NEW YORK (Reuters Health) – Prolonged preoperative chemotherapy is associated with associated with “excellent” overall survival in some patients with locally advanced/borderline resectable (LA/BR) pancreatic cancer, researchers have found.
“Prolonged preoperative chemotherapy for patients with locally advanced pancreatic cancer results in an optimal patient selection for surgery,” Dr. Timothy R. Donahue from the University of California, Los Angeles, told Reuters Health by email. “Those patients in our series who responded to treatment and were taken to surgery experienced an outstanding survival — among the best recorded.”
Pancreatic ductal adenocarcinoma has a dismal five-year overall survival (only 5.8%) that has not improved during the past decade. Preoperative chemotherapy aims to shrink tumors to enable complete surgical removal, thereby improving survival rates.
Dr. Donahue and colleagues analyzed their institution’s experience with 49 stage III LA/BR pancreatic adenocarcinoma patients who were initially unresectable, were down-staged through chemotherapy, and underwent surgical resection. They focused on overall survival, lymph-node negativity, and prognostic biomarkers that could help guide a decision for the use of adjuvant therapy.
Down-staging therapy in these patients brought a significant decrease in median tumor size (from 3.1 cm to 1.7 cm) and in serum CA19-9 levels (from 96.3 U/mL to 20.0 U/mL), the team reports in JAMA Surgery, online December 4.
Most patients had received a multidrug regimen of gemcitabine- or 5-fluorouracil-based therapy for a median 7.1 months of down-staging chemotherapy, longer than in other reported series.
Fifteen patients had apparent resolution of vascular involvement by CT after down-staging therapy. Twenty-four (49.0%) patients initially underwent attempted resection that had to be aborted due to apparent vascular invasion. All of these patients were subsequently reexplored and successfully resected after down-staging therapy.
In the overall cohort, only three of 49 tumors required vascular resection (and only one of the resected vein walls was involved with invasive carcinoma).
Most patients (85.7%) had margin-negative resections, and three-quarters had lymph-node-negative disease at resection.
Eleven of 24 patients who had a reported histopathologic response had no viable cancer found in the excised specimen.
Lymph-node-negative patients had received chemotherapy for a longer duration (mean, 8.2 months) than had lymph-node-positive patients (mean, 6.2 months), though the difference fell short of statistical significance.
Median overall survival was 40.1 months, and median disease-free survival was 23.2 months. The overall five-year survival was 42.9%, and only three patients had evidence of local recurrence at last follow-up. Thirteen had distant recurrence, and eight patients were assumed to have recurred based on increasing CA19-9 levels and/or otherwise unexplained death.
On multivariate analyses, histopathologic treatment response, perineural invasion, and SMAD4 protein expression status were most closely correlated with survival for patients after down-staging therapy and surgical resection, suggesting to the researchers that “they could be used to help determine which of these patients receive optimal benefit from adjuvant therapy.”
“This is a single institution retrospective study, so we cannot definitively say that prolonged chemotherapy is better than shorter duration regimens,” Dr. Donahue explained. “However, from our data, we can conclude that our approach to locally advanced disease resulted in excellent survival for patients who underwent surgical resection. One of the core components to our approach is prolonged preoperative chemotherapy.”
Dr. L. Andrew DiFronzo from Kaiser Permanente in Los Angeles wrote an invited commentary on the study. He told Reuters Health by email, “If the primary goal is to down-stage the tumor and render it resectable, then perhaps just enough chemotherapy should be given to get the patient to that specific point. In some patients that may take 4-6 cycles, but others may need 8-12 cycles or more. Some may need radiation in the preoperative setting, in addition to chemotherapy, to get them to the point of resectability.”
“On the other hand, if the goal is to select patients for operative therapy based on both response/resectability, as well as a prescribed length of time to see if distant metastases develop, then perhaps longer periods of chemotherapy would be appropriate,” Dr. DiFronzo said. ”In other words, even if a patient becomes resectable after 6 cycles, perhaps they should still receive 12 cycles.”
“This question is of critical importance and ideally would be answered by a randomized clinical trial,” Dr. DiFronzo said. “Additionally, the question of the potential benefit of preop chemo in a resectable (not LA/BR) case is being addressed by an American College of Surgeons Oncology Group (ACOSOG) study, which just recently closed to accrual, and hopefully we’ll have results in a few years.”
Dr. Volkan Cetin from Albert Einstein College of Medicine in Bronx, New York, who was not involved in the research, called the issue “a very gray area.”
“There is no solid scientific evidence for us to recommend a particular neoadjuvant chemotherapy or chemo-radiation regimen for all patients with locally advanced or borderline resectable disease,” he told Reuters Health by email. “There are consensus-based guidelines to define borderline resectability, but no standard treatment for it.”
Dr. Cetin agreed that “conducting a randomized clinical trial is a must to confirm survival benefits of prolonged treatment.”
Dr. Kathryn T. Chen from Fox Chase Cancer Center, Philadelphia, recommended a full course of neoadjuvant chemotherapy for all patients with borderline or locally advanced potentially resectable pancreatic cancer.
“This helps to select patients who will derive the most benefit from surgery; additionally, these patients also experience improved R0 resections and pathologic response,” Dr. Chen, who was not part of the new study, told Reuters Health by email. “Similarly, we looked at our experience with patients who received prolonged chemotherapy following chemoradiation, and those who had the longest course of chemotherapy in general had more favorable outcomes with respect to overall survival.”
“The main takeaway is that patients with borderline resectable tumors deserve a multidisciplinary evaluation,” Dr. Chen concluded. “Even those patients who do not appear to be surgical candidates at the onset may, through prolonged chemotherapy, become resectable.”
JAMA Surg 2013.