemoradiation indicates that EUS may be helpful prior to surgery. OBJECTIVE: To determine staging accuracy of EUS after neoadjuvant chemotherapy, predictors of tumor response, and survival in locally advanced esophageal cancer. METHODS: Single-center retrospective evaluation of patients with locally advanced esophageal cancer on a prospective chemotherapy study. Patients who underwent EUS without FNA pre- and postchemotherapy were included. RESULTS: A total of 49 patients (43 men and 6 women) were evaluated with EUS pre- and postneoadjuvant chemotherapy. Forty-seven patients had tumor localized at the GE junction and two had mid-esophageal lesions. The median survival time was 53 months. Tumor and nodal staging accuracy postchemotherapy were 60% (27 of 45). T-stage accuracy postchemotherapy was superior in patients without a response to chemotherapy (95.7% vs 26.1%, p < 0.0001). More than 50% in reduction of tumor thickness postchemotherapy was associated with tumor downstage and better survival. NO disease on final pathology was the best predictor of improved survival. CONCLUSION: Accuracy of EUS postchemotherapy is lower than initial staging accuracy; therefore the ability to predict downstaging based on EUS is marginal. Pathology N1 disease postchemotherapy is the best predictor of survival. EUS staging postneoadjuvant chemotherapy should focus on improving nodal staging accuracy with FNA.

Purpose: The purpose of this phase II multi-institutional study was to define the efficacy and toxicity of infusional 5-FU in combination with PALA and leucovorin in patients with advanced colorectal cancer. Patients and methods: Patients were required to have histologically confirmed colorectal cancer with distant metastases. The treatment regimen consisted of 5-FU 2600 mg/m2 as a 24-hours continuous infusion given once a week, concurrently with leucovorin (LV) at 500 mg/m2 as a 24-hour continuous infusion. PALA was administered 24 hours prior to 5-FU/LV at a dose of 250 mg/m2 iv over 15 minutes weekly. Patients were continued on the assigned treatment regimen until progression of disease, unacceptable toxicity, or the patient declined further therapy. Results: This study accrued 28 patients and all were eligible and evaluable for toxicity. Four patients had inadequate assessment of response and are considered non-responders. There was one complete response and five partial responses for an overall response rate of 6/28 or 21% (95% confidence interval 8–41%). Estimated median survival was 17.4 months (95% confidence interval 13.3–20.5 months). One patient died of a treatment related infection. This patient also had grade 4 diarrhea and vomiting. Conclusion: The combination of 5-FU, leucovorin, and PALA in the doses and schedule used here, produces a response rate similar to other modulated schedules of 5-FU with similar survival and toxicity profiles.

Purpose: The purpose of this phase II multi-institutional study was to define the efficacy and toxicity of infusional 5-FU in combination with PALA and leucovorin in patients with advanced pancreatic cancer. Patients and methods: Patients were required to have histologically confirmed pancreatic cancer that was locally advanced, unresectable or disseminated. The treatment regimen consisted of weekly 5-FU 2600 mg/m2 given concurrently with leucovorin at 500 mg/m2. Both drugs were administered by 24-hour continuous infusion. PALA was administered 24 hours prior to the administration of 5-FU/LV at a dose of 250 mg/m2 IV over 15 minutes weekly. Patients were continued on the assigned treatment regimen until progression of disease, unacceptable toxicity, or the patient declined further therapy. Results: This study accrued 30 patients. Four of these patients were ineligible. All 26 eligible patients were evaluated for toxicity. One patient had inadequate assessment of response and was considered a non-responder. Three of the twenty-six eligible patients had partial responses, for a response rate of 12% (95% confidence interval 2% to 30%). All 26 eligible patients have died and the median overall survival was 7 months (95% confidence interval: 5.2 to 9 months). Four patients experienced grade 4 toxicities, including bilirubin increase (2 patients), vomiting (1 patient) and non-local skin ulceration (1). Two patients discontinued therapy due to toxicity. Conclusion: The dual modulation of 5-FU with PALA and leucovorin in the dose and schedule used here, has a response rate similar to other single agents in pancreatic cancer and can result in some long term survival while having relatively mild toxicity.

