Impact of tumor grade on pancreatic cancer prognosis: validation of a novel TNMG staging system.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) patients demonstrate highly variable survival within each stage of the American Joint Committee on Cancer (AJCC) staging system. We hypothesize that tumor grade is partly responsible for this variation. Recently our group developed a novel tumor, node, metastasis, grade (TNMG) classification system utilizing Surveillance Epidemiology and End Results (SEER) data in which the presence of high tumor grade results in advancement to the next higher AJCC stage. This study's objective was to validate this TNMG staging system utilizing single-institution data. METHODS: All patients with PDAC who underwent resection at UCLA between 1990 and 2009 were identified. Clinicopathologic data reviewed included age, sex, node status, tumor size, grade, and stage. Grade was redefined as a dichotomous variable. The impact of grade on survival was assessed by Cox regression analysis. Disease was restaged into the TNMG system and compared to the AJCC staging system. RESULTS: We identified 256 patients who underwent resection for PDAC. Patients with low-grade tumors experienced a 13-month improvement in median survival compared to those with high-grade tumors. On multivariate analysis, tumor grade was the strongest predictor of survival with a hazard ratio of 2.02 (p = 0.0005). Restaging disease according to the novel TNMG staging system resulted in improved survival discrimination between stages compared to the current AJCC system. CONCLUSIONS: We were able to demonstrate that grade is one of the strongest independent prognostic factors in PDAC. Restaging with our novel TNMG system demonstrated improved prognostication. This system offers an effective and convenient way of adding grade to the current AJCC staging system.

ChemoSensitivity Assay Guided Metronomic Chemotherapy Is Safe and Effective for Treating Advanced Pancreatic Cancer.

Cytotoxic chemotherapy remains the mainstay of treatment for advanced pancreatic adenocarcinoma (PDAC). Emerging studies support metronomic chemotherapy (MCT) as effective, challenging established paradigms of dosing and schedules. The blood-based ChemoSensitivity Assay has been shown to predict response and survival in advanced PDAC patients treated with standard chemotherapy. The current study combines these concepts for a highly personalized treatment approach. This was a retrospective analysis; a pilot (n = 50) and validation cohort (n = 45) were studied. The ChemoSensitivity Assay was performed at baseline and during therapy; results were correlated to drugs administered and patient outcomes. MCT was administered based on the assay results at the treating physician's discretion. Patients in the pilot cohort experienced favorable survival compared with historical controls (median overall survival (mOS) 16.8 mo). Patients whose treatment closely matched the ChemoSensitivity Assay predictions experienced longer median time on lines of therapy (5.3 vs. 3.3 mo, p = 0.02) and showed a trend for longer mOS (20.9 vs. 12.5 mo, p = 0.055) compared with those not closely matched. These findings were confirmed in the validation cohort. Overall, patients treated with MCT closely matching Assay results experienced a remarkable mOS of 27.7 mo. ChemoSensitivity profiling-guided MCT is a promising approach for personalized therapy in advanced PDAC.

Low-Dose Continuous 5-Fluorouracil Combined with Leucovorin, nab-Paclitaxel, Oxaliplatin, and Bevacizumab for Patients with Advanced Pancreatic Cancer: A Retrospective Analysis.

BACKGROUND: Continuous-infusion 5-fluorouracil (5FU) and calcium leucovorin plus nab-paclitaxel and oxaliplatin have been shown to be active in patients with pancreatic cancer. As a protracted low-dose infusion, 5FU is antiangiogenic, and has synergy with bevacizumab. As shown in the treatment of breast cancer, bevacizumab and nab-paclitaxel are also synergetic. OBJECTIVE: In this paper we retrospectively analyze the survival of 65 patients with advanced pancreatic cancer who were treated with low-dose continuous (metronomic) chemotherapy given in conjunction with conventional anti-VEGF therapy. PATIENTS AND METHODS: Since July of 2008, we have treated 65 patients with 5FU (180 mg/m2/day × 14 days) via an ambulatory pump. Calcium leucovorin (20 mg/m2 IV), nab-paclitaxel (60 mg/m2) IV as a 30-min infusion, and oxaliplatin (50 mg/m2) IV as a 60-min infusion were given on days 1, 8, and 15. Bevacizumab (5 mg/kg) IV over 30 min was administered on days 1 and 15. Cycles were repeated every 28-35 days. There were 42 women and 23 men, and the median age was 59 years. Forty-six patients had stage IV disease. RESULTS: The median survival was 19 months, with 82% of patients surviving 12 months or longer. The overall response rate was 49%. There were 28 patients who had received prior treatment, 15 of whom responded to therapy. Fifty-two patients had elevated CA 19-9 prior to treatment. Of these, 21 patients had 90% or greater reduction in CA 19-9 levels. This cohort had an objective response rate of 71% and a median survival of 27 months. Thirty patients stopped treatment due to disease progression, and an additional 22 stopped because of toxicity. One patient died while on therapy. CONCLUSIONS: This non-gemcitabine-based regimen resulted in higher response rates and better survival than what is commonly observed with therapy given at conventional dosing schedules. Low-dose continuous (metronomic therapy) cytotoxic chemotherapy combined with antiangiogenic therapy is safe and effective.

