Distal Pancreatectomy with En Bloc Celiac Axis Resection for Locally Advanced Pancreatic Adenocarcinoma Following Neoadjuvant Therapy

Background

Celiac trunk encasement by adenocarcinoma of the pancreatic body is generally regarded as a contraindication for surgical resection. Recent studies have suggested that a subset of stage III patients will succumb to their disease in the absence of distant metastases. We hypothesized that patients with stage III tumors invading the celiac trunk, who are free of distant disease following neoadjuvant therapy, may derive prolonged survival benefit from aggressive surgical resection.

Methods

We performed a retrospective review of distal pancreatectomies with en bloc celiac axis resection for pancreatic adenocarcinoma.

Results

Eleven patients underwent a distal pancreatectomy with en bloc celiac axis resection after completing neoadjuvant chemoradiation therapy. Median operative time was 8?h, 14?min, and median estimated blood loss was 700?ml. Median length of stay was 9?days. Five patients (45%) had postoperative complications; three were Clavien grade I. Four patients (35%) had pancreatic leaks; two were ISGPF grade B, and two were grade A. There were two 90-day perioperative deaths. Ten patients had R0 resections (91%). After a median follow-up of 41?weeks, six patients recurred. Four of the five patients with SMAD4 loss recurred, and two of the five patients with intact SMAD4 recurred. Median disease-free and overall survival were 21?weeks and 26?months, respectively.

Conclusions

Resection of pancreatic body adenocarcinoma with celiac axis resection is technically feasible with acceptable perioperative morbidity and mortality.     

Adjuvant Chemoradiation Therapy for Adenocarcinoma of the Distal Pancreas

Background

This study was designed to examine the effect of adjuvant 5-FU-based chemoradiation therapy (CRT) after distal pancreatectomy for adenocarcinoma of the distal pancreas.

Methods

All patients underwent curative resection for adenocarcinoma of the distal pancreas between December 1985 and June 2006. Patients who received adjuvant CRT were compared with those who underwent surgery alone. A Kaplan–Meier estimate of the survival curve was used to determine estimates of the median survival and proportion alive at 1 and 2 years; log-rank tests were used to make comparisons between groups.

Results

A total of 123 patients underwent distal pancreatectomy; 29 patients were excluded for distant metastases at the time of surgery (n = 12, 10%) or before adjuvant therapy (n = 11, 9%), death within 2 months of surgery (n = 2, 2%), or if CRT treatment status was unknown (n = 4, 3%). Of the remaining 94 patients, 72% received adjuvant 5-FU-based CRT and 28% underwent surgery alone. Overall median survival was 16.2 (95% confidence interval (CI), 13.1–18.9) months. The groups were similar with respect to tumor size, nodal status, and margin status. There was no significant difference in overall survival between patients treated with adjuvant CRT versus surgery alone (p = 0.23). An exploratory subgroup analysis suggested a potential survival benefit of adjuvant CRT in patients with lymph node metastases (16.7 vs. 12.1 months, p < 0.01).

Conclusions

Adjuvant CRT did not increase survival compared with surgery alone; however, patients with node-positive disease appear to benefit from adjuvant CRT.     

Neoadjuvant Radiochemotherapy in Adenocarcinoma of the Esophagus: ERCC1 Gene Polymorphisms for Prediction of Response and Prognosis

Introduction

Neoadjuvant radiochemotherapy (RT/CTx) regimens were primarily designed for treatment of squamous cell carcinoma of the esophagus. Own preliminary results demonstrate that also patients with locally advanced adenocarcinoma of the esophagus may achieve a major response in 30% with a 3-year survival rate of 80%. To identify these patients, ERCC1 (rs11615) gene polymorphisms were analyzed. ERCC1 is a key enzyme of the nucleotide excision and repair (NER) complex to prevent DNA inter- and intra-strand crosslinks.