Thirty patients with primary hepatocellular carcinoma or liver metastases were entered into a program of chemoembolization with cisplatin, lipiodol, and escalating doses of thiotepa. Doses of cisplatin were 100/m2, and thiotepa doses ranged from 9 mg/m2 to 24 mg/m2. Two of three patients with ocular melanoma had partial responses in the liver metastases for 3+ and 16 months. In patients with either hepatocellular carcinoma (15 patients) or primary cholangiocarcinoma of the liver (three patients), there were two partial responses, for 22 and 33 months. Five patients had minor responses: four with a 40% reduction in tumor and one with a mixed response. There were four early deaths, which involved sepsis in two patients, respiratory failure in one, and acute myocardial infarction in one. Otherwise, toxicity was tolerable and reversible and included abdominal pain and transient elevation of serum creatinine, bilirubin, and transaminases. Less common toxicities included ototoxicity and peripheral neuropathy. Chemoembolization of the liver with cisplatin, thiotepa, and lipiodol can produce responses, but toxicity can be significant. The recommended starting phase II dose for future studies is thiotepa 24 mg/m2 and cisplatin 100 mg/m2.

5-Fluorouracil (5-FU) remains the agent of choice for the treatment of colorectal cancer. Research has focused on the biomodulation of 5-FU in order to attempt to improve the cytotoxity and therapeutic effectiveness of this drug in the treatment of advanced colorectal cancer. Modulation of 5-FU by methotrexate (MTX), trimetrexate (TMTX), interferon-alpha (IFN-alpha), leucovorin (LV), or N-(phosphonacetyl)-L-asparte acid (PALA) has produced higher response rates than those observed with 5-FU alone. Methotrexate may improve the durability of response to or survival with 5-FU, but with inferior results compared with those in trials of 5-FU and leucovorin. Trimetrexate produces a number of responses, and further phase III trials are in progress to confirm the results of promising phase II trials with this drug. IFN-alpha has shown therapeutic efficiency when combined with 5-FU alone or with 5-FU and leucovorin, but latest studies with these combinations have shown increased toxicity. Initial single-institution phase I trials with 5-FU and PALA reported promising responses, but the latter responses with PALA were not substantiated in randomized multicenter trials. Leucovorin enhances the cytotoxic activity of 5-FU in vitro and in vivo, and several clinical trials have shown improved response rates and possible trends in improved survival when such therapy is compared with the use of 5-FU as a single-agent. More recent randomized trials have focused their attention on determining the optimal dose and schedule with this combination for producing a better clinical response with minimal toxicity. Schedules using infusional 5-FU appear to be the most active regimens when 5-FU is used as a single agent, as demonstrated by recent randomized trials. The Southwest Oncology Group (SWOG) and the Eastern Cooperative Oncology Group (ECOG) have performed separate randomized trials and have shown that the optimal regimens employ infusional 5-FU as a single agent, and that these are the least toxic regimens, perhaps more effective, and associated with a better quality of life. Future studies will focus on infusional regimens involving either short-term, high-dose protracted or long-term, low-dose protracted infusion of 5-FU, since these regimens have shown the most favorable toxicity spectrum and produced the longest survival times. Future research will also focus on the evaluation of various methods of delivery of 5-FU, including oral administration of the drug in combination with compounds that can modify its catabolism.

Cryotherapy using liquid nitrogen delivered endoscopically has been used for mucosal ablation of esophageal neoplasia. There are no data for the human esophagus on the depth of injury and effects of this technique. Prospective study to examine the effect of treatment and depth of injury to the human esophagus of liquid nitrogen spray cryotherapy for subjects with esophageal neoplasia before planned esophagectomy. Liquid nitrogen spray cryoablation was performed seven days before scheduled esophagectomy for seven males with esophageal carcinoma. Subjects were assigned to either treatment of four cycles of 10 s each (group 1) or two cycles of 20 s each (group 2) applied to a 2-cm segment of healthy esophagus above the tumor area. Main outcomes measured were: mean depth of injury (mm); surface displaying mucosal ablation, and adverse events. Mucosal destruction was similar for both groups (group 1, 95 %; group 2, 93 %; p = NS). Deeper injury was observed for group 2; mean depth was 5.4 mm compared with 4.0 mm for group 1. Cryonecrosis reached the submucosa for 60 % (12/20) of subjects in group 1 versus 93 % (14/15) of subjects in group 2 (p = 0.04, two-tailed Fisher’s exact test). No serious adverse events occurred. No perforation was seen in the resected esophagus. Mucosal ablation with liquid nitrogen spray cryotherapy was highly effective in inducing mucosal necrosis; the doses assessed had similar effects. Ablation reached the submucosa more often with longer spray time despite fewer treatment cycles.

