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Lessons Learned Antitumor activity was observed in the study population. Dose modifications of cabozantinib improve long-term tolerability. Biomarkers are needed to identify patient populations most likely to benefit. Further study of cabozantinib with or without panitumumab in patients with metastatic colorectal cancer is warranted. Background The epidermal growth factor receptor (EGFR) antibody panitumumab is active in patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC), but nearly all patients experience resistance. MET amplification is a driver of panitumumab resistance. Cabozantinib is an inhibitor of multiple kinases, including vascular endothelial growth factor receptor 2 (VEGFR2) and c-MET, and may delay or reverse anti-EGFR resistance. Methods In this phase Ib clinical trial, we established the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of cabozantinib and panitumumab. We then treated an expansion cohort to further describe the tolerability and clinical activity of the RP2D. Eligibility included patients with KRAS WT mCRC (later amended to include only RAS WT mCRC) who had received prior treatment with a fluoropyrimidine, oxaliplatin, irinotecan, and bevacizumab. Results Twenty-five patients were enrolled and treated. The MTD/RP2D was cabozantinib 60 mg p.o. daily and panitumumab 6 mg/kg I.V. every 2 weeks. The objective response rate (ORR) was 16%. Median progression free survival (PFS) was 3.7 months (90% confidence interval [CI], 2.3–7.1). Median overall survival (OS) was 12.1 months (90% CI, 7.5–14.3). Five patients (20%) discontinued treatment due to toxicity, and 18 patients (72%) required a dose reduction of cabozantinib. Conclusion The combination of cabozantinib and panitumumab has activity. Dose reductions of cabozantinib improve tolerability.

Background: An intravenous formulated extract of the venom of the wild toad Bufo bufo gargarizans Cantor or Bufo melanostictus Schneider, huachansu, is currently used in China for the treatment of lung, liver, pancreatic, and colorectal cancers. We performed a randomised, single-blinded, phase II clinical study of huachansu plus gemcitabine versus placebo plus gemcitabine in patients with locally advanced and/or metastatic pancreatic adenocarcinomas. Methods: Patients with tissue-proven locally advanced and/or metastatic pancreatic adenocarinoma were randomly assigned to receive either gemcitabine 1000 mg m−2 on days 1, 8, and 15 with huachansu 20 ml m−2 daily for 21 days (arm A) or placebo (arm B); treatment cycles were 28 days in length. Primary end point was 4-month progression-free overall survival (PFS); secondary end points were objective radiographical response rate (ORR), time to progression (TTP), and toxicity. Results: A total of 80 subjects were enrolled; 76 patients were evaluable (received at least 1 week therapy). Median overall survival was 160 days for arm A and 156 days for arm B (P=0.339); ORR was 9 and 3% in arms A and B, respectively (P=0.332), median TTP was 98 and 115 days, respectively (P=0.825); the median 4-month PFS was 99 and 98 days, respectively (P=0.679). Conclusion: Huachansu when combined with gemcitabine did not improve the outcome of patients with locally advanced and/or metastatic pancreatic cancer.

Survivin is a universal tumor antigen that is being currently targeted in vaccine approaches against cancer. Our study here examined the immunogenicity of a novel variant of an HLA-A0201-binding decamer peptide from region 95 to 104 of Survivin (ELMLGEFLKL) with a T→M modification at position 3 in the peptide. We found that this new modified 10-mer peptide had enhanced HLA-A0201 binding and induced a stronger T-cell response over its wild type counterpart peptide (ELTLGEFLKL) in select HLA-A0201(+) normal donors. In addition, when compared to the previously characterized altered 96-104 peptide (LMLGEFLKL) from the same region of Survivin currently used in vaccine trials, we found that both peptides had similar immunogenicity, but donor T cells preferentially reacted strongly to either one or the other, but not strongly to both. These results suggest that these two closely related Survivin peptides yield distinct T-cell responses and that most individuals dominantly respond to one or the other altered peptide. We also found a novel association between positive reactivity to the new altered decamer Survivin peptide in some individuals and their expression of the HLA-C0701 allele along with HLA-A0201. Thus, vaccinating with both the 10-mer and 9-mer peptides would be required to immunize a maximum number of individuals in the HLA-A0201(+) population and could lead to more consistent T-cell responses against this region of Survivin.