Patients and Methods

Genomic DNA from 217 patients with cT3/4 adenocarcinoma of the esophagus was extracted from paraffin-embedded tissues. Of these patients, 153 underwent neoadjuvant RT/CTx (CDDP, 5-FU, 36?Gy). For analysis of ERCC1 single nucleotide polymorphisms (SNPs), allelic discrimination was performed by quantitative real-time PCR. Two allele-specific TaqMan probes in competition were used for amplification of ERCC1 (rs11615). Allelic genotyping was correlated with histomorphologic tumor regression after neoadjuvant RT/CTx and survival. Major response (MaHR) was defined as <10% vital residual tumor cells (VRTC).

Results

Analysis of tumor regression revealed a MaHR in 56/153 (36.6%) patients with a 5-year survival rate (5-YSR) of 74% (p?n?=?27 (12.4%), TT: n?=?98 (45.2%), C/T: n?=?92 (42.4%). ERCC1 polymorphism CT was identified as a predictor for response to the neoadjuvant RT/CTx (p?Conclusion Analysis of ERCC1 (rs11615) gene polymorphisms reveals a significant correlation with response and survival in patients with adenocarcinoma of the esophagus treated with a neoadjuvant radiochemotherapy. Single nucleotide polymorphisms of ERCC1 (rs11615) could therefore be applied to further individualize therapy in esophageal cancer.     

Neoadjuvant Chemoradiation for Localized Adenocarcinoma of the Pancreas

Background: The use of neoadjuvant preoperative chemoradiotherapy CRT for pancreatic cancer has been advocated for its potential ability to optimize patient selection for surgical resection and to downstage locally advanced tumors. This article reports our experience with neoadjuvant CRT for localized pancreatic cancer.Methods: Since 1995, 111 patients with radiographically localized, pathologically confirmed pancreatic adenocarcinoma have received neoadjuvant external beam radiation therapy EBRT; median, 4500 cGy with 5-flourouracil–based chemotherapy. Tumors were defined as potentially resectable PR, n = 53 in the absence of arterial involvement and venous occlusion and locally advanced LA, n = 58 with arterial involvement or venous occlusion by CT.Results: Five patients 4.5% were not restaged due to death n = 3 or intolerance of therapy n = 2. Twenty-one patients 19% manifested distant metastatic disease on restaging CT. Twenty-eight patients with initially PR tumors 53% and 11 patients with initially LA tumors 19% were resected after CRT. Histologic examination revealed significant fibrosis in all resected specimens and two complete responses. Surgical margins were negative in 72%, and lymph nodes were negative in 70% of resected patients. Median survival in resected patients has not been reached at a median follow-up of 16 months.Conclusions: Neoadjuvant CRT provided an opportunity for patients with occult metastatic disease to avoid the morbidity of resection and resulted in tumor downstaging in a minority of patients with LA tumors. Survival after neoadjuvant CRT and resection appears to be at least comparable to survival after resection and adjuvant postoperative CRT.Presented at the 54th Annual Meeting of the Society of Surgical Oncology, Washington, DC, March 15-18, 2001.     

Adenocarcinoma of the Esophagus in the Young

Introduction

Practitioners have noted a striking increase in the number of young patients under the age of 40 years old who develop esophageal adenocarcinoma. The aim of this study was to characterize the presentation, pathology and therapeutic outcome of these young patients.

Methods

The records of patients who presented to the Foregut Surgical Service at the University of Southern California with esophageal adenocarcinoma between 2000 and 2007 were retrospectively reviewed. The presentation, tumor stage and histology, therapy and outcome of the patients under the age of 40 were compared to those ≥40.

Results

Of the 374 patients reviewed, 20 (5 %) were under the age of 40. There were two patients in their second and 18 in their third decade of life. The youngest patient was 25 years old. A history of gastroesophageal reflux disease or Barrett’s esophagus was less common in patients <40 than in those ≥40; 15 and 5 % compared to 61 and 46 %. Similarly, patients <40 had a significantly longer time interval between the onset of symptoms and the diagnosis of their cancer than those ≥40; 4.5 vs. 2 months, p?=?0.04. They also had a higher prevalence of stage IV disease (30 vs. 6 %, p?=?0.0003), a shorter time to recurrence (9.5 vs.19 month, p?=?0.002), and a poorer median survival (17 vs. 43 month, p?=?0.04).

