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Using Neoadjuvant Therapy to Reduce Early Recurrences, Increase Survival in Patients With Pancreatic Cancer


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USE OF THE FOLFIRINOX regimen (fluorouracil, leucovorin, irinotecan, and oxaliplatin) was associated with a 4.9-month improvement in overall survival compared to gemcitabine/ nab-paclitaxel (Abraxane) in the neoadjuvant treatment of resectable and borderline-resectable pancreatic head adenocarcinoma, after adjusting for covariates, in a retrospective review of consecutive cases at the University of Pittsburgh. The results were presented at the 2018 Society of Surgical Oncology (SS0) Annual Cancer Symposium1 in Chicago by Mashaal Dhir, MD, Assistant Professor of Surgery, State University of New York Upstate Medical University, Syracuse. The current study was conducted by Dr. Dhir while he was a fellow at the University of Pittsburgh Medical Center, under the mentorship of Dr. Zureikat. 

Mashaal Dhir, MD

Mashaal Dhir, MD

“Pancreatic adenocarcinoma is the third leading cause of cancer-related mortality,” Dr. Dhir noted. Accordingly, several presentations dealt with pancreatic cancer treatment, including the increasing use of neoadjuvant therapy. 

Although the standard of care for resectable pancreatic head adenocarcinoma remains surgery followed by adjuvant therapy, according to Dr. Dhir, 50% of patients don’t receive adjuvant chemotherapy following pancreatoduodenectomy due to postoperative complications. Neoadjuvant chemotherapy, he explained, has several theoretical advantages, including early treatment of disease, assessment of chemoresponsiveness, downstaging of nodal disease, and increasing the rates of margin-negative resection. 

Number of Cycles Significant 

IN THE STUDY reported by Dr. Dhir, 73 patients were treated with neoadjuvant FOLFIRINOX, and 120 patients received neoadjuvant gemcitabine/nab-paclitaxel. Those who received FOLFIRINOX were relatively younger (median age = 63 years vs 69 years for those who received gemcitabine/nab-paclitaxel), had fewer comorbidities, and were more likely to have borderline-resectable disease (79% vs 59%) and larger tumors on computed tomography scan (median size = 2.9 vs 2.7 cm). 

“Pathology specimens of patients who received FOLFIRINOX were less likely to demonstrate lymphovascular invasion as well as positive lymph nodes,” Dr. Dhir stated. R0 resection status “was over 80% in both groups,” he added (84.9% for the FOLFIRINOX group, 80.8% for gemcitabine/nab-paclitaxel). Approximately 75% of patients in both groups received adjuvant therapy. 

On multivariable analysis, “only the number of neoadjuvant cycles was an independent predictor of survival,” the researchers reported. In this study, 1 cycle was 1 month of therapy. 

Armando E. Giuliano, MD

Armando E. Giuliano, MD

Asked by session moderator Armando E. Giuliano, MD, Director, Division of Surgical Oncology, Cedars-Sinai Medical Center, Los Angeles, if that finding would “lead you to conclude that you should increase the duration of neoadjuvant chemotherapy for these patients,” Dr. Dhir noted that the University of Pittsburgh experience, presented at the 2017 SSO symposium, showed “most patients should try to undergo six cycles of chemotherapy overall.” That could be “neoadjuvant or adjuvant or neoadjuvant plus adjuvant,” Dr. Dhir explained. “It would make sense to prolong the neoadjuvant therapy,” he said, “especially if there is a concern that a patient may not be able to receive adjuvant chemotherapy because of postoperative complications.” 

Using inverse probability-weighted estimators for 166 patients showed “the average treatment effect of FOLFIRINOX was to increase overall survival by 4.9 months over the average treatment effect of gemcitabine/nab-paclitaxel,” Dr. Dhir noted. 

“It would make sense to prolong the neoadjuvant therapy, especially if there is a concern that a patient may not be able to receive adjuvant chemotherapy because of postoperative complications.”
— Mashaal Dhir, MD

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“The results of the ongoing randomized SWOG S1505 trial will provide further insight into the effectiveness of neoadjuvant FOLFIRINOX and gemcitabine/nab-paclitaxel in localized pancreatic head adenocarcinoma,” Dr. Dhir said. 