Background. The use of permanent intravenous access devices for chemotherapy administration has become a common practice in clinical oncology. Therefore, awareness of potential complications is important. The authors previously reported the use of high dose 5-fluorouracil (5-FU) (2600 mg/m2) and leucovorin (500 mg/m2) as a weekly 24-hour infusion for patients with colorectal carcinoma. In this report, a new complication of permanent indwelling catheters with high dose 5-fluorouracil (2600 mg/m 2 ) and leucovorin (500 mg/m 2 ) as a weekly 24-hour infusion for colorectal carcinoma is described. Methods. Twenty-two patients in the previous Phase II trial on weekly high dose 5-FU and leucovorin were included in this study. All patients had either a single-lumen Port-o-cath (Pharmacia Deltec, St. Paul, MN) or Hickman catheter (Travenol Laboratories, Deerfield, IL). Occluded catheters were explanted, and the material found in their lumen was analyzed using infrared spectroscopy. Results. Eleven of 22 patients had catheter blockage, and calcium carbonate formation (Calcite 100%) was identified within these catheters. Conclusion. Calcite formation causing catheter occlusion is a new and important complication resulting from using intravenous access devices for chemotherapy administration. Oncologists should be alerted to this phenomenon when high dose 5-FU and leucovorin are administered for 24 hours by continuous infusion using a single-port port-o-cath. Cancer 1995 ; 75 :2165-8.

124 Background: A complete pathological response to neoadjuvant chemotherapy without the use of radiation has infrequently been reported in operable chemo-naïve stage III gastro esophageal adenocarcinoma patients. Methods: Twenty-nine patients were enrolled in this study. Neoadjuvant therapy consisted of Floxuridine, Leucovorin, Oxaliplatin, and Docetaxel and was administered in 2, four week cycles. Chemotherapy consisted on day one and day fifteen; Oxaliplatin, Docetaxel, FUDR, and Leucovorin. The latter two drugs were given concurrently over twenty four hours. On day eight, chemotherapy consisted of Docetaxel, FUDR, and Leucovorin. Following therapy, patients underwent surgical resection. Those patients having residual disease were offered adjuvant chemotherapy. Patients having a complete pathological response were not offered any further therapy. Results: Twenty-four out of twenty-nine patients completed neoadjuvant therapy and underwent esophagectomy. Two were declared inoperable after treatment. Three patients died prior to surgery. The median follow-up of all patients is now sixty months. The median overall survival has not been reached at sixty months. Five yr actual OS is 51%. Clinical response to neoadjuvant therapy was seen in (72.4%) patients. Complete pathological response to neoadjuvant therapy was seen in (16.7%) who are disease free at sixty month follow-ups. Seven out of twenty-four patients achieved partial pathological response (29.1%) and received adjuvant chemotherapy. They are all alive (100%). Eight patients achieved less than partial pathological response and received adjuvant chemotherapy, four out of eight are alive at sixty months (50%). Grade three and four toxicities were seen in sixteen out of twenty nine patients during neoadjuvant therapy. Grade three and four toxicities were seen in six out of fourteen patients during adjuvant therapy. Conclusions: Our chemotherapy regimen of Floxuridine, Leucovorin, Oxaliplatin and Docetaxel (FLOD) has resulted in long term survival in patients with adenocarcinoma of the esophagus. Clinical trial information: NCT00448760.

