Therapy For Pancreatic Adenocarcinoma Research Articles

Safety and Efficacy of Capecitabine as a Radiosensitizer in Adjuvant Chemoradiation Therapy for Pancreatic Adenocarcinoma

Safety and Efficacy of Capecitabine as a Radiosensitizer in Adjuvant Chemoradiation Therapy for Pancreatic Adenocarcinoma

Gemcitabine-related pneumonitis: Elucidation of risk factors.

e15243 Background: Gemcitabine (G) is a key component of therapy for pancreatic adenocarcinoma (PC). Pulmonary injury is an infrequent but not rare adverse effect of varying manifestation and is ob...

Chemoradiation therapy sequencing for resected pancreatic adenocarcinoma in the National Cancer Data Base

Pancreatic adenocarcinoma (PAC) has low overall survival (OS) rates and high recurrence rates following surgical resection. The role for preoperative radiation therapy (prRT) for PAC versus postoperative RT (poRT) remains uncertain. The authors used the National Cancer Data Base (NCDB) to report prRT outcomes for the largest multi-institutional patient cohort to date. NCDB data were obtained for all patients who underwent resection and external beam radiation (RT) for PAC from 1998 to 2002. Patients with metastatic (M1) disease, intraoperative RT, RT both before and after surgery, missing OS, or missing RT variables were excluded. Univariate (UV) and multivariate (MV) analysis were run using treatment characteristics, tumor characteristics, and patient demographics. The difference in patients' known characteristics was described by a chi-square test or analysis of variance. A total of 5414 patients were identified. Of these, 277 received prRT and 5137 received poRT. Overall, 92.9% received chemotherapy and 7.1% received RT alone; 56% (2990 of 5307) of patients had stage III disease, according to American Joint Commission on Cancer (AJCC) staging manual, 5th edition. Median tumor size was 3 cm (range: 0-9.9 cm); 82% (199 of 244) of patients with prRT had negative surgical margins; 72% (3383 of 4699) of patients with poRT had negative margins. Forty-one percent (71 of 173) of patients with prRT were lymph node (LN)-positive; 65% (3159 of 4833) of patients with poRT were LN-positive. Median OS for patients with prRT was 18 months (95% CI = 18-19 months) and for patients with poRT, 19 months (95% CI = 17-22 months). Receipt of prRT was associated with lower stage, higher rates of negative margins, and lower rates of lymph node positivity at resection. However, there was no significant difference in median OS versus that of the poRT group.

Impact of preoperative therapy on patterns of recurrence in pancreatic cancer

BackgroundA theoretical advantage of preoperative therapy in pancreatic adenocarcinoma is that it facilitates the early treatment of micrometastases and reduces postoperative systemic recurrence. MethodsMedical records of 309 consecutive patients undergoing resection of adenocarcinoma in the head of the pancreas were reviewed. Survival was calculated using the Kaplan–Meier method. Associations between preoperative therapy and patterns of recurrence were determined using chi-squared analysis. ResultsPreoperative therapy was administered to 108 patients and upfront surgery was performed in 201 patients. Preoperative therapy was associated with a significantly longer median disease-free survival of 14 months compared with 12 months in patients submitted to upfront surgery (P = 0.035). The rate of local disease as a component of first site of recurrence was significantly lower with preoperative therapy (11.3%) than with upfront surgery (22.9%) (P = 0.016). Preoperative therapy was associated with a lower rate of hepatic metastasis (21.7%) than upfront surgery (34.3%) (P = 0.026). Preoperative therapy did not affect rates of peritoneal or pulmonary metastasis. ConclusionsPreoperative therapy for pancreatic cancer was associated with longer disease-free survival and lower rates of local and hepatic recurrences. These data support the use of preoperative therapy to reduce systemic and local failures after resection.

Novel combinatorial therapy for pancreatic adenocarcinoma

CONCLUSIONS: These data suggest that TXA decreases the time to initial clot formation and increases the rate of clot propagation indicating its procoagulant effects beyond fibrinolysis, which are relevant to both potential benefit as well as safety. Thus, it is imperative to confirm a diagnosis of pathologic fibrinolysis prior to treatment with TXA to avoid exposure of a patient to a potentially thrombogenic drug.