In vivo therapeutic responses contingent on Fanconi anemia/BRCA2 status of the tumor.

PURPOSE: BRCA2, FANCC, and FANCG gene mutations are present in a subset of pancreatic cancer. Defects in these genes could lead to hypersensitivity to interstrand cross-linkers in vivo and a more optimal treatment of pancreatic cancer patients based on the genetic profile of the tumor. EXPERIMENTAL DESIGN: Two retrovirally complemented pancreatic cancer cell lines having defects in the Fanconi anemia pathway, PL11 (FANCC-mutated) and Hs766T (FANCG-mutated), as well as several parental pancreatic cancer cell lines with or without mutations in the Fanconi anemia/BRCA2 pathway, were assayed for in vitro and in vivo sensitivities to various chemotherapeutic agents. RESULTS: A distinct dichotomy of drug responses was observed. Fanconi anemia-defective cancer cells were hypersensitive to the cross-linking agents mitomycin C (MMC), cisplatin, chlorambucil, and melphalan but not to 5-fluorouracil, gemcitabine, doxorubicin, etoposide, vinblastine, or paclitaxel. Hypersensitivity to cross-linking agents was confirmed in vivo; FANCC-deficient xenografts of PL11 and BRCA2-deficient xenografts of CAPAN1 regressed on treatment with two different regimens of MMC whereas Fanconi anemia-proficient xenografts did not. The MMC response comprised cell cycle arrest, apoptosis, and necrosis. Xenografts of PL11 also regressed after a single dose of cyclophosphamide whereas xenografts of genetically complemented PL11(FANCC) did not. CONCLUSIONS: MMC or other cross-linking agents as a clinical therapy for pancreatic cancer patients with tumors harboring defects in the Fanconi anemia/BRCA2 pathway should be specifically investigated.

Combination therapy for advanced pancreatic cancer using Herceptin plus chemotherapy.

The HER2/neu oncogene is overexpressed in up to 70% of human pancreatic cancer specimens when compared to normal pancreatic tissue. This cell surface receptor can be targeted specifically by the neutralizing antibody Herceptin. Herceptin has been successfully used in combination with other chemotherapeutic agents in breast cancer, a cancer in which only 30% of patients harbor elevated HER2/neu levels. In the present study, we investigated the therapeutic efficacy of Herceptin in combination with gemcitabine and docetaxel. Gemcitabine is currently the standard chemotherapeutic agent used to treat pancreatic cancer. In contrast, docetaxel, a taxane, is only just being investigated in pancreatic cancer. Tumor cell resistance to taxanes is at least in part mediated by the HER2/NEU oncogene. We have previously characterized HER2/NEU expression in human pancreatic cancer cell lines and studied the anti-tumor activity of Herceptin monotherapy in vitro and in vivo. In the present study, combination therapy resulted in a dramatic improvement of animals bearing human pancreatic cancer xenografts. Furthermore, metastasis and production of ascites was lower when a combination of these three agents was used. We conclude that, as with breast cancer, the anti-tumor activity of Herceptin may be improved by combination with taxanes or gemcitabine.

Improved survival for adenocarcinoma of the ampulla of Vater: fifty-five consecutive resections.