BACKGROUND Preclinical and clinical data suggest that N-phosphonacetyl-L-aspartic acid (PALA) can augment the cytotoxic effects of 5-fluorouracil (5-FU). In addition, the combination of 5-FU and radiation therapy has been used with success in prolonging survival and providing palliation of symptoms in patients with advanced unresectable pancreatic carcinoma. This Phase I study was undertaken to determine the feasibility and evaluate the qualitative and quantitative toxicities of PALA and escalating doses of 5-FU administered concomitantly with radiation therapy in patients with locally advanced nonmetastatic pancreatic adenocarcinoma. METHODS Ten previously untreated patients with advanced nonmetastatic adenocarcinoma of the pancreas were treated with 250 mg/m2 of PALA given as an intravenous bolus followed 24 hours later by 5-FU, which was given by continuous 24-hour infusion every week. The 5-FU doses were assigned according to a Phase I drug escalation (1000 mg/m2, 1300 mg/m2, and 1700 mg/m2). Radiation therapy was delivered concurrently with chemotherapy at a dose of 180 cGy per fraction (900 cGy per week) over 6 1/2 weeks. PALA and 5-FU were continued weekly after the end of radiation therapy, with disease assessments made every 8 weeks. Chemotherapy was continued until the disease progressed. RESULTS All 10 patients were evaluable. The maximum tolerated dose (MTD) of 5-FU was 1300 mg/m2. Two of the four patients treated at the 1700 mg/m2 dose level experienced dose-limiting toxicities, nausea/vomiting and mucositis, respectively. Toxicities were mild to moderate at the 1000 mg/m2 and 1300 mg/m2 dose levels. Two patients treated with 5-FU at the 1300 mg/m2 dose level had complete responses, and one patient treated at the 1700 mg/m2 dose level had a partial response. The median survival was 12.5 months, and four patients survived more than 1 year. CONCLUSIONS PALA and 5-FU administered concomitantly with radiation therapy is an active regimen in locally advanced, unresectable pancreatic cancer. Dose-limiting toxicities are nausea/vomiting and mucositis. The MTD of 5-FU is 1300 mg/m2. The regimen is well tolerated and administered in an outpatient setting.

Background. Radioimmunodetection of cancer using monoclonal antibody fragments offers certain potential advantages over that with whole monoclonal antibodies, including the ability to image early (i.e., to provide images at an early time after injection of the radio-antibody) while minimizing the incidence of human anti-mouse antibody response. This paper reports a prospective trial comparing radioimmunodetection with IMMU-4 (a murine anti-CEA monoclonal antibody) 99m Tc-labeled Fab' fragments to conventional imaging in 35 colorectal cancer patients. Methods. All patients were investigated by conventional diagnostic methods (CDM) within 4 weeks of radioimmunodetection

Background The role of neoadjuvant and adjuvant therapy for gastric cancer remains undefined. We compared the outcomes for patients treated with surgery alone or with the addition of adjuvant or neaodjuvant treatment. Methods A single-institution, retrospective evaluation of a prospective database of gastric cancer patients treated from 2000 to 2008 was performed. Results Overall, 173 patients with gastric cancer underwent surgical extirpation. Of the 173 patients, 43% had early-stage disease (less than stage 2) and 57% had late-stage disease (stage 2 or greater; American Joint Committee on Cancer, 2010). The median survival from the date of diagnosis for those treated with neoadjuvant chemotherapy (NAC) (n = 35), adjuvant chemotherapy (n = 21), adjuvant chemoradiotherapy (n = 18), both NAC and adjuvant chemotherapy (n = 11), or surgery alone (n = 88) was 26.3, 17.3, greater than 60, greater than 60, and 50.3 months, respectively. The addition of NAC to surgery was detrimental to survival in those with early-stage disease (P = 0.002) and did not improve survival in those with late-stage disease (P = 0.687). For those with late-stage disease, surgery with adjuvant chemoradiotherapy exhibited the best overall survival compared with surgery alone (P = 0.021) or surgery with adjuvant chemotherapy (P = 0.01). Patients treated with NAC had a greater rate of R0 resection compared with surgery alone (P = 0.049). Conclusions NAC for patients with gastric cancer does not significantly improve the overall outcomes for those with late-stage disease and could be detrimental to survival for those with early-stage disease. However, treatment with NAC resulted in an improved rate of R0 resection.

Thymidylate synthase (TS) gene contains 28-bp polymorphic sequence and 6-bp insert at the 5'- and 3'-untranslated region, respectively. We investigated the role of these two polymorphic traits on TS mRNA expression in nine different cultured human cancer cell lines in vitro. Three cell lines each were 2R/2R, 2R/3R and 3R/3R genotypes. Six of the nine cell lines tested homozygous for the presence of 6-bp insert (+6/+6) and the rest three lacked this insert (-6/-6). TS expression analyses associated homozygous three repeats (3R/3R) to higher TS expression.