To explore the utility of multidisciplinary approaches in the treatment of patients with pancreatic cancer with liver metastases (PCLM).From 2002 to 2007, a total of 164 consecutive patients with PCLM treated with chemotherapy, radiation therapy, and/or Chinese herbal medicine were included in this study. Clinical parameters, treatments received, and survival time from initial diagnosis were analyzed.Of the 164 patients, 113 (69%) were men and 51 (31%) were women, with median age of 58 years. One hundred thirty-two patients (80%) had synchronous liver metastases, and 57 patients (35%) had extrahepatic metastases. Overall median survival time of the 164 patients was 4.7 months; 23 (14%) were alive at least 12 months after initial diagnosis of liver metastases. Karnofsky performance status of less than 80, weight loss (10% within 6 months), ascites, and carbohydrate antigen 19-9 of 1000 U/mL or greater were the most relevant predictors of poor survival. Multivariate analysis showed that chemotherapy and Chinese herbal medicine were protective factors.Multimodality treatment is well tolerated by patients with PCLM and may be effective in prolonging their survival. Awareness of the implications of these prognostic factors may assist in evaluating the survival potential of patients and selecting the most appropriate treatments.

Purpose The primary goal of this study was to evaluate whether pathologic response to chemotherapy predicts patient survival after preoperative chemotherapy and resection of colorectal liver metastases (CLM). The secondary goal of the study was to identify the clinical predictors of pathologic response. Patients and Methods A retrospective review was performed of 305 patients who underwent preoperative irinotecan- or oxaliplatin-based chemotherapy, followed by resection of CLM. Pathologic response was systematically evaluated and reported as the mean of the percentage of cancer cells remaining within each tumor. Univariate and multivariate analyses were performed to identify the predictors of pathologic response and survival. Results Cumulative 5-year overall survival rates by pathologic response status were as follows: 75% complete response (no residual cancer cells), 56% major response (1% to 49% residual cancer cells), and 33% minor response (≥ 50% residual cancer cells; complete v major response, P = .037; major v minor response, P = .028). Multivariate analysis revealed that only surgical margin status (P = .050; hazard ratio [HR], 1.77) and pathologic response (major response: P = .034; HR, 4.80; minor response: P = .007; HR, 6.93) were independent predictors of survival. Multivariate analysis of the predictors of pathologic response revealed that carcinoembryonic antigen level ≤ 5 ng/mL, tumor size ≤ 3 cm, and chemotherapy with fluoropyrimidine plus oxaliplatin and bevacizumab were independent predictors of pathologic response. Conclusion Pathologic response predicts survival after preoperative chemotherapy and resection of CLM. Degree of pathologic response represents a new outcome end point for prognosis after resection of CLM.

BACKGROUND. The current study evaluated the effect of bevacizumab added to fluoropyrimidine-plus-oxaliplatin (5FU/OX) chemotherapy for colorectal liver metastases (CLM) on the pathologic response and nontumorous liver histology. METHODS. A total of 105 consecutive patients treated preoperatively with 5FU/OX chemotherapy with (n = 62) or without (n = 43) bevacizumab were analyzed. The response to chemotherapy was evaluated by pathologic analysis of tumor viability (percentage of viable tumor in relation to tumor surface area). The incidence and grade of hepatic sinusoidal dilation were also investigated. RESULTS. Bevacizumab-containing regimens significantly reduced the degree of tumor viability compared with 5FU/OX-only chemotherapy (32.9% vs 45.3%; P = .02). After stratification according to the magnitude of tumor viability, a higher proportion of patients treated with bevacizumab than without had