Impact of Adjuvant Radiotherapy on Survival after Pancreatic Cancer Resection: An Appraisal of Data from the National Cancer Data Base

The impact of adjuvant radiotherapy for pancreatic adenocarcinoma (PAC) remains controversial. We examined effects of adjuvant therapy on overall survival (OS) in PAC, using the National Cancer Data Base (NCDB). Patients with resected PAC from 1998 to 2002 were queried from the NCDB. Factors associated with receipt of adjuvant chemotherapy (ChemoOnly) versus adjuvant chemoradiotherapy (ChemoRad) versus no adjuvant treatment (NoAdjuvant) were assessed. Cox proportional hazard modeling was used to examine effect of adjuvant therapy type on OS. Propensity scores (PS) were developed for each treatment arm and used to produce matched samples for analysis to minimize selection bias. From 1998 to 2002, a total of 11,526 patients underwent resection of PAC. Of these, 1,029 (8.9%) received ChemoOnly, 5,292 (45.9%) received ChemoRad, and 5,205 (45.2%) received NoAdjuvant. On univariate analysis, factors associated with improved OS included: younger age, higher income, higher facility volume, lower tumor stage and grade, negative margins and nodes, and absence of adjuvant therapy. On multivariate analysis with matched PS, factors independently associated with improved OS included: younger age, higher income, higher facility volume, later year of diagnosis, smaller tumor size, lower tumor stage, and negative tumor margins and nodes. ChemoRad had the best OS (hazard ratio 0.70, 95% confidence interval 0.61-0.80) in a PS matched comparison with ChemoOnly (hazard ratio 1.04, 95% confidence interval 0.93-1.18) and NoAdjuvant (index). Adjuvant chemotherapy with radiotherapy is associated with improved OS after PAC resection in a large population from the NCDB. On the basis of these analyses, radiotherapy should be a part of adjuvant therapy for PAC.

Predictive value of phase II clinical trials in pancreatic cancer: Rethinking the road to progress.

4036 Background: Few new therapies for pancreatic adenocarcinoma (PC) have been approved by the Food and Drug Administration (FDA) or recommended by the National Comprehensive Cancer Network (NCCN), reflecting frequent failures in phase III trials. We hypothesize that the high failure rate in large trials is due to a low predictive value for “positive” phase II studies. Methods: Given a median time from initiation of clinical trials to FDA approval of 6.3 years, we conducted a systematic search of the clinicaltrials.gov database for phase II interventional trials of antineoplastic therapy in PC initiated from 1999-2004. We reviewed drug labels and NCCN guidelines for FDA approval and guideline recommendations. Results: We identified 70 phase II trials that met our inclusion criteria. Forty-five evaluated compounds without preexisting FDA approval, 23 evaluated drugs approved in other diseases, and 2 evaluated cellular therapies. With a median follow-up of 12.5 years, none of these drugs gained FDA approval in PC. Four trials, all combining chemotherapy with radiation, eventually resulted in NCCN recommendations. Forty-two of the trials have been published. Of 16 studies providing pre-specified type I error rates, these rates were ≥0.1 in 8 studies, 0.05 in 6 studies and <0.025 in 2 studies. Of 21 studies specifying type II error rates, 7 used >0.1, 10 used 0.1, and 4 used <0.1. Published studies reported a median enrollment of 47 subjects. Fourteen trials reported utilizing a randomized design. Conclusions: The low rate of phase II trials resulting in eventual regulatory approval of therapies for PC reflects the challenge of conquering a tough disease as well as deficiencies in the statistical designs. New strategies are necessary to quantify and improve odds of success in drug development. Statistical parameters of individual or coupled phase II trials should be tailored to achieve the desired predictive value prior to initiating pivotal phase III studies. Positive predictive value of a phase II study assuming a 1%, 2%, or 5% prior probability of success and 10% type II error rate. [Table: see text]

Factors affecting the administration of adjuvant therapy in patients with pancreatic adenocarcinoma.

