The Landmark Series: Preoperative Therapy for Pancreatic Cancer

Annals of Surgical Oncology - The surgical treatment of pancreas ductal adenocarcinoma (PDAC) is plagued by high rates of distant recurrences despite complete resection, highlighting the importance...     

Resection of Locally Advanced Pancreatic Cancer without Regression of Arterial Encasement After Modern-Era Neoadjuvant Therapy

Introduction

Modern-era systemic therapy for locally advanced pancreatic adenocarcinoma (LAPC) offers improved survival relative to historical regimens but not necessarily improved radiographic downstaging to allow more patients to undergo resection. The aim of this study was to evaluate the survival, progression, and pathologic outcomes after resection of LAPC that did not regress from > 180 degrees arterial encasement after neoadjuvant therapy.

Methods

Sixty-one LAPC patients were brought to the operating room after neoadjuvant therapy for NCCN-defined unresectable pancreatic cancer between 2012 and 2017. Pts were explored with intent of pancreatectomy and irreversible electroporation for margin extension; 5 (8%) had metastatic lesions on exploratory laparoscopy and were excluded from analyses. Imaging was re-examined to confirm LAPC prior to surgery. Data were analyzed from a prospective pancreatic cancer database.

Results

Patients had arterial involvement of the celiac axis (37.5%) and/or superior mesenteric artery (42.9%) and/or an extended length of the common hepatic (n = 44.6%) artery. Twenty-nine males and 27 females, median 65 years of age, received neoadjuvant gemcitabine-based (58.9%) or FOLFIRINOX (35.7%) chemotherapy and stereotactic body (42.9%) or intensity-modulated (51.8%) radiation therapy. Median months from initiation of neoadjuvant therapy to surgery was 7.5. Sixty-one percent underwent Whipple, 21% distal, and 18% modified Appleby procedures; 57% patients underwent venous reconstruction. Ninety-day mortality was 2%. An R0 margin was achieved in 80%, and 53% were N0. Median overall and progression-free survival was 18.5 (95%CI 12.27–32.33) and 8.5 months (95%CI 6.0–15.0), respectively. One- and 3-year survival from surgery was 68.5% (95%CI 53.0–79.7) and 39.0% (95%CI 23.7–53.8), respectively.

Conclusion

With modern-era neoadjuvant therapy, R0 resections can be achieved in a majority of non-metastatic patients with locally advanced, unresectable disease based on cross-sectional imaging.

     

The Role of Radiation Therapy in Locally Advanced Breast Cancer

Abstract: The purpose of the study was to evaluate and compare the impact of postoperative radiotherapy, whether it was based on the clinical stage at presentation of the disease or on the pathological downstaged disease after initial chemotherapy for non‐inflammatory locally advanced breast cancer (LABC). We retrospectively analyzed locoregional recurrence (LRR), relapse free survival (RFS), overall survival (OS) and disease free survival (DFS) in 55 patients treated for non‐inflammatory LABC with neoadjuvant chemotherapy and surgery with or without radiotherapy. The mean follow‐up was 55 months. The 3‐year OS was 74%, DFS 73% and RFS 87%. The OS and DFS benefit was seen in those receiving radiation, with a mean OS of 89 months versus 68 months (p = 0.029) and mean DFS of 72 months versus 54 months (p = 0.029). Total LRR was 11% (8% versus 17% in the non‐radiotherapy group, p = 0.349) and mean RFS of 95 months versus 86 months (p = 0.164). If the treatment planning was to be based on the original extent of the disease, then all patients in our study should have received adjuvant radiotherapy. Significantly lower OS and DFS without the addition of radiotherapy suggests that indication for radiation treatment should be based on the clinical pre‐chemotherapy stage rather than the pathological post‐chemotherapy stage. Radiation should therefore always be considered regardless of the response to initial chemotherapy for non‐inflammatory LABC.     

Irreversible Electroporation in Locally Advanced Pancreatic Cancer: Potential Improved Overall Survival

Background

Locally advanced unresectable pancreatic adenocarcinoma (LAC) is characterized by poor survival despite chemotherapy and conventional radiation therapy. We have recently reported on the safety of using irreversible electroporation (IRE) for the management of LAC. The purpose of this study was to evaluate the overall survival in patients with LAC treated with IRE.