High-Volume Surgical Centers 

PATIENTS WITH pancreatic cancer treated in medical centers that perform a high volume of pancreatectomies and more commonly use neoadjuvant therapy have improved overall survival rates, according to an analysis of data from 109 high-volume centers.2 But improved overall survival was seen “for all patients treated at those centers, whether or not they received neoadjuvant therapy,” according to a study by Alexander V. Fisher, MD, a resident at the University of Wisconsin, Madison, and colleagues. 

Alexander V. Fisher, MD

Alexander V. Fisher, MD

In addition to previously cited reasons for using neoadjuvant therapy, Dr. Fisher noted, “Early recurrence after a surgery-first approach has been estimated to occur in 15% to 30% of patients, and these early recurrences, defined as within 6 months of surgery, are associated with a median survival of only 9 months.” 

Using the National Cancer Data Base, the researchers identified patients with a diagnosis of pancreatic adenocarcinoma undergoing curative-intent resection between 2006 and 2014. “We limited our analysis to treatment at hospitals that were in the top three quintiles for surgical volume,” Dr. Fisher said. This corresponded to hospitals performing more than 10 pancreatectomies per year on average. Patients with carcinoma in situ or stage III or IV pancreatic cancer were excluded, as were those with unknown treatment sequences for surgery and chemotherapy/radiation. 

At the 109 high-volume hospitals, “the average hospital used neoadjuvant therapy in 14% of patients who had undergone resection,” Dr. Fisher reported, although “there is tremendous variation in the utilization of a neoadjuvant approach—from 0% to 75%.” For this study, “adjuvant and neoadjuvant therapies were defined as either chemotherapy and/or radiation or chemoradiation,” Dr. Fisher noted. 

Five hospitals were “high outliers for neoadjuvant therapy,” with more than 40% of patients who underwent surgery having received neoadjuvant therapy, Dr. Fisher explained. Other hospitals were classified by use of neoadjuvant therapy as medium-high (7 hospitals, with 27% to 40% of patients receiving neoadjuvant therapy), medium (30 hospitals, with 14% to 26% receiving neoadjuvant therapy), and low (65 hospitals, with less than 14% of patients receiving neoadjuvant therapy). 

“Significantly longer overall survival was seen at hospitals that are high outliers for neoadjuvant therapy utilization.
— Alexander V. Fisher, MD

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Survival Difference Widened 

LOOKING AT pathologic outcomes, Dr. Fisher reported, “high rates of R0 resections were achieved most frequently in the high outliers for neoadjuvant therapy at 86%, compared with 77% for the low utilizers of neoadjuvant therapy. On multivariable analysis, … R0 resection was a strong predictor of improved survival, with a hazard ratio of 0.64.” 

Unadjusted Kaplan-Meier curves showed overall survival from the date of diagnosis as 28.9 months for high neoadjuvant therapy use vs 21.1 months for low use. “In adjusted multivariable survival analysis, the difference in overall survival between high and low utilization of neoadjuvant therapy widened to almost 12 months—35.6 months vs 24.3 months,” Dr. Fisher noted. 

“Both medium-high and high neoadjuvant utilization hospitals, with hazard ratios of 0.8 and 0.68 respectively, predicted improved survival.” When patients who received neoadjuvant therapy were excluded from the analysis, there remained an association of improved overall survival in hospitals with high use of neoadjuvant therapy. 

“Significantly longer overall survival was seen at hospitals that are high outliers for neoadjuvant therapy utilization,” Dr. Fisher concluded. “This is true both for patients receiving neoadjuvant therapy and those receiving surgery first. Neoadjuvant utilization may be a marker for institutional factors and processes that correlate with survival outcomes.” Further studies are needed to define these factors. ■

DISCLOSURE: Drs. Dhir, Giuliano, and Fisher reported no conflicts of interest. 

REFERENCES 

1. Dhir M, Zenati MS, Hamad A, et al: FOLFIRINOX versus gemcitabine/nab-paclitaxel for neoadjuvant treatment of resectable and borderline resectable pancreatic adenocarcinoma: A propensity matched analysis. 2018 Society of Surgical Oncology Annual Cancer Symposium. Abstract 7. Presented March 23, 2018

2. Fisher A, Abbott D, Campbell-Flohr S, et al: Neoadjuvant therapy utilization for pancreatic cancer among high volume surgical centers: Is it a marker of quality? 2018 Society of Surgical Oncology Annual Cancer Symposium. Abstract 59. Presented March 23, 2018.


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