Pancreatic cancer is a rapidly fatal malignancy. The prognosis is extremely poor because this disease is usually diagnosed at a late stage and the tumors are highly aggressive and resistant to most treatments.1 Resistance to therapy leads to large individual variation in response to cytotoxic cancer therapies. To improve treatment efficacy, novel strategies are needed to help clinicians select the most suitable treatment regimen for each patient. Recent developments in pharmacogenomics and gene profiling have provided such opportunities.2 Several studies have shown that genetic variations in DNA repair and drug metabolism significantly affect the clinical outcome of patients receiving cytotoxic therapies.3–7 Gemcitabine and radiotherapy are currently the main therapeutic modalities for advanced pancreatic cancer.8 However, it is not clear what factors influence the clinical response to such treatment. Gemcitabine is a potent radiosensitizer.9 Little is known about DNA repair pathways that may alter cytotoxicity or radio-sensitivity with gemcitabine. On the other hand, it is well known that oxidative DNA damage and resulting DNA strand breaks are the most common type of radiation lesions that lead to mammalian cell death.10 The base excision repair (BER) pathway and the DNA strand break repair pathway are the major repair systems that contribute to the processing of oxidative lesions.11,12 In our previous studies we have shown a significant effect of DNA homologous recombination gene polymorphisms on overall survival of patients with pancreatic cancer.13,14 The current study focuses on the BER pathway. Two subpathways of BER have been characterized by in vitro methods and classified according to the length of the repair patch: the short patch pathway repairs single nucleotides and the long patch pathway repairs lesions of 2–10 nucleotides.15 Short patch repair is the primary pathway for the repair of oxidative DNA damages, but long patch repair may occur when components of short patch repair are saturated or missing. The short patch repair process requires a number of enzymes: a DNA glycosylase, such as 8-oxo-guanine DNA glycosylase (hOGG1), removes the damaged base (e.g., 8-oxoguanine); apurinic/apyrimidinic endonuclease I (APEX1) recognizes and cleaves the resulting abasic (AP) site, introducing a single strand break; X-ray repair cross complementing protein 1 (XRCC1) is a scaffold protein that brings polymerase β (POLB) and ligase III (LIG3) together at the site of repair. DNA POLB adds a single nucleotide to the 3′-end of the nicked AP site and removes the resulting 5′-deoxyribose phosphate group, and a DNA LIG3-XRCC1 complex seals the generated nick.16 Polymorphisms of DNA repair genes may be capable of serving as a genetic marker for individual susceptibility to cytotoxic cancer therapy because of the role of DNA repair in protecting cells from DNA damage-mediated death. To test the hypothesis that genetic variations in BER affect clinical response to chemoradiotherapy and thus patient survival, we examined 9 single nucleotide polymorphisms of 6 major genes (hOGG1, APEX1, POLB, XRCC1, LIG3 and LIG4) that are involved in each step of the short patch BER pathway in 378 patients with a diagnosis of pancreatic ductal adenocarcinomas and who were treated at The University of Texas M. D. Anderson Cancer Center between 1999 and 2004. Overall survival was compared between patients with different genotypes.

It is estimated that, in 2006, approximately 33,730 Americans will develop pancreatic cancer, and 32,300 will die from this disease.1 The mortality rate of pancreatic cancer (10.5 per 100,000 population) is almost equal to its incidence rate (11.0 per 100,000 population) for both sexes and all ethnic groups.2 Cigarette smoking is the only established environmental risk factor for pancreatic cancer. Very little is known about how genetic and environmental factors interact to foster the development of this malignancy.3 Clinically, treatment of pancreatic cancer remains a challenge, and there is great heterogeneity in the way patients respond to chemotherapy. Therefore, it is important to understand how genetic factors contribute to both predisposition to and clinical outcome of this disease. The cytosolic glutathione S-transferases (GSTs) (Enzyme Commission no. 2.5.1.18) are a family of phase II isoenzymes that are important parts of the cell defense against numerous harmful chemicals that are produced endogenously and exogenously. GSTs catalyze the addition of reduced glutathione (GSH) to a variety of electrophilic compounds, including tobacco carcinogens4-6 and anticancer agents.7 Eight families of soluble GSTs in humans have been identified,8 and they have overlapping substrate specificities. GST-μ,GST-Θ, and GST-π are encoded by the GSTM1, GSTT1, and GSTP1 genes, respectively; and these 3 genes have been examined extensively in association with genetic susceptibility9,10 and clinical outcomes of several types of human cancer.11-15 Homozygous deletion of the GSTM1 and GSTT1 genes (null genotype) has been associated with the loss or lack of enzyme activity and increased vulnerability to cytogenetic damage.16,17 It has been shown that the exon 5 A1404G, which encodes an isoleucine (Ile)→valine (Val) exchange at codon 105 (Ile105Val) (reference single nucleotide polymorphism [rs] no. 947894), and exon 6 C2294T, which encodes an Ala→Val exchange at codon 114 (Ala114Val) (rs no. 1799811) of the GSTP1 gene, confer lower levels of metabolizing activity toward a variety of carcinogens and anticancer agents.18-20 GST-μ,GST-Θ,and GST-π all are expressed in the human gastrointestinal tract.21 In particular, GST-π appears to be one of the constitutive elements of the human pancreas.22 In the current study, we investigated the association between GST gene polymorphisms and the risk of pancreatic cancer as well as the clinical outcome of patients with cancer. We hypothesized that these polymorphisms influence the detoxification of carcinogens, reactive oxygen species, and anticancer drugs, thereby influencing susceptibility to pancreatic cancer as well as the clinical outcome of patients.23

