More research needed on pancreatic cancer treatment strategies, expert says
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Despite a significant amount of data in the adjuvant setting for pancreatic cancer, more research is needed to better define perioperative and neoadjuvant treatment strategies, according to a speaker at Chemotherapy Foundation Symposium.
“We sorely need these trials so that we know better what to do for our patients with pancreatic cancer,” Kim A. Reiss, MD, assistant professor of medicine at Abramson Cancer Center at University of Pennsylvania, said during a presentation.
Reiss began her talk with a discussion about landmark trials in the adjuvant setting.
“In 2013, the randomized, phase 3 trial of adjuvant gemcitabine for 6 months compared with observation after surgical resection among patients with pancreatic cancer set the treatment standard,” Reiss said. “During training in my early years of practice, every patient received adjuvant gemcitabine for 6 months. [That continued] until 2017, when the ESPAC-4 trial came out and established a new treatment paradigm overnight — gemcitabine plus capecitabine.”
However, the combination treatment has been difficult on patients, Reiss added.
“I am unsure of what it is about this combination, but patients seem to struggle with capecitabine when it is combined with gemcitabine,” she said. “This trial was also a landmark moment for looking at R0 and R1 resections for our patients, in which researchers found that patients with R0 resection had longer OS regardless of treatment group. While we don’t know if patients received radiation or if they had local or distant recurrences, this brings home the point that R1 resection is not a great thing to have and we need to do better to prevent patients from having it.”
In 2018, the randomized, phase 3 PRODIGE trial set the current standard for pancreatic cancer treatment.
“This study looked at adjuvant gemcitabine compared with adjuvant mFOLFIRINOX after surgical resection of pancreatic cancer, and the primary endpoint of DFS was met with a rate of 21 months vs. 12 months,” Reiss said. “As one of my mentors said, ‘You could drive a bus through those curves,’ which is always a good sign.”
The trial also demonstrated a significant survival benefit with mFOLFIRINOX.
“This was powerful data and it instantly turned a page in terms of what we do for these patients,” she said. “However, there are a couple of things to note about this regimen. As oncologists, we sometimes struggle with this specific recommendation because it is not easy. Sometimes our patients are older and some have undergone the Whipple procedure, so there are questions about how to use this in real-life practice.”
Of note, many patients included in PRODIGE did not receive the full-dose regimen, she added.
“The modification that was made in the trial compared with the full-dose regimen is an absolute must for tolerability. More than 50% of patients received less than 70% of the dose and one-third of patients did not complete the full 6 months of treatment,” Reiss said. “Patients in the curative-intent and metastatic settings are often worried about compromising the efficacy of a regimen if a dose is missed. As oncologists, we share that concern in the curative-intent setting, but we do not worry as much about it in the metastatic setting. These data drive home the message that we can dose-reduce and stop early if we need to.”
In the phase 3 APACT study, researchers compared adjuvant gemcitabine vs. gemcitabine plus nab-paclitaxel for 6 months after resection for pancreatic cancer.
“The primary endpoint was DFS by central review of imaging, which the authors have proclaimed was probably not the best because local recurrences were not so easy to diagnose on imaging for patients who had resection. Whether it is scar tissue vs. an actual recurrence can be hard to assess by imaging alone and requires clinical context to help make that decision. The central reviewers did not have that available.”
In 2019, the randomized phase 3 APACT trial examined the use of nab-paclitaxel (Abraxane, Celgene) plus gemcitabine in the adjuvant setting.
“APACT was ultimately a negative study and did not meet its primary endpoint,” Reiss said. “That being said, the APACT researchers recently announced 5-year data that showed there was a significant improvement in OS among patients who received gemcitabine and nab-paclitaxel compared with their counterparts who received gemcitabine alone, with an OS difference of 38% vs. 31% at 5 years. However, this is still controversial in that OS was not the primary endpoint, but some people feel this is still a very valid and powerful endpoint. People are debating whether to use this as an adjuvant regimen, and it is not incorrect to do so, in my opinion.”
Bottom line in adjuvant therapy, mFOLFIRINOX has the best data to date for patients who can tolerate it, she said.
“If a patient cannot tolerate mFOLFIRINOX, then gemcitabine plus capecitabine, gemcitabine alone or even gemcitabine plus nab-paclitaxel can be considered as reasonable alternatives,” Reiss added.
In more recent years, there has been a paradigm shift to neoadjuvant therapy.
“This is a much less clear, less complete picture but there is rationale for wanting to give our patients neoadjuvant therapy. We are trying to get a high rate of R0 resection, the tolerability of chemotherapy is better preoperatively, and there is theoretical control of microscopic disease before patients need months to recover from surgery,” Reiss said. “There is also the idea of preventing futile surgery with neoadjuvant therapy, but the specific regimens and the timing remain undefined. Some people give total neoadjuvant therapy, others split it and others give all adjuvant treatment. My personal practice is that I start with 2 months of treatment and reassess every 2 months with the goal of making sure that the patient is tolerating the treatment and to keep an eye on what is happening with the tumor.”
Looking ahead, Reiss said there is great interest in targeted therapies and vaccines to improve upon what is currently available for patients with potentially curable pancreatic cancer.
References:
Conroy T, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1809775.
Neoptolemos JP, et al. Lancet. 2017;doi:10.1016/S0140-6736(16)32409-6.
Neoptolemus JP, et al. Abstract 4516. Presented at: ASCO20 Virtual Scientific Program; May 29-31, 2020.
Oettle H, et al. JAMA. 2013;doi:10.1001/jama.2013.279201.
Reiss KA. Neoadjuvant/ adjuvant approaches for pancreatic cancer. Presented at: 39th Annual Chemotherapy Foundation Symposium: Innovative Cancer Therapy for Tomorrow; Nov. 3-5, 2021.
Tempero MA, et al. Abstract 4000. Presented at: ASCO Annual Meeting; May 31-June 4; 2019; Chicago.
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Reiss KA. Neoadjuvant/adjuvant approaches for pancreatic cancer. Presented at: 39th Annual Chemotherapy Foundation Symposium: Innovative Cancer Therapy for Tomorrow; Nov. 3-5, 2021.
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