Conclusion

Esophageal adenocarcinoma in patients <40 years old commonly presents with an advanced stage of the disease and an associated poor survival. This is likely due to a low index of suspicion that dysphagia seen in younger patients is due to a malignancy.     

Treatment Trends and Predictors of Adjuvant and Neoadjuvant Therapy for Gastric Adenocarcinoma in the United States

Purpose

Over the last decade, evidence suggesting the benefits of adjuvant therapy in the treatment of stage IB–III gastric adenocarcinoma has emerged, though the influence of these clinical trials and current treatment patterns is unknown. Our objectives were (1) to assess changes in gastric adenocarcinoma treatment over time, (2) to identify predictors of neoadjuvant or postoperative adjuvant therapy use, and (3) to identify factors associated with neoadjuvant therapy use.

Methods

Patients with stage IB–III gastric adenocarcinoma diagnosed between 1998 and 2007 in the National Cancer Data Base who underwent surgical resection were selected. Models were developed to identify factors associated with treatment.

Results

We identified 30,448 patients diagnosed with stage IB–III gastric adenocarcinoma who underwent surgical resection. Rates of systemic therapy receipt (either before or after surgery) increased by 71 % from 1998 to 2007 (p < 0.001). Receipt of neoadjuvant therapy receipt increased by 237 % over 10 years (p < 0.001), with the highest rate of increase seen at high-volume academic centers. American Joint Committee on Cancer (AJCC) stage and age were the strongest predictors of pre- or postoperative systemic therapy among surgical patients. Neoadjuvant therapy receipt was most strongly predicted by tumor location in the gastric cardia.

Conclusions

Treatment trends over the past decade reflect rapid adoption of evidence from randomized controlled trials by increased receipt of pre- and postoperative systemic therapy in the treatment of stage IB–III gastric adenocarcinoma. Although age and AJCC stage are strongly associated with receiving systemic adjuvant therapy, tumor location is the most significant predictor of neoadjuvant therapy.     

Comparison of the Clinical Profile and Outcome for Squamous Cell Carcinoma and Adenocarcinoma of the Distal Esophagus and Cardia in India

This retrospective review aimed to assess the clinical profile and outcome of squamous cell carcinoma as compared with adenocarcinoma of the lower third of esophagus and cardia following a transhiatal esophagectomy. A total of 169 patients were analyzed retrospectively in this series from 1989 to 1994. There were 100 patients with squamous cell carcinoma (SCC) and 69 patients with adenocarcinoma (ADC). All tumors were assessed by an esophagogram, upper gastrointestinal endoscopy, and abdominal ultrasonography. The surgical procedure performed in all cases was a transhiatal esophagectomy (THE). The mean age of the patients with SCC and ADC was comparable (48 ± 14 vs 54 ± 12 years). Male/female ratio was 1.0 : 1.4 in the SCC group while in the ADC group it was 8.8 : 1.0. The main symptom in both the groups was grade II dysphagia (62% in SCC and 60% in ADC). The mean length of the tumor was 6.6 ± 4.5 cm in the SCC group and 4.2 ± 3.3 cm in the ADC group. The resectability rate of the SCC group was significantly higher (76%) than in the ADC group (55%). The 6-month and 1-year survival for the SCC patients was not significantly different from the ADC patients (83.7% and 49.3% vs 85.0% and 54.0%). The 5-year survival achieved in SCC was higher than in the ADC group (11.6% vs 7.2%) but the difference was not statistically significant. Adenocarcinoma arising from the distal esophagus and cardia was more common in males, and also occurred in a higher age group and had a lower resectability rate than squamous cell carcinoma. No case of Barrett's esophagus was encountered. The short- and long-term survival in both tumors were similar. Received: May 9, 2000 / Accepted: November 20, 2000     