The current study evaluated the effect of bevacizumab added to fluoropyrimidine-plus-oxaliplatin (5FU/OX) chemotherapy for colorectal liver metastases (CLM) on the pathologic response and nontumorous liver histology.A total of 105 consecutive patients treated preoperatively with 5FU/OX chemotherapy with (n = 62) or without (n = 43) bevacizumab were analyzed. The response to chemotherapy was evaluated by pathologic analysis of tumor viability (percentage of viable tumor in relation to tumor surface area). The incidence and grade of hepatic sinusoidal dilation were also investigated.Bevacizumab-containing regimens significantly reduced the degree of tumor viability compared with 5FU/OX-only chemotherapy (32.9% vs 45.3%; P = .02). After stratification according to the magnitude of tumor viability, a higher proportion of patients treated with bevacizumab than without had25% residual viable tumor cells (45% vs 23%; P = .02). However, the addition of bevacizumab to 5FU/OX did not appear to increase the incidence of complete pathologic response (11.3% vs 11.6%; P = .59). The incidence and severity of sinusoidal dilation was lower in patients treated with bevacizumab than in those treated with 5FU/OX only (any grade: 27.4% vs 53.5%; moderate or severe: 8.1% vs 27.9%; both P.01).In patients treated with 5FU/OX chemotherapy, bevacizumab improves the pathologic response, as demonstrated by a reduction of the degree of tumor viability, and reduces the incidence and severity of hepatic injury. This retrospective study provides additional evidence supporting the use of bevacizumab in combination with 5FU/OX for CLM.

Background & Aims Differentiated pancreatic acinar cells expressing endogenous levels of mutant K-Ras do not spontaneously develop pancreatic ductal adenocarcinoma (PDAC). However, we hypothesized that acinar cells would develop PDAC in the presence of Ras activity levels mimicking those of human tumor cells. Methods We measured Ras activity in PDAC cells from mice and humans using a Raf pull-down assay. We compared the effects of acinar cell expression of mutant K-Ras at endogenous and elevated levels on Ras activity and on the development of PDAC. Results Ras activity was greatly elevated in PDAC cells compared with nontransformed cells expressing endogenous levels of mutant K-Ras. Expression of endogenous levels of mutant K-Ras in differentiated acinar cells resulted in moderately elevated Ras activity and in sparse murine pancreatic intraepithelial neoplasias (mPanINs) that did not spontaneously advance to PDAC unless the tumor suppressor p53 was simultaneously deleted. In contrast, expression of mutant K-Ras at higher levels generated Ras activity equal to that in PDAC. High Ras activity mimicking levels in PDAC led to acinar cell senescence and generated inflammation and fibrosis resembling the histologic features of chronic pancreatitis. With higher Ras activity in acinar cells, abundant mPanINs formed and spontaneously progressed to both cystic papillary carcinoma and metastatic PDAC. Conclusions There is an important relationship between Ras activity levels and the progression of PDAC. Sufficient Ras activity in pancreatic acinar induces several important pancreatic disease manifestations not previously reported and supports a potential direct linkage between chronic pancreatitis, cystic papillary carcinoma, and PDAC.