e15087 Background: Adjuvant therapy for pancreatic adenocarcinoma is now considered standard of care. The proportion of patients receiving adjuvant therapy (ADT) following pancreatic resection is a good quality indicator of cancer care. The aim of this study was to evaluate factors associated with receiving ADT in patients with pancreatic cancer. Methods: Between years 2000-2010, all patients undergoing pancreaticoduodenectomy for pancreatic adenocarcinoma at a single high-volume hepatotopancreatobiliary center were evaluated. The impact of demographic, peri-operative and pathological risk factors affecting the administration of ADT were analyzed using univariate and multivariate logistic regression analysis. Results: There were 258 patients identified. Median age was 65 (37-84) years, 54% were females. There was a 15% margin positivity rate, 14% pancreatic leak rate, 14.7% major complication rate, and 1.2% 90 day/in-hospital mortality rate. Overall, 160/258 (70%) of patients received adjuvant therapy. On multivariate analysis; age, presence of major complications, node-negative disease and earlier era (2000-2004) were significantly associated with a lower probability of receiving ADT. Reasons for not receiving ADT were; patient preference: 20/67 (32%), not recommended: 14/67 (23%), disease recurrence: 12/67 (9.5%) and being medically unfit for ADT: 18/67 (11.5%). None of these reasons were different between time-periods except for fewer patients being offered ADT from 2000-2005 (15.4% vs. 2.5%, p <0.001). Conclusions: Thirty percent of patients do not receive ADT following pancreatectomy. Those with advanced age; node-negative disease and those who had major complications after pancreaticoduodenectomy were less likely to receive ADT. The impact of these factors should be taken into account when considering the administration of ADT.

Novel aspects of preoperative chemoradiation therapy improving anti‐tumor immunity in pancreatic cancer

Pancreatic cancer is an aggressive cancer with poor prognosis. Little is known about the immune response in the tumor microenvironment after chemotherapy for initially unresectable tumor. The purpose of this study was to investigate the immunological effects of chemoradiation therapy in the tumor microenvironment of pancreatic adenocarcinoma. Seventeen patients with pancreatic adenocarcinoma with and without preoperative chemoradiation therapy were retrospectively analyzed using immunohistochemical methods for HLA class I heavy chain, CD4(+), CD8(+), CD45RO(+) and Foxp3(+) T cell infiltrations. Seven of the 17 study patients received preoperative chemoradiation therapy. There were no statistically significant differences in the number of CD4(+) and CD8(+) T cell infiltrations in the tumor microenvironment. However, the number of Foxp3(+) T cell infiltrations was significantly lower in the neoadjuvant chemoradiation therapy group. The HLA class I expression status was the same between the two groups. In conclusion, preoperative chemoradiation therapy in pancreatic adenocarcinoma is useful for reducing regulatory T cell levels in combination with its direct cytotoxic effects.

Phase II study of erlotinib combined with adjuvant chemoradiation and chemotherapy for resectable pancreatic cancer.

269 Background: Amplification and overexpression of the EGFR gene and surface protein have been described in up to 80% of pancreatic tumors, making EGFR an attractive target in developing new adjuvant therapy for pancreatic adenocarcinoma (PDAC). Inhibition of EGFR has been suggested to provide additive activity when combined with capecitabine and radiation. Here we evaluate the antitumor activity and toxicity profile of erlotinib combined with adjuvant chemoradiotherapy (CRT) and chemotherapy. Methods: 50 patients with resected stage I/II PDAC were enrolled in a phase II trial of adjuvant erlotinib and capecitabine administered concurrently with IMRT (50.4 Gy), followed by 4 cycles of erlotinib and gemcitabine. Results: Median length of follow-up was 18.2 months (IQR, 13.8-27.1). Seventy-nine percent of tumors were of the pancreatic head, 85% had nodal involvement, and 17% had positive margins. Median RFS was 15.6 months (95% CI, 14.1-17.1), local RFS 21.1 months (95% CI, 17.1-25.1), and OS 24.4 months (95% CI, 17.1-31.6). Local recurrence was only observed in 19% patients and synchronous recurrence in 8%. Patients with maximum tumor diameter of ≤3 cm showed superior RFS (17.9 vs. 14.0 months; P=0.049), as did patients with cutaneous reaction to erlotinib (16.3 vs. 9.3 months, P=0.021). Superior OS was associated with less than median (32.3U/mL) pre-CRT CA19-9 values (28.2 vs. 19.0 months, P=0.012). During CRT, 31% patients experienced grade 3 toxicity and 2% grade 4, while 31% patients required a treatment break/stopped treatment early. During post-CRT chemotherapy, 35% patients experienced grade 3 toxicity and 8% grade 4, while 30% required a dose reduction. Conclusions: Results of this phase II trial suggest erlotinib combined with standard adjuvant CRT and chemotherapy provides excellent local disease control and reasonable tolerability compared with existing adjuvant regimens. Patients with maximum tumor diameter of ≤3 cm, cutaneous reaction to erlotinib, and less than median pre-CRT CA19-9 values appear to especially benefit from this new adjuvant regimen. Clinical trial information: NCT00962520.