Sphincter-Sparing Treatment for Distal Rectal Adenocarcinoma

Background: Studies suggest that the anal sphincter can be preserved in some patients with distal rectal adenocarcinoma (DRA), but this has not been validated in any prospective multi-institutional trial.Methods: To test the hypothesis that the anal sphincter can be preserved in some patients with DRA, the Cancer and Leukemia Group B and collaborators reviewed 177 patients who had T1/T2 adenocarcinomas 4 cm in diameter, which encompassed 40% of bowel wall circumference, and were 10 cm from the dentate line. Of the 177 patients, 59 patients who were eligible for the study had T1 adenocarcinomas and received no further treatment; 51 eligible T2 patients received external beam irradiation (5400 cGY/30 fractions 5 days/week) and 5-fluorouracil (500 mg/m² IV d1–3, d29–31) after local excision.Results: At 48 months median follow-up, 6-year survival and failure-free survival rates of the eligible patients are 85% and 78% respectively. Three patients died of unrelated disease. Two patients were treated for second primary colorectal tumors; both remain disease free (NED). Another eight patients died of disease, four with distant recurrence only. One T1 patient is alive with distant disease. Two T1 and seven T2 patients experienced isolated local recurrences; all underwent salvage abdominoperineal resection (APR). After APR, one T1 and four of seven T2 patients were NED at the time of last visit (2–7 years). One T1 patient died of local and distant disease. Three of seven T2 patients died with distant disease.Conclusions: We conclude that sphincter preservation can be achieved with excellent cancer control without initial sacrifice of anal function in most patients. After local recurrence, salvage resection appears effective, but longer follow-up time of local and distant disease-free survival is advised before extrapolation to patients with T3 primaries.Presented at the 1999 Annual Meeting of the Society of Surgical Oncology, Orlando, Florida, March 4–7, 1999.     

Neoadjuvant Hormonal Therapy in Stage C Adenocarcinoma of the Prostate and Incidence of Biochemical Recurrence

This report describes the effects of neoadjuvant hormonal therapy (NHT) in 31 patients with clinical stage T3 adenocarcinoma of the prostate (CaP) who underwent radical prostatectomy (RP) and the incidence of biochemical recurrence, as evidenced by serum prostate specific antigen (PSA) >0.2 ng/mL after RP. Twenty-six patients received combined androgen blockade consisting of a gonadotropin-releasing hormone (GnRH) agonist (leuprolide) and an antiandrogen (flutamide), and the remaining five received flutamide alone. The mean Gleason score was 7.1 +/- 0.3. Five patients were found to have pathologic stage T(2c), 14 stage T(3a), 7 stage T(3b), and 4 stage T(3c) disease. One specimen had no evidence of adenocarcinoma in the whole-mount specimen. The mean PSA concentration decreased from 25.4 ng/mL (Hybritech method) to 1.18 ng/mL. The prostate volume decreased a mean of 47%, and pathologic effects of hormonal deprivation were observed in all patients. Approximately 39% of the patients (12/31) demonstrated evidence of biochemical recurrence, with the mean time to biochemical failure being 28.9 months after NHT. Follow-up ranged from 5 to 83 months with a mean of 52.7 months. Of the variables studied (pretreatment PSA, Gleason score, final pathologic stage, and nadir PSA before surgery), pretreatment PSA (p = 0.001, Fisher's exact test) and pathologic stage T(3c) (p = 0.012, Fisher's exact test) were found to have a statistically significant correlation with biochemical recurrence. Although there was a 39% biochemical recurrence rate in our study, we conclude that NHT offers an alternative mode of management for patients with stage T(3) CaP.     

Molecular Profiling of Direct Xenograft Tumors Established from Human Pancreatic Adenocarcinoma After Neoadjuvant Therapy

Background

Pancreatic adenocarcinoma is among the most resistant of human cancers, yet specific mechanisms of treatment resistance remain poorly understood. Models to study pancreatic cancer resistance remain limited and should reflect in vivo changes that occur within patient tumors. We sought to identify consistent, differentially expressed genes between treatment of naive pancreatic tumors and those exposed to neoadjuvant therapy using a strict, in vivo direct xenograft model system.