HYPOTHESIS: After resection of an adenocarcinoma of the ampulla of Vater, certain clinical and pathologic characteristics influence long-term survival. DESIGN: Retrospective case series. SETTING: Major academic medical and pancreatic surgical center. PATIENTS: Fifty-five consecutive patients who underwent Whipple resection for ampullary adenocarcinoma from 1988 through 2001. INTERVENTIONS: Pylorus-preserving Whipple resection in 32 patients and standard Whipple resection in 23 patients. MAIN OUTCOME MEASURES: Postoperative survival. A multivariate Cox proportional hazards model was used to determine the effects of various factors on long-term survival after resection. RESULTS: There were no operative deaths, and all patients left the hospital. After a mean follow-up of 46.9 months, the overall 5-year Kaplan-Meier survival estimate was 67.7%. The median survival of the entire group has not yet been reached. Five-year postoperative survival estimates for node-negative (n = 32) and node-positive patients (n = 23) were 76.5% and 53.4%, respectively (P =.26). Patients whose tumors demonstrated perineural invasion (n = 12) had a 5-year survival estimate of 29.2% vs 78.8% for those whose did not (P<.001). On multivariate analysis, the absence of perineural invasion (P<.001) was an independent predictor of significantly improved postoperative survival. CONCLUSIONS: Compared with previous reports from our own and other centers, this series demonstrates improved postoperative survival by 10% to 20% in patients undergoing Whipple resection for adenocarcinoma of the ampulla of Vater. The reasons for this improved outcome are unclear, and the effect of adjuvant treatment cannot be determined from this analysis. The major factor associated with prolonged survival was the absence of perineural invasion in the resected tumor specimen.

Locally advanced pancreatic cancer: association between prolonged preoperative treatment and lymph-node negativity and overall survival.

IMPORTANCE: Treatment of patients with locally advanced/borderline resectable (LA/BR) pancreatic ductal adenocarcinoma (PDAC) is not standardized. OBJECTIVE: To (1) perform a detailed survival analysis of our institution's experience with patients with LA/BR PDAC who were downstaged and underwent surgical resection and (2) identify prognostic biomarkers that may help to guide a decision for the use of adjuvant therapy in this patient subgroup. DESIGN, SETTING, AND PARTICIPANTS: Retrospective observational study of 49 consecutive patients from a single institution during 1992-2011 with American Joint Committee on Cancer stage III LA/BR PDAC who were initially unresectable, as determined by staging computed tomography and/or surgical exploration, and who were treated and then surgically resected. MAIN OUTCOMES AND MEASURES: Clinicopathologic variables and prognostic biomarkers SMAD4, S100A2, and microRNA-21 were correlated with survival by univariate and multivariate Cox proportional hazard modeling. RESULTS: All 49 patients were deemed initially unresectable owing to vascular involvement. After completing preoperative chemotherapy for a median of 7.1 months (range, 5.4-9.6 months), most (75.5%) underwent a pylorus-preserving Whipple operation; 3 patients (6.1%) had a vascular resection. Strikingly, 37 of 49 patients were lymph-node (LN) negative (75.5%) and 42 (85.7%) had negative margins; 45.8% of evaluable patients achieved a complete histopathologic (HP) response. The median overall survival (OS) was 40.1 months (range, 22.7-65.9 months). A univariate analysis of HP prognostic biomarkers revealed that perineural invasion (hazard ratio, 5.5; P=.007) and HP treatment response (hazard ratio, 9.0; P=.009) were most significant. Lymph-node involvement, as a marker of systemic disease, was also significant on univariate analysis (P=.05). Patients with no LN involvement had longer OS (44.4 vs 23.2 months, P=.04) than LN-positive patients. The candidate prognostic biomarkers, SMAD4 protein loss (P=.01) in tumor cells and microRNA-21 expression in the stroma (P=.05), also correlated with OS. On multivariate Cox proportional hazard modeling of HP and prognostic biomarkers, only SMAD4 protein loss was significant (hazard ratio, 9.3; P=.004). CONCLUSIONS AND RELEVANCE: Our approach to patients with LA/BR PDAC, which includes prolonged preoperative chemotherapy, is associated with a high incidence of LN-negative disease and excellent OS. After surgical resection, HP treatment response, perineural invasion, and SMAD4 status should help determine who should receive adjuvant therapy in this select subset of patients.

Downstaging chemotherapy and alteration in the classic computed tomography/magnetic resonance imaging signs of vascular involvement in patients with pancreaticobiliary malignant tumors: influence on patient selection for surgery.