Objective: A complete pathologic response to neoadjuvant chemotherapy, without the use of radiation, has infrequently been reported in operable chemo-naive stage III esophageal adenocarcinoma patients. Methods: Twenty-nine eligible patients were enrolled in the study. Neoadjuvant therapy con- sisted of 5-fluorodeoxyuridine, leucovorin, oxaliplatin and docetaxel and was administered in two 4-week cycles. Following therapy, patients underwent surgical resection. Those patients having residual disease were offered adjuvant chemotherapy. Patients having a complete pathologic response were not offered any further chemotherapy. Results: Twenty-four out of 29 patients finished neoadjuvant therapy and underwent curative esophagectomy. Two patients were declared inoperable after treatment, and three patients died prior to surgery. The median follow-up on all patients was 20.2 months. Median pro- gression-free survival and median overall survival were 13.6 and 21.4 months, respectively. Clinical response to neoadjuvant chemotherapy was seen in 21 out of 29 patients (72.4%). Complete pathologic response with neoadjuvant chemotherapy was seen in 4 out of 24 patients (16.7%). Those four patients have been alive and progression-free for 20-37 months. Grade 3-4 toxicities occurred in 16 of the 29 patients during neoadjuvant therapy. Grade 3-4 toxicities were seen in 6 out of 14 patients during adjuvant therapy. 18 F-fluorodeoxyglucose-positron emission tomography standardized uptake values of � 8 correlated with better progression-free survival. Conclusion: 5-Fluorodeoxyuridine, leucovorin, oxaliplatin and docetaxel regimen is active in patients with esophageal adenocarcinoma. Toxicity profiles are manageable. Neoadjuvant chemotherapy allowed achievement of complete pathologic response without radiation. 18 F- fluorodeoxyglucose-positron emission tomography standardized uptake values might be prognostic.

Doxorubicin (DOX) efflux in drug-resistant cells is blocked by phenothiazines such as trifluoperazine (TFP) and prochlorperazine (PCZ) in vitro. The present phase I study was conducted in 13 patients with advanced, incurable, nonhematologic tumors to determine whether PCZ plasma levels high enough to block DOX efflux could be achieved in vivo. The treatment schedule consisted of prehydration and i.v. administration of 15, 30, 50, and 75 mg/m2 PCZ followed by a standard dose of 60 mg/m2 DOX. The hematologic toxicities attributable to DOX were as expected and independent of the PCZ dose used. Toxicities attributable to PCZ were sedation, dryness of the mouth, cramps, chills, and restlessness. The maximal tolerated dose (MTD) of PCZ in this schedule was 75 mg/m2. Pharmacokinetic analysis indicated a large interpatient variation in peak plasma PCZ levels that ranged from 95 to 1100 ng/ml. The three plasma half-lives of PCZ were: t1/2 alpha (+/- SE), 20.9 +/- 5.3 min; t1/2 beta, 1.8 +/- 0.3 h; and t1/2 gamma, 21.9 +/- 5.3 h. The volume of distribution (Vd), total clearance (ClT), and area under the curve (AUC) for PCZ were 2254 +/- 886 l/m2, 60.2 +/- 13.5 l m-2 h-1, and 1624 +/- 686 ng ml-1 h, respectively. DOX retention in tumor cells retrieved from patients during the course of therapy indicated the appearance of cells with enhanced DOX retention. The combination of DOX and high-dose i.v. PCZ appeared to be safe, well tolerated, and active in non-small-cell lung carcinoma.

Identification of new agents with antitumor activity in chemoresistant tumors is urgently needed for the treatment of colorectal cancer. Arsenic trioxide (As(2)O(3)), a Food and Drug Administration (FDA) approved drug is successfully being used to treat acute promyelocytic leukemia (APL). Several clinical trials also suggest its ineffectiveness on solid tumors. We proposed that arsenic trioxide may be used as chemosensitizer, especially to 5-fluorouracil (5-FU). The effect of arsenic trioxide on cell proliferation of 5-FU-sensitive and -resistant HT29 colorectal cancer cells in vitro was tested by trypan blue dye exclusion assay, 2, 3-bis(2-methoxy-4-nitro-5-sulfophenyl)-S-[(phenylamino) carbonyl]-2H-tetrazolium hydroxide (XTT) cell proliferation assay and cell cycle analysis using flow cytometry. Gene expression was analyzed using real-time polymerase chain reaction (PCR) and Western blot methods. There was a dose-dependent increase in cell detachment and proliferation in HT29 and HT29FU cells. As a single agent, arsenic trioxide also down-regulated thymidylate synthase (TS) expression without affecting the expression of some other genes analyzed in the above cell lines. Combination of arsenic trioxide and 5-FU increased cytotoxicity. In vitro data show that as a single agent, arsenic trioxide down-regulated TS expression in HT29 cells. Addition of 5-FU to these sensitized cells increased cytotoxicity. These findings open up a possibility to use arsenic trioxide as a chemosensitizer in combination therapy.