Monoclonal Antibodies and Other Targeted Therapies for Pancreatic Cancer

Pancreatic cancer continues to be a challenging disease to treat because of its aggressive nature, advanced stage at the time of diagnosis, and limited treatment options that are available. Traditional cytotoxic chemotherapy provides modest benefit to patients with pancreatic adenocarcinoma. Recently, a FOLFIRINOX regimen revealed improved response in overall and progression-free survival over single-agent gemcitabine in metastatic pancreatic cancer, but there is still much needed advancement in the systemic treatment of pancreatic cancer. There is a growing interest in the development of novel agents, while our understanding of molecular pathogenesis of pancreatic adenocarcinoma continues to expand. With identification of various molecular pathways in pancreatic cancer tumorigenesis, potential targets for drug development have been pursued with the use of monoclonal antibodies and small-molecule inhibitors. Although preclinical studies with multiple targeted therapies demonstrated encouraging results in pancreatic cancer, only erlotinib, an epidermal growth factor receptor inhibitor, showed a marginal survival benefit in a phase III clinical trial, when combined with gemcitabine. As further signaling pathways and their importance in pancreatic cancer tumorigenesis are better understood, further clinical trials will need to be designed to study these targeted agents as single agents, in combination with other novel agents or in combination with cytotoxic chemotherapy. In this review, we present the current knowledge on targeted therapy in pancreatic adenocarcinoma and its application in clinical practice.

Successful Resection After Neoadjuvant Therapy in Pancreatic Adenocarcinoma

A 59-year-old woman presented with borderline resectable pancreatic adenocarcinoma involving the neck and body of the pancreas. She was treated with systemic chemotherapy followed by chemoradiation, with subsequent downstaging of the tumor by imaging. Subsequent resection had negative margins and negative lymph nodes with only microscopic disease present in the tumor specimen. Neoadjuvant therapy is controversial but could play a role in borderline resectable disease by allowing for higher chance of negative margins at surgery and increasing the chance for cure in these patients. Microscopic disease at time of resection is rare.

TRPM8 ion channel is aberrantly expressed and required for preventing replicative senescence in pancreatic adenocarcinoma

Pancreatic adenocarcinoma is mostly fatal and generally resistant to conventional treatments, such that effective therapies with tolerable side effects are desperately needed. Ion channels including the transient receptor potential (TRP) channels have been implicated in human malignancies, but their roles in pancreatic cancer were mostly unknown. Recent identification of the melastatin-subfamily members of the TRP family of ion channels, and their functions in pancreatic epithelia and adenocarcinoma, is expected to provide a new perspective to understanding the mechanism underlying pancreatic tumorigenesis. In this report, we present the clinical and pathological features of a mini-series of patients with pancreatic adenocarcinoma, which aberrantly exhibits immunoreactivity against the TRPM8 channel. We have recently demonstrated the proliferative role of TRPM8 channel in pancreatic cancer cells. Here, we present evidence that RNA interference-mediated silencing of TRPM8 induces replicative senescence in pancreatic adenocarcinoma cells. This suggests that the aberrantly expressed TRPM8 channel may contribute to pancreatic tumorigenesis by preventing oncogene-induced senescence, and targeted inhibition of TRPM8 may enhance tumor sensitivity to therapeutics. Based on these observations, we hypothesize that the TRPM8 ion channel plays a crucial role in the growth and progression of pancreatic neoplasia during tumorigenesis. We propose that TRPM8 can be exploited as a clinical biomarker and as a therapeutic target for developing personalized therapy in pancreatic adenocarcinoma.

