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ABSTRACT: 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.
Retrospective cohort study; prospective database.
University pancreatic disease center.
Patients with unresectable pancreaticobiliary cancer who underwent curative intent surgery after completing DCTx.
Use of CT/MRI scan, pancreatic resection, and palliative bypass.
Resectability after DCTx and disease-specific survival.
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.
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.
Archives of surgery (Chicago, Ill.: 1960) 07/2011; 146(7):836-43. · 4.32 Impact Factor
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ABSTRACT: Patients with unresectable pancreatic cancer (PDAC) or endocrine tumors (PET) often develop splenic vein thrombosis, hypersplenism, and thrombocytopenia which limits the administration of chemotherapy.
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.
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.
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.
Journal of Gastrointestinal Surgery 03/2010; 14(6):1012-8. · 2.83 Impact Factor
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Journal of Clinical Oncology 02/2008; 26(1):162-4. · 18.37 Impact Factor
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ABSTRACT: To test the hypothesis that dual biochemical modulation of fluorouracil (FU) in combination with mitomycin improves the survival of patients with pancreas cancer.
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.
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.
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.
Journal of Clinical Oncology 06/2007; 25(13):1665-9. · 18.37 Impact Factor
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ABSTRACT: 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.
International Journal of Oncology 11/2005; 27(4):1125-30. · 2.40 Impact Factor
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Michiel S van der Heijden,
Jonathan R Brody,
David A Dezentje,
Eike Gallmeier,
Steven C Cunningham,
Michael J Swartz,
Angelo M DeMarzo,
G Johan A Offerhaus, William H Isacoff,
Ralph H Hruban,
Scott E Kern
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ABSTRACT: 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.
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.
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.
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.
Clinical Cancer Research 11/2005; 11(20):7508-15. · 7.74 Impact Factor
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ABSTRACT: After resection of an adenocarcinoma of the ampulla of Vater, certain clinical and pathologic characteristics influence long-term survival.
Retrospective case series.
Major academic medical and pancreatic surgical center.
Fifty-five consecutive patients who underwent Whipple resection for ampullary adenocarcinoma from 1988 through 2001.
Pylorus-preserving Whipple resection in 32 patients and standard Whipple resection in 23 patients.
Postoperative survival. A multivariate Cox proportional hazards model was used to determine the effects of various factors on long-term survival after resection.
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.
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.
Archives of Surgery 09/2003; 138(9):941-8; discussion 948-50. · 4.24 Impact Factor
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ABSTRACT: Patients with locally advanced pancreatic adenocarcinoma who receive conventional therapy with radiation with S-fluorouracil(5-FU)
have median survivals ranging from 8 to 12 months. Here we report our experience with a four-drug chemotherapeutic regimen
that resulted in sufficient downstaging of tumor in some patients to justify surgical reexploration and resection. From April
1991 through April 1994,38 patients received 5-FU as a continuous infusion (200 mg/m2/day), calcium leucovorin weekly by imravenous bolus injection (30 mg/m2), mitomycin-C every 6 weeks (10 mg/m2 intravenously), and dipyridamole daily orally (75 mg) for locally advanced unresected pancreatic cancer. All of these patients
were evaluable for response, toxicity, and survival. There were 14 partial responses and one complete response—a 39% response
rate. The median survival for all patients was 15.5 months; the l-year survival rate from time of initial diagnosis was 70%.
Six of 15 responding patients had sufficient tumor regression to meet clinical criteria for resectability and reexploration,
four of whom underwent a curative resection. The median survival of these six patients was 28 months from the time of original
diagnosis. The l-year survival was 83 %, with one patient still alive and free of disease at 53 months. We believe this unique
experience from a single institution justifies a prospective multi-institutional trial to evaluate the efficacy of this approach
iu a larger number of patients.
Journal of Gastrointestinal Surgery 03/1998; 2(2):159-166. · 2.83 Impact Factor