Resistance to chemotherapy is a major issue in treating malignant diseases. 5-Fluorouracil (5-FU) is the drug of choice in managing colorectal cancer (CRC) patients. However, 5-FU resistance leads to eventual treatment failure. Therefore, delaying or reversing the onset of 5-FU resistance will benefit these terminally ill patient populations. A metabolite of 5-FU irreversibly binds thymidylate synthase (TS) thus inhibiting its activity. Many studies demonstrated that these resistant patients had an increased intratumoral TS level. We used TS-siRNA to reduce TS and resensitize HT29FU CRC cells back to this uracil analogue. We exposed the CRC cell line HT29 to an increasing concentration of 5-FU or 5-fluorouridine (FUR) and established a derivative cell line (HT29FU and HT29FUR). Using real-time polymerase chain reaction (PCR) and Western immunodetection assays, we analyzed the expression of TS and p53 mRNA and protein in control and experimental groups. Cytotoxicity to 5-FU was determined by reduction of 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT assay) or trypan blue dye exclusion assay. The HT29FU and HT29FUR cells have a distinct morphology: they are generally asteroid shaped. The half maximal inhibitory concentration (IC(50)) values for the resistant cell line for 5-FU is over 148 microM compared to 5 microM for the sensitive parental cell line. The resistant cell lines expressed more of TS and less of p53. TS-siRNA suppressed TS only. Other pathways were not significantly altered. It also marginally (20%) re-sensitized resistant cells to 5-FU. Restoration of partial sensitivity to 5-FU by TS-siRNA reiterates the primacy of the DNA synthesis pathway in 5-FU mode of action. We speculate that the short half-life of the transiently transfected siRNA may contribute to the marginal restoration of sensitivity. By integrating TS-siRNA expression vector into the genome and regulating its expression, we may be able to reverse 5-FU resistance and make the cells as sensitive as the parental cell line.

BACKGROUND: 4'-0-tetrahydropyranyladriamycin (Pirarubicin, Meiji Seika (USA) Inc., New York, NY) may be less toxic than doxorubicin. METHODS: A Phase II trial of Pirarubicin was done in 26 patients who had not previously had chemotherapy and who had measurable and incurable head and neck carcinoma. All patients received an intravenous bolus dose of 60 mg/m2 Pirarubicin in the first cycle without any prophylactic antiemetic. The cycles were repeated every 3 weeks. Based on tumor response, nadir counts, or complications of myelosuppression, the doses were escalated or de-escalated by 10 mg/m2, if necessary, in the second cycle to achieve mild leukopenia (3000-4000 leukocytes/microliters). RESULTS: Leukopenia was mild, moderate (2000-2999 leukocytes/microliters), severe (1000-1999 leukocytes/microliters), and life threatening (less than 1000 leukocytes/microliters) in 13%, 31%, 27%, and 9% of the first two courses, respectively. The median interval to nadir leukopenia was 13 days (range, 7-21 days), with a median of 8 days (range, 5-13 days) to recover to normal. One patient with a leukocyte count of 800/microliters and an absolute granulocyte count (AGC) of 488/microliters died of sepsis 15 days after the first course. All patients had at least one course that resulted in leukopenia. One episode each of mild (100,000-150,000 platelets/microliters) and severe (25,000-49,999 platelets/microliters) thrombocytopenia occurred in the first two courses. Leukocyte, granulocyte, and platelet counts were not done routinely after the second cycle. Six patients who received four or more courses with cumulative doses of 310, 610, 340, 260, 660, and 550 mg/m2 had decrements of 0%, 1%, 7%, 10%, 12%, and 13%, respectively, in radionuclide left ventricular ejection fraction (LVEF). All other toxic effects were mild. CONCLUSIONS: In the 24 patients with disease evaluable for response to Pirarubicin therapy, 1 had a complete response that lasted 5 months and 4 had a partial response of 2, 3, 6, and 8 months. The median survival time in patients with disease that responded to Pirarubicin therapy was 27 months; in patients with disease that did not respond to Pirarubicin therapy, the median survival time was 4 months, and in the total cohort, it was 5 months. Pirarubicin was well tolerated and was an active agent in head and neck squamous cell carcinoma.