OBJECTIVES: To determine whether computed tomography (CT)/magnetic resonance imaging (MRI) signs of vascular involvement are accurate after downstaging chemotherapy (DCTx) and to highlight factors associated with survival in patients who have undergone resection. DESIGN: Retrospective cohort study; prospective database. SETTING: University pancreatic disease center. PATIENTS: Patients with unresectable pancreaticobiliary cancer who underwent curative intent surgery after completing DCTx. INTERVENTIONS: Use of CT/MRI scan, pancreatic resection, and palliative bypass. MAIN OUTCOME MEASURES: Resectability after DCTx and disease-specific survival. RESULTS: We operated on 41 patients (1992-2009) with locally advanced periampullary malignant tumors after a median of 8.5 months of DCTx. Before DCTx, most patients (38 [93%]) were unresectable because of evidence of vascular contact on CT/MRI scan or operative exploration. Criteria for exploration after DCTx were CT/MRI evidence of tumor shrinkage and/or change in signs of vascular involvement, cancer antigen 19-9 decrease, and good functional status. None had progressive disease. At operation, we resected tumors in 34 of 41 patients (83%), and 6 had persistent vascular involvement. Surprisingly, CT/MRI scan was only 71% sensitive and 58% specific to detect vascular involvement after DCTx. "Involvement" on imaging was often from tumor fibrosis rather than viable cancer. Radiographic decrease in tumor size also did not predict resectability (P = .10). Patients with tumors that were resected had a median 87% decrease in cancer antigen 19-9 (P = .04) during DCTx. The median follow-up (all survivors) was 31 months, and disease-specific survival was 52 months for patients with resected tumors. CONCLUSIONS: In patients with initially unresectable periampullary malignant tumors, original CT/MRI signs of vascular involvement may persist after successful DCTx. Patients should be chosen for surgery on the basis of lack of disease progression, good functional status, and decrease in cancer antigen 19-9.

Impact of splenectomy on thrombocytopenia, chemotherapy, and survival in patients with unresectable pancreatic cancer.

BACKGROUND: Patients with unresectable pancreatic cancer (PDAC) or endocrine tumors (PET) often develop splenic vein thrombosis, hypersplenism, and thrombocytopenia which limits the administration of chemotherapy. METHODS: From 2001 to 2009, 15 patients with recurrent or unresectable PDAC or PET underwent splenectomy for hypersplenism and thrombocytopenia. The clinical variables of this group of patients were analyzed. The overall survival of patients with PDAC was compared to historical controls. RESULTS: Of the 15 total patients, 13 (87%) had PDAC and 2 (13%) had PET. All tumors were either locally advanced (n = 6, 40%) or metastatic (n = 9, 60%). The platelet counts significantly increased after splenectomy (p < 0.01). All patients were able to resume chemotherapy within a median of 11.5 days (range 6-27). The patients with PDAC had a median survival of 20 months (range 4-67) from the time of diagnosis and 10.6 months (range 0.6-39.8) from the time of splenectomy. CONCLUSIONS: Splenectomy for patients with unresectable PDAC or PET who developed hypersplenism and thrombocytopenia that limited the administration of chemotherapy, significantly increased platelet counts, and led to resumption of treatment in all patients. Patients with PDAC had better disease-specific survival as compared to historical controls.

Phase II trial of infusional fluorouracil, leucovorin, mitomycin, and dipyridamole in locally advanced unresectable pancreatic adenocarcinoma: SWOG S9700.

PURPOSE: To test the hypothesis that dual biochemical modulation of fluorouracil (FU) in combination with mitomycin improves the survival of patients with pancreas cancer. PATIENTS AND METHODS: Eligibility included stage II or III unresectable adenocarcinoma of the pancreas, performance status of 0 to 2, and adequate organ function. Treatment included FU 200 mg/m2/d via continuous intravenous infusion for 4 weeks followed by 1 week of rest; leucovorin 30 mg/m2 administered via intravenous bolus infusion on days 1, 8, 15, and 22, followed by 1 week rest; mitomycin 10 mg/m2 intravenous bolus infusion every 6 weeks for a total of four doses. Dipyridamole 75 mg was administered orally three times daily during the FU administration. RESULTS: Fifty patients (median age, 61 years; 23 males, 27 females) with localized unresectable pancreatic cancer were eligible for this trial. Twenty-seven patients survived past 1 year for a 1-year survival probability of 54% (95% CI, 40% to 68%). Overall, the objective response rate was 26% (confirmed and unconfirmed) in the 47 patients with measurable disease, with two complete responders. Six of the responding patients underwent curative successful resection of the tumor. The most common toxicity to treatment was stomatitis. Three patients had reversible hemolytic uremic syndrome. Five patients experienced grade 4 toxicity. There were no treatment-related deaths. CONCLUSION: Potential improvement in survival and resectability of localized unresectable pancreatic cancer may be attained without radiation. The strategy of dual biochemical modulation of FU warrants additional investigation in a randomized fashion.