Methods

Over a 42-week period, 12 untreated and treated patient tumors were successfully engrafted into NOD/SCID mice. RNA from each treatment group (5 untreated and 4 treated) was isolated in triplicate and subjected to global gene expression analysis. Consistent gene expression changes with treatment were identified and confirmed using RT-PCR and immunohistochemistry.

Results

Engraftment of untreated patient tumors was more frequent than treated tumors (17 of 21 versus 16 of 49, P = .0002) but without differences in observed time until tumor formation. The histology of patient tumors was recapitulated in direct xenograft tumors. Relative to untreated tumors, treated tumors consistently demonstrated more than a 2-fold reduction in TGFβ-R2 mRNA expression and more than a 5-fold increase in IGFBP3 expression (P < .0218) and were confirmed by immunohistochemistry.

Conclusion

Engraftment of human pancreatic tumors into immunodeficient mice prior to and following neoadjuvant therapy is possible and provides an in vivo platform for comparison of global gene expression patterns. The decreased TGFβ-R2 expression and increased IGFBP3 expression among direct xenograft tumors derived from treated tumors relative to untreated tumors suggests a role in therapy resistance and warrants further study.

     

Molecular Profiling of Direct Xenograft Tumors Established from Human Pancreatic Adenocarcinoma After Neoadjuvant Therapy

Background

Pancreatic adenocarcinoma is among the most resistant of human cancers, yet specific mechanisms of treatment resistance remain poorly understood. Models to study pancreatic cancer resistance remain limited and should reflect in vivo changes that occur within patient tumors. We sought to identify consistent, differentially expressed genes between treatment of naive pancreatic tumors and those exposed to neoadjuvant therapy using a strict, in vivo direct xenograft model system.

Methods

Over a 42-week period, 12 untreated and treated patient tumors were successfully engrafted into NOD/SCID mice. RNA from each treatment group (5 untreated and 4 treated) was isolated in triplicate and subjected to global gene expression analysis. Consistent gene expression changes with treatment were identified and confirmed using RT-PCR and immunohistochemistry.

Results

Engraftment of untreated patient tumors was more frequent than treated tumors (17 of 21 versus 16 of 49, P = .0002) but without differences in observed time until tumor formation. The histology of patient tumors was recapitulated in direct xenograft tumors. Relative to untreated tumors, treated tumors consistently demonstrated more than a 2-fold reduction in TGFβ-R2 mRNA expression and more than a 5-fold increase in IGFBP3 expression (P < .0218) and were confirmed by immunohistochemistry.

Conclusion

Engraftment of human pancreatic tumors into immunodeficient mice prior to and following neoadjuvant therapy is possible and provides an in vivo platform for comparison of global gene expression patterns. The decreased TGFβ-R2 expression and increased IGFBP3 expression among direct xenograft tumors derived from treated tumors relative to untreated tumors suggests a role in therapy resistance and warrants further study.

     

Recommendations from an International Consensus Conference on the Current Status and Future of Neoadjuvant Systemic Therapy in Primary Breast Cancer

The use of neoadjuvant systemic therapy (NST) for the treatment of primary breast cancer has constantly increased, especially in trials of new therapeutic regimens. In the 1980 s, NST was shown to substantially improve breast-conserving surgery rates and was first typically used for patients with inoperable locally advanced or inflammatory breast cancer. Investigators have since also used NST as an in vivo test for chemosensitivity by assessing pathologic complete response. Today, by using pathologic response and other biomarkers as intermediate end points, results from trials of new regimens and therapies that use NST are aimed to precede and anticipate the results from larger adjuvant trials. In 2003, a panel of representatives from various breast cancer clinical research groups was first convened in Biedenkopf to formulate recommendations on the use of NST. The obtained consensus was updated in two subsequent meetings in 2004 and 2006. The most recent conference on recommendations on the use of NST took place in 2010 and forms the basis of this report.