Neoadjuvant Chemotherapy Generates a Significant Tumor Response in Resectable Pancreatic Cancer Without Increasing Morbidity: Results of a Prospective Phase II Trial

Swiss HPB-Center, Department of Surgery and Institute of Surgical Pathology, Zurich, Switzerland.
Annals of surgery (Impact Factor: 8.33). 01/2009; 248(6):1014-22. DOI: 10.1097/SLA.0b013e318190a6da
Source: PubMed


To evaluate the morbidity of pancreaticoduodenectomy after neoadjuvant chemotherapy for resectable pancreatic cancer and to assess its histologic and metabolic response.
Adjuvant chemotherapy improves the outcome of pancreatic cancer, but 25% of patients remain unfit after surgery. Neoadjuvant chemotherapy can be offered to all patients in a multimodality approach, but its efficacy and surgical morbidity are unknown.
Patients with resectable, cytologically proven adenocarcinoma of the pancreatic head received 4 bi-weekly cycles of gemcitabine (1000 mg/m(2)) and cisplatin (50 mg/m(2)) in this prospective phase II trial. Staging and restaging included chest x-ray, abdominal computed tomography (CT), positron emission tomography (PET)/CT, endoscopic ultrasound, and laparoscopy. Fluorodeoxyglucose uptake was quantified by the standard-uptake value (SUV) on baseline and restaging PET/CT. Immunohistochemistry for GLUT-1 and Ki-67 was performed. The histologic response, cytopathic effects, and surgical complications were graded by respective scores.
Twenty-four of 28 patients had resection for histologically confirmed adenocarcinoma. The surgical morbidity was low without perioperative death and one pancreatic fistula. Histologic response was documented in 54% and cytopathic effects in 83% of the patients. A significant SUV decrease occurred during chemotherapy (P = 0.031), which correlated with the baseline SUV (P = 0.001), Ki-67 expression (P = 0.016), and histologic response (P = 0.01). Neither the metabolic nor the histologic response was predictive of the median disease-free (9.2 months) or overall survival (26.5 months).
Neoadjuvant chemotherapy induced a significant metabolic and histologic response, which was best predicted by PET. Most importantly, surgery after neoadjuvant chemotherapy for pancreatic cancer was safe.