P-0109 Survival Analysis of Maintenance Therapy with Capecitabine in Patients with Resected Pancreatic Adenocarcinoma after Adjuvant Therapy, a Retrospective Cohort Study

IntroductionThe 5-year survival of pancreatic adenocarcinoma (PAC) with surgery alone is less than 10%, and with adjuvant chemotherapy increases to about 20%. The original GITSG adjuvant study demonstrated a survival benefit compared to surgery, and could have been attributed to the weekly IV bolus of 5FU for 2 years, in addition to chemoradiation. In theory, the prolonged exposure to therapy could maintain pressure on dormant cancer cells that remain in G0 arrest, and kill them as they infrequently enter G1/S phase. To evaluate this hypothesis, we retrospectively evaluated patients at Georgetown University Hospital (GUH) who were treated with maintenance capecitabine, and compared to the patients who completed standard adjuvant gemcitabine at GUH and at the Ohio State University (OSU). MethodsPatients in the Georgetown/Lombardi Cancer Center and the Ohio State University EMR were sought for PAC that was resected with curative intent, and had received standard adjuvant chemotherapy with or without chemoradiation. After 6 months of gemcitabine without recurrence, the study group received maintenance capecitabine for up to 2 years, and the control groups received no further therapy until disease relapse. Only patients with complete follow-up survival data were analyzed. Results20 patients from GUH met the criteria as the maintenance group, and 58 and 14 patients from GUH and OSU respectively as the control group. In the maintenance group, capecitabine was usually given 1000mg orally twice a day, Monday through Friday following adjuvant therapy, for an indefinite period, up to 2 years. Patients received capecitabine for median duration of 12.5 months (2 to 24 months), and the median follow-up duration was 33 months (16 to 78 months). The median overall survival (OS) for the maintenance group was 48 months. The 2 year OS was 94%, and 5 year OS was 40%. The median recurrence free survival (RFS) was 39 months. The 2 year RFS was 67%, and the 5 year RFS was 25%. Common toxicities were mild hand-and-foot syndrome and fatigue. Four patients discontinued capecitabine due to toxicities: febrile neutropenia, severe fatigue, weight loss and diarrhea. The GUH control group was of comparable staging, and the median OS was 22 months, 2 year OS was 86.6%, 5 year OS rate was 16%, median RFS was 13 months, 2 year RFS was 19%. For the OSU control group, the median OS was 16.33 months, 2 yr OS was 35.7%, median RFS was 14.8 months, 2yr RFS was 20%. ConclusionIn this retrospective controlled cohort study, capecitabine maintenance therapy following adjuvant therapy in resected PAC is associated with a significantly (p<0.05) higher OS and RFS compared to the control group. The outcome of the capecitabine maintenance group is promising in the context of survival data from the two institutions and historical record in publications. This approach should be studied in a RCT.

Survival analysis of maintenance therapy with capecitabine (Cape) in patients with resected pancreatic adenocarcinoma (PAC) after adjuvant therapy: A retrospective cohort study.

e14658 Background: The 5-year survival of PAC with surgery alone is below 10%, and with adjuvant chemotherapy increases to about 20%. The original GITSG adjuvant study demonstrating a survival benefit compared to surgery could be attributed to the use of 2-years of weekly IV bolus 5FU, and not only chemoradiation. In theory, the prolonged exposure to therapy could maintain pressure on dormant cancer cells that may remain in G0 arrest, by attacking them as they infrequently enter G1/S phase. To evaluate this hypothesis, we retrospectively evaluated our pts who were treated with or without maintenance Cape. Methods: Pts in the Georgetown/Lombardi Cancer Center EMR since Oct 2007 were sought for PAC that was resected with curative intent, received standard adjuvant chemotherapy with or without chemoradiation. The study group received maintenance cape for at least 2 months, and the control group was monitored until disease recurrence. Only pts with complete follow-up survival data were analyzed. Results: 20 pts met the criteria as study group, and 58 pts as the control group. In the study group, cape was usually given 1000mg orally twice a day, Monday through Friday following adjuvant therapy, for an indefinite period, up to 2 years. Pts received cape for median duration of 12.5 months (2 to 24 months), and the median follow-up duration was 33 months (16 to 78 months). The median overall survival (OS) for the study group was 48 months. The 2 year OS was 94%, and 5 year OS was 40%. The median recurrence free survival (RFS) was 39 months. The 2 year RFS was 67%, and the 5 year RFS was 25%. Common toxicities were mild hand-and-foot syndrome and fatigue. 4 pts discontinued cape due to toxicities: febrile neutropenia, severe fatigue, weight loss and diarrhea. The control group was of comparable staging, and the median OS was 22 months, 5 year OS rate was 16%, median RFS was 13 months, 2 year RFS was 19%. Conclusions: In this single institute retrospective controlled cohort study, Cape maintenance therapy following adjuvant therapy in resected PAC is associated with a significantly (p&lt;0.05) higher OS and PFS compared to the control group. This approach should be studied in a RCT.