Methods

A prospective, multi-institutional evaluation of 54 patients who underwent IRE for unresectable pancreatic cancer from December 2009 to October 2010 was evaluated for overall survival and propensity matched to 85 matched stage III patients treated with standard therapy defined as chemotherapy and radiation therapy alone.

Results

A total of 54 LAC patients have undergone IRE successfully, with 21 women, 23 men (median age, 61 (range, 45–80) years). Thirty-five patients had pancreatic head primary and 19 had body tumors; 19 patients underwent margin accentuation with IRE and 35 underwent in situ IRE. Forty-nine (90 %) patients had pre-IRE chemotherapy alone or chemoradiation therapy for a median duration 5 months. Forty (73%) patients underwent post-IRE chemotherapy or chemoradiation. The 90 day mortality in the IRE patients was 1 (2 %). In a comparison of IRE patients to standard therapy, we have seen an improvement in local progression-free survival (14 vs. 6 months, p = 0.01), distant progression-free survival (15 vs. 9 months, p = 0.02), and overall survival (20 vs. 13 months, p = 0.03).

Conclusions

IRE ablation of locally advanced pancreatic tumors remains safe and in the appropriate patient who has undergone standard induction therapy for a minimum of 4 months can achieve greater local palliation and potential improved overall survival compared with standard chemoradiation–chemotherapy treatments. Validation of these early results will need to be validated in the current multi-institutional Phase 2 IDE study.

     

Irreversible Electroporation in Locally Advanced Pancreatic Cancer: Potential Improved Overall Survival

Background

Locally advanced unresectable pancreatic adenocarcinoma (LAC) is characterized by poor survival despite chemotherapy and conventional radiation therapy. We have recently reported on the safety of using irreversible electroporation (IRE) for the management of LAC. The purpose of this study was to evaluate the overall survival in patients with LAC treated with IRE.

Methods

A prospective, multi-institutional evaluation of 54 patients who underwent IRE for unresectable pancreatic cancer from December 2009 to October 2010 was evaluated for overall survival and propensity matched to 85 matched stage III patients treated with standard therapy defined as chemotherapy and radiation therapy alone.

Results

A total of 54 LAC patients have undergone IRE successfully, with 21 women, 23 men (median age, 61 (range, 45–80) years). Thirty-five patients had pancreatic head primary and 19 had body tumors; 19 patients underwent margin accentuation with IRE and 35 underwent in situ IRE. Forty-nine (90 %) patients had pre-IRE chemotherapy alone or chemoradiation therapy for a median duration 5 months. Forty (73%) patients underwent post-IRE chemotherapy or chemoradiation. The 90 day mortality in the IRE patients was 1 (2 %). In a comparison of IRE patients to standard therapy, we have seen an improvement in local progression-free survival (14 vs. 6 months, p = 0.01), distant progression-free survival (15 vs. 9 months, p = 0.02), and overall survival (20 vs. 13 months, p = 0.03).

Conclusions

IRE ablation of locally advanced pancreatic tumors remains safe and in the appropriate patient who has undergone standard induction therapy for a minimum of 4 months can achieve greater local palliation and potential improved overall survival compared with standard chemoradiation–chemotherapy treatments. Validation of these early results will need to be validated in the current multi-institutional Phase 2 IDE study.

     

32P as an Adjunct to Standard Therapy for Locally Advanced Unresectable Pancreatic Cancer: A Randomized Trial

This prospective randomized trial was undertaken to determine the added efficacy of (32)P in treating locally advanced unresectable pancreatic cancer. Thirty patients with biopsy proven locally advanced unresectable adenocarcinoma of the pancreas were assessable after receiving 5-fluorouracil and radiation therapy with or without (32)P, followed by gemcitabine. Intratumoral (32)P dose was determined by tumor size and volume and was administered at months 0, 1, 2, 6, 7, and 8. Tumor cross-sectional area and liquefaction were determined at intervals by computed tomography scan. Tumor liquefaction occurred in 78% of patients receiving (32)P and in 8% of patients not receiving (32)P, although tumor cross-sectional area did not decrease. Serious adverse events occurred more often per patient for patients receiving (32)P (4.2 +/- 3.1 vs. 1.8 +/- 1.9; p = 0.03) leading to more hospitalizations. Death was because of disease progression (23 patients), gastrointenstinal hemorrhage (4 patients), and stroke (1 patient). One patient not receiving (32)P and one receiving (32)P are alive at 28 and 13 months, respectively. (32)P did not prolong survival (7.4 +/- 5.5 months with (32)P vs. 11.5 +/- 8.0 months without (32)P, p = 0.16). (32)P promoted tumor liquefaction, but did not decrease tumor size. Intratumoral (32)P was associated with more serious adverse events and did not improve survival for locally advanced unresectable pancreatic cancer.     