Twenty-eight patients with refractory advanced malignancies were treated with a 24 hr infusion of 5-fluorouracil (5-FU), Leucovorin (LV), and N-(phosphonacetyl)-L-aspartic acid (PALA) weekly. Twenty-seven patients were evaluable for the assessment of toxicity and anti-tumor activity. PALA was administered as intravenous bolus over 15 min at a fixed dose, 250 mg/m2 24 hr before the start of 5-FU and LV infusions. 5-FU was initially administered at 750 mg/m2 and was incrementally increased to 2600 mg/m2. LV was administered in a fixed dose of 500 mg/m2 concurrently with 5-FU over a 24-hr period. The course was repeated weekly. Diarrhea, stomatitis, nausea, and vomiting were among dose-limiting toxic effects. Other toxicities observed were hand-foot syndrome, hair loss of scalp/eyelashes, overall weakness, rhinitis, and chemical conjunctivitis. Maximum tolerated dose (MTD) of 5-FU in this combination and schedule was 2600 mg/m2. Seven of 14 patients treated at 2600 mg/m2 were able to tolerate the chemotherapy on a weekly basis without interruption. The other seven patients required dose de-escalation, a majority of whom contained 5-FU at a dose of 2100 mg/m2. Twenty-three of 27 patients had been previously treated. Eight patients achieved a partial response, all of whom were previously treated, except three patients. A complete response was observed in a patient with pancreatic carcinoma, previously untreated. Overall response rate for the patients who were treated at the 5-FU dose of 2100 mg/m2 or 2600 mg/m2 is 9 of 18 patients (50%).

Twenty-eight patients with refractory advanced malignancies were treated with a 24-hour infusion of 5-fluorouracil (5-FU), leucovorin (LV), and N-(phosphonacetyl)-L-aspartic acid (PALA) weekly. Twenty-seven patients were evaluable to assess toxicity and antitumor activity. The PALA was administered as an intravenous bolus over 15 minutes at a fixed dose (250 mg/m2) 24 hours before the start of the 5-FU and leucovorin infusions. Initially the dose of 5-FU was 750 mg/m2; this was increased incrementally to 2600 mg/m2. The LV was administered in a fixed dose of 500 mg/m2 concurrently with the 5-FU over a 24-hour period. This regimen was repeated weekly. Diarrhea, stomatitis, nausea, and vomiting were among the dose-limiting toxicities. Others were hand-foot syndrome, hair loss of the scalp and eyelashes, overall weakness, rhinitis, and chemical conjunctivitis. The maximum tolerated dose of 5-FU in this combination and schedule was 2600 mg/m2. Seven of 14 patients treated with 2600 mg/m2 were able to tolerate the chemotherapy on a weekly basis without interruption. The other seven patients required dose reductions, but most received 5-FU at a dose of 2100 mg/m2. Twenty-three of 27 patients were treated previously. Eight patients had a partial response; five of these were treated previously. A complete response was observed in one patient with pancreatic carcinoma, previously untreated. The overall response rate for patients treated with 2100 or 2600 mg/m2 of 5-FU was nine of 18 patients (50%). Three of four previously untreated patients with pancreatic cancer responded to this treatment (two responded partially, and one had a complete response). One of three heavily pretreated patients with non-small cell lung cancer had a partial response as did a patient with breast cancer. Four of ten patients with colorectal cancer responded to the treatment (four partial responses), of whom three had been treated previously.

Twenty-two patients with advanced colorectal carcinoma were enrolled in this study. Ten patients had received prior chemotherapy that included the combination of fluorouracil (5-FU) and leucovorin (LV). All patients required subcutaneous port insertion and portable external infusion pumps to allow outpatient treatment. 5-FU (2,600 mg/m2) was administered concurrently with LV (500 mg/m2) over 24 hours of continuous infusion. The mean steady-state plasma concentration of 5-FU was 10 mumol/L (range, 7 to 14 mumol/L). The 5-FU dose was based on our previous phase I study, in which maximum-tolerated dose (MTD) of 5-FU was determined to be 2,600 mg/m2 in combination with a fixed dose of LV at 500 mg/m2. The treatment was repeated weekly. Twenty-two patients received a total of 560 courses of treatment. Eleven instances of grade 2-3 toxicity were observed: diarrhea (five), stomatitis (three), hand/foot syndrome (three). The overall objective response was 45% (10 of 22) and among previously untreated patients was 58%. Three of the responders achieved complete response (CR), with lung and liver as the metastatic sites. The median duration of survival for the previously untreated patients was not reached at 22 months, and was 10 months for the previously treated patients. These results suggest that short-term infusional therapy of 5-FU and LV in patients with advanced metastatic colorectal cancer generates acceptable toxicity, with equivalent or superior survivability in previously treated and untreated patients versus alternative methods of administration of the two agents.