1060 Redirecting Effector Lymphocytes for Adoptive Cell Therapy of Pancreatic Adenocarcinoma in Mice

1060 Redirecting Effector Lymphocytes for Adoptive Cell Therapy of Pancreatic Adenocarcinoma in Mice

Abstract LB-121: Randomized phase II study of the efficacy and safety of gemcitabine + TH-302 (G+T) vs gemcitabine (G) alone in previously untreated patients with advanced pancreatic cancer

Abstract A hypoxic microenvironment is believed to be a characteristic of solid tumors including pancreatic adenocarcinoma (PAC) and is associated with resistance to chemotherapy. The hypoxia-activated prodrug, TH-302, is designed to specifically target the hypoxic microenvironment. Combining G with TH-302 may enable the targeting of both the normoxic and hypoxic regions of PAC. TH-302 was investigated with full-dose G as part of a Phase 1/2 study with a 21% response, median PFS and OS of 5.9 and 8.5 months, respectively, and one-year survival of &amp;gt;40%. Based upon these data, a randomized Phase 2B study (NCT01144455) was conducted to assess the benefit of G+T to standard dose G for first-line therapy of PAC. An open-label multi-center study of two dose levels of TH-302 (240 mg/m2 or 340 mg/m2) in combination with G versus G alone (randomized 1:1:1) was initiated in June 2010. G (1000 mg/m2) and T were administered IV over 30-60 minutes on Days 1, 8 and 15 of a 28-day cycle. Patients on the G arm could crossover after progression and be randomized to a G+T arm. The primary efficacy endpoint is a comparison of progression-free survival (PFS) between the combination arms and G alone (80% power to detect 50% improvement in PFS with one-sided alpha of 10%). 214 pts (69 G: 71 G+T240: 74 G+T340) with advanced PAC including 77% distant metastases, 62% involving liver and 11% with prior adjuvant tx; median age: 65 (range 29-86); 126 M/88 F; 79/128 ECOG 0/1. Median cycles received: G - 4, G+T240 - 5, G+T340 - 6. Median PFS was 3.6 mo in G vs 5.6 mo in G+T arms with HR of 0.61 (95% CI: 0.43 - 0.87) and logrank p-value of 0.005. Median PFS in G + T340 was 6.0 mo. RECIST best response was 12% in G, 17% in G+T 240 and 27% in G+T340. 153 (71%) patients had elevated CA19-9 and follow-up. CA19-9 decreases were significantly greater in the G+T groups and greatest in the G+T340 arm which had 37 of 53 (70%) pts with a greater than 50% CA19-9 decrease. One death (suicide) was considered possibly related to study drug. Adverse events leading to discontinuation were: 16% G, 15% G+T240 and 11% G+T340. Serious adverse events were balanced across the treatment arms. The most common non-laboratory events, fatigue (49%), nausea (43%), constipation (34%) and peripheral edema (38%), were similar across groups. Rash (14% G, 39% G+T240 and 45% G+T340) and stomatitis (6% G, 17% G+T240 and 36% G+T340) were significantly greater with G+T combination but no Grd 4 (4 pts with Grade 3). Grd 3/4 thrombocytopenia (11% G, 39% G+T240 and 59% G+T340) and Grd 3/4 neutropenia (28% G, 56% G+T240 and 59% G+T340) were higher with G+T. G+T combination with full dose G improved the efficacy of G with significantly longer PFS, higher response rate and greater CA19-9 declines. The G+T combination was well tolerated. Skin and mucosal toxicity and myelosuppression were the most common related adverse events with no increase in treatment discontinuation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-121. doi:1538-7445.AM2012-LB-121