Neoadjuvant Therapy and Vascular Resection During Pancreaticoduodenectomy: Shifting the Survival Curve for Patients with Locally Advanced Pancreatic Cancer

Background

Neoadjuvant therapy and vascular resection may offer patients with locally advanced pancreatic cancer potential cure.

Methods

We reviewed medical records of patients with ductal adenocarcinoma who underwent pancreaticoduodenectomy (PD) from 1992 through 2011. We identified patients who received neoadjuvant therapy (NA+) or required vascular resection (VR+) for locally advanced disease and compared outcomes to those who did not.

Results

Of the 643 patients who were initially explored, 506 (143 NA+ and 363 NA? patients) ultimately underwent PD. There were no significant differences in R0 resection or morbidity. Mortality was higher in the NA+ versus NA? group (7.0 vs 3.0 %, p = 0.04). More NA+ patients underwent PD VR+ (p < 0.001). Among VR+ patients, neoadjuvant therapy resulted in significantly lower R1 resection. Among resected patients, survival of NA+ patients was significantly longer than both NA? patients (27.3 vs 19.7 months, p < 0.05) and patients abandoned because of locally advanced disease. Age, tumor grade, lymph node ratio, and R1 resection were independent predictors of poor survival.

Conclusions

Neoadjuvant therapy and vascular resection offer patients with locally advanced pancreatic cancer the chance for cure with acceptable morbidity and mortality. These patients have improved survival over patients deemed locally inoperable by traditional criteria.     

NeoGemTax: Gemcitabine and Docetaxel as Neoadjuvant Treatment for Locally Advanced Nonmetastasized Pancreatic Cancer

Background  

About 30% of patients with pancreatic cancer suffer from locally advanced nonmetastatic carcinoma at the time of diagnosis. We conducted a prospective phase II clinical trial using neoadjuvant chemotherapy, consisting of gemcitabine and docetaxel, to assess the rate of complete radical resection and overall survival.     

Hormonal Therapy and Radiation Therapy in the Treatment of Locally Advanced Prostate Cancer

Adjuvant hormonal therapy with radiation may improve local control or survival in patients with locally advanced prostate cancer, as shown by EORTC 22863 and RTOG 85-31. Another trial, RTOG 86-10, showed better local control with adjuvant hormonal therapy and radiation but no difference in survival from patients receiving radiation alone. There are many unanswered questions concerning the optimal timing of androgen ablation and radiation, the duration and type of androgen ablation, and the population of patients who will obtain the greatest benefit.     

Neoadjuvant Radiation Therapy in Locally Advanced Colon Cancer: a Cohort Analysis

Background

A paucity of data exists in the use of neoadjuvant chemoradiation therapy (NRT) for T4, non-metastatic colon cancer. This study was conducted to determine the effect of NRT on outcomes after resection for T4 colon cancer.

Methods

All patients with non-metastatic resected clinical T4 colon cancer from 2000 to 2012 at a tertiary care center were included. The cohort was divided into two groups—those that received NRT and those that did not (non-NRT). The primary outcomes were margin-negative resection and overall survival (OS).

Results

One hundred and thirty-one consecutive patients with non-metastatic clinical T4 colon cancer with a mean age of 65 years were included. NRT was used in 23 patients (17.4%). NRT group was noted to have non-statistically significant improvement in R0 resection rate (NRT 95.7% vs non-NRT 88.0%; p?=?0.27) and local recurrence (NRT 4.3% vs non-NRT 15.7%; p?=?0.15). There was a significant difference in T-stage downstaging between the two groups (NRT 30.4% vs non-NRT 6.5%; p?=?0.007). In a bivariate analysis, NRT was associated with improved 5-year OS (NRT 76.4% vs non-NRT 51.5%; p?=?0.03). This relationship did not persist in a Cox proportional hazard analysis that included age and comorbidity (HR 2.19; 95% CI 0.87–5.52; p?=?0.09).