Background A phase II trial to evaluate neoadjuvant (NAD), surgery and adjuvant (AD) combination chemotherapy without radiation therapy (RT) for patients with esophageal adenocarcinoma staged with endoscopic ultrasound and CT as T3N1 was carried out. Methods Thirty-three eligible patients were enrolled. NAD therapy was administered in two 49-day cycles and included cisplatin, floxuridine, paclitaxel and leucovorin. Esophageal resection was performed followed by AD therapy. Results Thirty-three patients initiated NAD therapy; 10 experienced grade 3 and 4 toxicities, which included leucopenia, fatigue, nausea, diarrhea and stomatitis. Additionally, 16 patients experienced grade 1 and 2 hematologic and non-hematologic toxicities. Fifteen patients were down-staged, of whom five were T2, seven were T1, and three had nodal disease with no evidence of residual cancer in the esophageal bed. Fifteen patients remained T3, and two showed progressive disease. Thirty-two patients proceeded to surgery and 30 were resected. Although all resected patients were eligible for AD therapy, 15 did not receive it either because of patient refusal or surgeon recommendation. Fifteen patients received AD therapy: nine who had remained T3 and six who had down-staged. Three patients experienced grade 3 and 4 toxicities similar to those in NAD therapy. Six patients had grade 1 and 2 toxicities. Kaplan-Meier estimates of overall survival at 1, 3 and 5 years were 73% (95% CI: 58-88%), 52% (95% CI: 34-69%) and 29% (95% CI: 13-45%), respectively. Median survival was 42 months. Conclusion Deletion of RT may safely allow for more aggressive chemotherapy and increase chances of survival. The results need to be confirmed in a randomized phase II or larger phase III trial.

Worldwide, esophageal carcinoma is a common gastrointestinal cancer with a high mortality. The incidence of adenocarcinoma of the esophagus is increasing in the western world, but squamous cell carcinoma remains dominant in the underdeveloped parts of the world. Both types of esophageal carcinoma remain equally virulent. Currently, there are no optimal preventative screening programs available and most patients present with advanced or metastatic disease. Although many options are available for improving diagnostic accuracy, a single method has not displayed significant advantages over the others. In addition, selecting a superior treatment regimen has not surfaced. Preferred resection techniques exist, but one method has not illustrated improvements in survival over the others. A lack of improved survival rates with single modality therapies has led to a multi modality approach. However, developments in neoadjuvant and adjuvant therapies have led to mixed conclusions. Collectively, past studies have not shown an optimal neoadjuvant or adjuvant regimen in terms of survival benefit. This review highlights existing staging modalities and treatment regimens for esophageal carcinoma, in an effort to illustrate the controversial nature surrounding its management.

N-(phosphonacetyl)-disodium L-aspartic acid (PALA) demonstrates a synergistic antitumor effect when combined with 5-Fluorouracil (5-FU) in in vitro studies. In a Phase II trial, 23 eligible patients with unresectable or metastatic adenocarcinoma of the stomach were treated with weekly i.v. bolus PALA (250 mg/M2) followed 24 hours later by a 24-hour infusion of 5-FU (2600 mg/M2) for an initial period of 8 weeks. No objective responses were noted. PALA and 5-FU is inactive against gastric adenocarcinoma at the doses and schedule used in this trial.

This phase II study was conducted to assess the efficacy of fluorodeoxyuridine (FUdR) in patients with metastatic, advanced pancreatic cancer who had no previous chemotherapy. Twenty patients were enrolled in this single institution trial. The primary endpoint of this study was the assessment of overall survivorship. The secondary endpoints were to estimate the time to tumor progression and the assessment of toxicity in this cohort of patients. Treatment consisted of FUdR 150 mg/kg dissolved in 500 cc normal saline intravenous infusion over 24 h. Eight weeks of treatment constituted one course of chemotherapy. Tumor measurements were conducted at 8-weekly intervals. Four patients achieved partial response and 16 patients had stable disease. Median survival of patients treated with FUdR was 11.6 months with a range of 3–16 months. Median progression-free survival was 6 months. Overall, chemotherapy was well tolerated with low incidence of grade 3 or 4 toxicity. Systemic chemotherapy with high dose FUdR administered on a weekly schedule has led to encouraging survival outcomes and improved quality of life as compared to previous phase II single agent chemotherapeutic trials.