Management of Patients with Pancreatic Adenocarcinoma: National Trends in Patient Selection, Operative Management, and Use of Adjuvant Therapy

Surgical resection remains the only potentially curative option for patients with pancreatic adenocarcinoma (PAC). Advances in surgical technique and perioperative care have reduced perioperative mortality; however, temporal trends in perioperative morbidity and the use of adjuvant therapy on a population basis remain ill-defined. Using Surveillance, Epidemiology, and End Results-Medicare data, 2,461 patients with resected PAC were identified from 1991 to 2005. We examined trends in preoperative comorbidity indices, adjuvant treatment, type of pancreatic resection, and changes in morbidity and mortality during 4 time intervals (ie, 1991-1996, 1997-2000, 2001-2003, and 2003-2005). The majority of patients underwent pancreaticoduodenectomy (n = 1,945; 79%). There was a temporal increase in mean patient age (p < 0.05) and the number of patients with multiple preoperative comorbidities (Elixhauser comorbidities ≥3: 1991-1996, 10% vs 2003-2005, 26%; p < 0.001). Perioperative morbidity (53%) did not, however, change over time (p = 0.97) and 30-day mortality decreased by half (1991-1996: 6% vs 2003-2005: 3%; p = 0.04). Overall, 51% (n = 1,243) of patients received adjuvant therapy, with the majority receiving chemoradiation (n = 817; 33%). Among patients who received adjuvant therapy, factors associated with receipt of adjuvant chemotherapy alone relative to chemoradiation included older patient age (odds ratio = 1.75; p < 0.001) and ≥3 medical comorbidities (odds ratio = 1.57; p = 0.007). Receipt of adjuvant chemotherapy alone also increased over time (2003-2005 vs 1991-1996, odds ratio = 2.21; p < 0.001). Perioperative 30-day mortality associated with resection for PAC decreased by one-half from 1991 to 2005. Although patients undergoing resection for PAC were older and had more preoperative comorbidities, the incidence of perioperative complications remained stable. The relative use of adjuvant chemotherapy alone vs chemoradiation therapy for PAC has increased in the United States during the 15 years examined.

New concepts in diagnosis and therapy of pancreatic adenocarcinoma A. Laghi (Ed.)

New concepts in diagnosis and therapy of pancreatic adenocarcinoma A. Laghi (Ed.)

Neoadjuvant therapy in pancreatic adenocarcinoma: A meta-analysis of phase II trials

Neoadjuvant treatment has proven beneficial for many gastrointestinal (GI) malignancies, but no phase III trials have been completed examining this approach in pancreatic cancer. This meta-analysis examines the best available phase II trials using neoadjuvant treatment for resectable and borderline/unresectable pancreatic adenocarcinoma. Phase II trials were identified using a MEDLINE search, and the Cochrane Central Register of Controlled Trials from 1960 to July 2010. Patients were divided into 2 groups: Patients with initially resectable tumors (group A), and patients with borderline/unresectable tumors (group B). Primary outcome measures were rate of resection and survival. Pooled proportions and 95% confidence intervals (CIs) were calculated using random-effects or fixed-effects models based on the heterogeneity of included studies. A total of 14 phase II clinical trials including 536 patients were analyzed. After treatment, resectability was 65.8% (95% CI, 55.4-75.6%) compared with 31.6% in group B (95% CI, 14.0-52.5%). A partial response was observed in patients with borderline/unresectable tumors; 31.8 (95% CI, 24.2-39.8%) in group B and 9.5% (95% CI, 2.9-19.4%) in group A (P = .003). Progressive disease was seen in 17.0% (95% CI, 11.9-22.7) of patients in group A versus 21.8% (95% CI, 10.1-36.5%) in group B (P = .006). Median survival in resected patients was 23 months for group A and 22 months for group B. Neoadjuvant treatment seems to have some activity in patients with borderline/unresectable pancreatic adenocarcinoma. Nearly one third of tumors initially deemed marginal for operative intervention were able to be ultimately resected after treatment. Until more effective targeted chemotherapeutics are developed, the only group of patients with pancreatic cancer that may benefit from neoadjuvant treatment are those with locally advanced disease.