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    • "The safety of this concept has been demonstrated in a recent phase II trial: 28 patients with resectable cancer of the pancreatic head received gemcitabine and cisplatin (GemCis) for two months before resection. This treatment was well tolerated with only a few grade III toxicities and al low surgical morbidity rate [11]. Furthermore, a significant histological and cytological response was documented resulting in a median survival of 26.5 months [12]. "
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    ABSTRACT: Despite major improvements in the perioperative outcome of pancreas surgery, the prognosis of pancreatic cancer after curative resection remains poor. Adjuvant chemotherapy increases disease-free and overall survival, but this treatment cannot be offered to a significant proportion of patients due to the surgical morbidity. In contrast, almost all patients can receive (neo)adjuvant chemotherapy before surgery. This treatment is safe and effective, and has resulted in a median survival of 26.5 months in a recent phase II trial. Moreover, neoadjuvant chemotherapy improves the nutritional status of patients with pancreatic cancer. This multicenter phase III trial (NEOPAC) has been designed to explore the efficacy of neoadjuvant chemotherapy. This is a prospective randomized phase III trial. Patients with resectable cytologically proven adenocarcinoma of the pancreatic head are eligible for this study. All patients must be at least 18 years old and must provide written informed consent. An infiltration of the superior mesenteric vein > 180° or major visceral arteries are considered exclusion criteria. Eligible patients will be randomized to surgery followed by adjuvant gemcitabine (1000 mg/m(2)) for 6 months or neoadjuvant chemotherapy (gemcitabine 1000 mg/m(2), oxaliplatin 100 mg/m(2)) followed by surgery and the same adjuvant treatment. Neoadjuvant chemotherapy is given four times every two weeks. The staging as well as the restaging protocol after neoadjuvant chemotherapy include computed tomography of chest and abdomen and diagnostic laparoscopy. The primary study endpoint is progression-free survival. According to the sample size calculation, 155 patients need to be randomized to each treatment arm. Disease recurrence will be documented by scheduled computed tomography scans 9, 12, 15, 21 and thereafter every 6 months until disease progression. For quality control, circumferential resection margins are marked intraoperatively, and representative histological sections will be centrally reviewed by a dedicated pathologist. The NEOPAC study will determine the efficacy of neoadjuvant chemotherapy in pancreatic cancer for the first time and offers a unique potential for translational research. Furthermore, this trial will provide the unbiased overall survival of all patients undergoing surgery for resectable cancer of the pancreatic head. NCT01314027.
    Full-text · Article · Aug 2011 · BMC Cancer
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    • "However, the heterogeneity of the patient populations studied makes this conclusion difficult to apply to individual patients with resectable disease who are being considered for neoadjuvant treatment prior to planned PD. Indeed, a recent prospective study of neoadjuvant chemoradiation prior to planned resection in 28 patients with resectable PC was unable to demonstrate any correlation between change in CA 19-9 and therapeutic response or ultimate resectability.15 Importantly, this study was small and did not take into account the effects of hyperbilirubinemia; the changes observed in CA 19-9 over the course of induction therapy may have been influenced by biliary decompression and not the anticancer therapy alone. "
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    ABSTRACT: The role of carbohydrate antigen (CA) 19-9 in the evaluation of patients with resectable pancreatic cancer treated with neoadjuvant therapy prior to planned surgical resection is unknown. We evaluated CA 19-9 as a marker of therapeutic response, completion of therapy, and survival in patients enrolled on two recently reported clinical trials. We analyzed patients with radiographically resectable adenocarcinoma of the head/uncinate process treated on two phase II trials of neoadjuvant chemoradiation. Patients without evidence of disease progression following chemoradiation underwent pancreaticoduodenectomy (PD). CA 19-9 was evaluated in patients with a normal bilirubin level. We enrolled 174 patients, and 119 (68%) completed all therapy including PD. Pretreatment CA 19-9 <37 U/ml had a positive predictive value (PPV) for completing PD of 86% but a negative predictive value (NPV) of 33%. Among patients without evidence of disease at last follow-up, the highest pretreatment CA 19-9 was 1,125 U/ml. Restaging CA 19-9 <61 U/ml had a PPV of 93% and a NPV of 28% for completing PD among resectable patients. The area under the receiver-operating characteristics curve of pretreatment and restaging CA 19-9 levels for completing PD was 0.59 and 0.74, respectively. We identified no association between change in CA 19-9 and histopathologic response (P = 0.74). Although the PPV of CA 19-9 for completing neoadjuvant therapy and undergoing PD was high, its clinical utility was compromised by a low NPV. Decision-making for patients with resectable PC should remain based on clinical assessment and radiographic staging.
    Full-text · Article · Feb 2010 · Annals of Surgical Oncology
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    ABSTRACT: Objectives Patients with borderline resectable pancreatic cancer (BRPC) have a higher probability of undergoing margin-negative resection after completing neoadjuvant therapy. Here, we describe a novel neoadjuvant approach using induction chemotherapy followed by stereotactic body radiation therapy (SBRT) for patients with BRPC. Methods This analysis included patients with nonmetastatic BRPC treated with neoadjuvant gemcitabine-based chemotherapy and five-fraction SBRT. Chemotherapy consisted of 3 cycles of Gemzar, Taxotere, and Xeloda. Patients were restaged to determine resectability, and nonmetastatic resectable patients underwent surgical resection. Results Thirty patients completed neoadjuvant treatment and were offered surgical exploration. Seventeen patients (56.7 %) reported no acute adverse effects during SBRT. No grade 3 or higher toxicity was observed from SBRT. Twenty-nine patients (96.7 %) underwent exploration. Twenty-one (95.6 %) of those who underwent pancreatic tumor resection achieved negative margins, with none requiring vessel resection. One (3.3 %) patient was resected with microscopic positive margins. Median follow-up was 15.6 months (range, 6.3–26.1 months). Median and 1-year overall survival was 20 months and 91 %, respectively. Median and 1-year progression-free survival was 14.9 months and 61 %, respectively. Conclusion SBRT-based neoadjuvant therapy for BRPC is well tolerated and can result in a high rate of margin-negative tumor resection.
    Full-text · Article · Sep 2012
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