4503 Background: Effective systemic therapy for advanced LGNET is lacking. Mutations involving the mTOR pathway including TSC2, NF-1, and vHL are associated with development of LGNET. mTOR also mediate signaling downstream of IGF1 and VEGF. RAD001 is a novel oral mTOR inhibitor. Octreotide has been described to inhibit VEGF and IGF1 production in solid tumors. Methods: Patients (pts) received depot octreotide 30 mg q28 days, and RAD001 5 (pts 1–30) or 10 mg (pts 31–60) po daily. Response was evaluated every 12 weeks (wks). Results: 30 carcinoid (C) and 30 islet cell (I) patients (pts) were enrolled between 2/05–7/06. 38 pts (23 C, 15 I) had prior octreotide. By RECIST criteria, there were 10 PR (17%), 45 SD (75%) (15 pts had > 15% reduction), 5 PD (8%). The response rates within C, and I groups were 13% and 20%. The response rates within the 5 mg and 10 mg groups were 13% and 20% respectively. Of 39 pts with PD prior to study entry, there were 7 (18%) PR, 27 (69%) SD (9 pts had > 15% reduction), 5 (13%) PD. PFS rate at 24 wks was 86%. The median PFS duration is 59 wks. The median PFS duration among the C and I groups were 69 and 39 wks. Among the 39 pts with progression at study entry, the median PFS duration was 38 wks. Of 24 pts with elevated chromogranin A at entry, 19 (56%) had > 50% reduction. Treatment was well tolerated. The most common toxicity was mild aphthous ulceration. CTC G3/4 toxicities included: thrombocytopenia (3), neutropenia (3), hypophosphatemia (5), hyperglycemia (4), hypoglycemia (2), hypokalemia (2), fatigue (6), diarrhea (6), aphthous ulcer (5), rash (3), and 1 each of anemia, hypertriglyceridemia, bilirubin, AST/ALT, pain, nausea, nail, dysgeusia, pneumonitis. Conclusions: RAD001 at 5 or 10 mg daily was well tolerated in combination with octreotide. Promising anti-tumor activity has been observed. The RADIANT (RAD001 In Advanced Neuroendocrine Tumors) trials are underway to evaluate RAD001 in larger patient groups. No significant financial relationships to disclose.

4089 Background: When compared to bolus 5-fluorouracil (F), leucovorin (L), and irinotecan (I) regimens such as IFL, the infusional F, L, I regimen (FOLFIRI) resulted in a improved toxicity profile with a response rate (RR) of 35% and median progression free survival (PFS) of 6.7 months. When combined with bevacizumab (B) as first-line treatment, IFL demonstrated improved activity with a RR of 45% and a median PFS of 10.6 months. Combining FOLFIRI and B may further improve the efficacy. Methods: We designed a single-arm, phase II trial of FOLFIRI+B with B (5mg/kg), I (180mg/m2), bolus of F (400mg/m2) and L (400mg/m2) with a 46-hour infusion of F (2400mg/m2) every 2 weeks. The primary endpoint was PFS. Chemotherapy naïve mCRC patients (pts) with a performance status of 0–2 received B alone on Day -14, starting FOLFIRI+B on Day 1. Proteomic and radiographic correlative studies were completed and will be reported separately. Results: N=41 pts, median age 56 y/o (range 26–78), M:F = 16:25, 5 pts with prior adjuvant therapy, were enrolled from 1/2005 to 1/2007. A total of 502 cycles have been administered (median = 12). The median PFS is 12.6 months. Response rate by intention-to-treat analysis was 62% (24 pts), with 33% stable disease (13 pts). Responses occurred after a median of 4 months of therapy. Fifteen pts remain on treatment; 26 pts are off study: 7 for progressive disease, 2 withdrew consent, 7 for toxicity and 2 for surgery unrelated to cancer. Eight pts were removed from the study for metastasectomies. Grade 3 or 4 toxicities included 17 occurrences of grade = 3 neutropenia, including 1 grade 4 febrile neutropenia, 4 grade 4 pulmonary emboli, 2 grade 3 hand-foot syndrome, and 1 grade 3 diarrhea. One pt included in the analysis developed a possible microperforation, manifested by peritonitis, after B alone and never received FOLFIRI. Conclusion: FOLFIRI+B is well-tolerated and efficacious, with an impressive PFS that compares favorably to historical controls. This regimen is an excellent choice as a first-line treatment for mCRC. No significant financial relationships to disclose.

Figure 1. A 27-year-old, 45-kg primigravid woman presented in early labor at 40 weeks' gestation. Six hours into her labor, an urgent vacuum-assisted vaginal delivery was performed because of fetal bradycardia. A healthy 3010-g male infant was delivered, with Apgar scores of 9 and 9 at one and five minutes, respectively. Immediately after delivery the patient reported anterior pelvic pain and was unable to move from the table. An anteroposterior radiograph of her pelvis was obtained while she lay on the delivery table and revealed a 5-cm diastasis of the pubic symphysis (Panel A). Because the sacroiliac joints were not . . .