Conclusions

The use of NRT in locally advanced T4 colon cancer is safe and associated with increased downstaging. While there was a trend toward improvement in local recurrence and the ability to obtain margin-negative resections in the NRT group, this was not significant. Significantly improved overall survival was not observed in a multivariable analysis.

     

Neoadjuvant Hormonal Therapy and Radical Prostatectomy for Locally Advanced Prostate Cancer

The management of locally advanced prostate cancer remains controversial. Cause-specific survival rates are high for organ-confined disease, but there is a disturbingly high incidence of positive margins in radical prostatectomy specimens. Thus, there has been much interest in neoadjuvant hormonal therapy as a means of shrinking the primary tumor. Both nonrandomized and randomized trials have revealed reductions in tumor size, but the effect on tumor stage and patient survival is less clear. Because the long-term value is not clear, and because neoadjuvant hormonal therapy does have side effects and increases treatment costs, it is at present not advisable outside the clinical research setting.     

The Landmark Series: Surgical Treatment of Colorectal Cancer Peritoneal Metastases

Background

Peritoneal metastases (PM) are a form of metastatic spread affecting approximately 5-15% of colon cancer patients. The attitude towards management of peritoneal metastases has evolved from therapeutic nihilism towards a more comprehensive and multidisciplinary approach, in large part due to the development of cytoreductive surgery (CRS), usually coupled with heated intraperitoneal chemotherapy (HIPEC), along with the constant improvement of systemic chemotherapy of colorectal cancer. Several landmark studies, including 5 randomized controlled trials have marked the development and refinement of surgical approaches to treating colorectal cancer peritoneal metastases.

Methods

This review article focuses on these landmark studies and their influence in 4 key areas: the evidence supporting surgical resection of peritoneal metastases, the identification and standardization of important prognostic variables influencing patient selection, the role of surgery and intraperitoneal chemotherapy in prevention of colorectal PM and the role of intraperitoneal chemotherapy as an adjuvant to surgical resection.

Results

These landmark studies indicate that surgical resection of colorectal PM should be considered as a therapeutic option in appropriately selected patients and when adequate surgical expertise is available. Standardized prognostic variables including the Peritoneal Cancer Index and the Completeness of Cytoreduction Score should be used for evaluating both indications and outcomes.

Conclusions

Current evidence does not support the use of second look surgery with oxaliplatin HIPEC or prophylactic oxaliplatin HIPEC in patients with high risk colon cancer nor the use of oxaliplatin HIPEC with CRS of colorectal PM.

     

The Landmark Series: Hilar Cholangiocarcinoma

Annals of Surgical Oncology - Hilar cholangiocarcinoma (HC) is a rare and highly aggressive biliary tract neoplasm. As such, the data driving the management of this disease generally are not based...     

Better Defining the Role of Total Neoadjuvant Radiation: Changing Paradigms in Locally Advanced Pancreatic Cancer

Annals of Surgical Oncology - This study was designed to better define the role of radiation (Neo-Rad) in addition to neoadjuvant multiagent chemotherapy (NAT) for the treatment of locally advanced...     

Irreversible Electroporation of Locally Advanced Pancreatic Head Adenocarcinoma

Irreversible electroporation of locally advanced pancreatic adenocarcinoma has been used to palliate appropriate patients with locally advanced pancreatic adenocarcinoma. The setting was at a university tertiary care center. Subjects are patients with locally advanced pancreatic adenocarcinoma who have undergone appropriate induction chemotherapy for at least 3 to 4 months in duration. Technique of open irreversible electroporation of locally advanced pancreatic adenocarcinoma is described. The technique of open irreversible electroporation with continuous intraoperative ultrasound imaging and consideration of intraoperative navigational system is described. Irreversible electroporation of locally advanced pancreatic adenocarcinoma is feasible for locally advanced unresectable pancreatic cancer.