1. Nolen, Lindsey

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While oncologists have long known that adjuvant chemotherapy can help target malignant cells not destroyed by surgery alone, the conclusive impact on survival rates has remained unclear. This is especially true among individual cancer types, including pancreatic ductal adenocarcinoma (PDAC).

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Thus, a team of researchers at the University of Colorado Cancer Center designed a research study to help determine the effectiveness of adjuvant chemotherapy after neoadjuvant chemotherapy (NAC) followed by surgery specifically for PDAC patients. Published in JAMA Oncology, the study utilized large-scale data and showed promising results (2022; doi: 10.1001/jamaoncol.2022.5808).


The study's co-leader Marco Del Chiaro, MD, Division Chief of Surgical Oncology at the University of Colorado Department of Surgery, explained that the goal of this research was simply to answer the question: Once a patient receives chemo and then surgery, is it useful to give them chemo after as well? His team was particularly interested in finding out if data could potentially support chemotherapy, surgery, and more chemotherapy someday becoming the new gold standard when treating the PDAC patient population. He noted that the role of chemo after surgery was already well-defined for the population of patients who did not receive chemo before surgery.


Ultimately, the importance of studying PDAC outcomes stems from the disease's aggressive 5-year overall survival rate of approximately 10 percent in the United States (CA: Cancer J Clin 2021; doi:10.3322/caac.21654). Historically, surgery has been used as a treatment option, but according to the research, "systematic treatment is also essential for long-term survival."


"Pancreas cancer is currently the third cause of cancer-related death in the United States, and it is expected to be the second one in 2030," Del Chiaro shared. "The treatment at the beginning is the key to prolonging the survival of those patients. The message here is that patients may have greater benefit if their treatment is aggressive from the beginning."


As such, adjuvant chemotherapy has been considered as a possible way to treat PDAC in hopes of better survival outcomes. To make any conclusive determinations regarding adjuvant chemotherapy's impact on survival, research using a matched dataset was necessary, as was one that looked at assessed propensity score matching.


To begin this study, the researchers conducted a nationwide, retrospective study that examined the overall survival of patients who received adjuvant chemotherapy and compared them to those who did not. The data was pulled from the National Cancer Database (NCDB) and included nearly 900 patients with PDAC diagnosed between 2010 and 2018.


The research shared that the NCDB contains data from approximately 1,500 accredited hospitals and clinics, representing about 70 percent of all newly diagnosed cancer cases in the U.S. (Ann Surg Oncol 2008; doi:10.1245/s10434-007-9747-3). The unadjusted rate of overall survival was compared between the adjuvant chemotherapy and non-adjuvant chemotherapy groups using Kaplan-Meier curves and log-rank tests.


Of note, participating patients were excluded if they had clinical or pathological Stage IV disease or had died within 90 days of their operation. The study reported that survival from the date of diagnosis and the date of the surgery was also reported as sensitivity analyses, with "follow-up time" being defined as the time from surgery to the date of death or last contact. The median follow-up time ended up being 21 months (interquartile range 12-33 months).


According to the research, 640 patients were included in the adjuvant chemotherapy group and 492 in the non-adjuvant chemotherapy group. The patients were then matched based on propensity score according to demographic and pathological findings, with 444 patients remaining in each group. Additionally, through their research, the authors found that the multivariable Cox regression model revealed an association with adjuvant chemotherapy and improved survival (HR: 0.71; 95% CI, 0.59-0.85; P<.001) adjusted for all covariates.


The results demonstrated that overall survival was significantly longer in patients regardless of pathological N stage and margin status and who received adjuvant chemotherapy after NAC followed by surgery. The study also found that PDAC tumors with aggressive biology were able to benefit from adjuvant chemotherapy even after surgery when compared to the patient population that did not receive this treatment. Specifically, "the 1-, 3-, and 5-year overall survival rates were 76 percent, 40 percent, and 22 percent in the AC group, and 65 percent, 31 percent, and 20 percent in the non-AC group, respectively."


Del Chiaro affirmed that the conclusion of the study did suggest that adjuvant chemotherapy before and after surgery could someday become the new gold standard. However, he said that this is, to some degree, determined by several individual patient factors. Specifically, the benefit of adjuvant chemotherapy was shown to vary by age, pathological T stage, and tumor differentiation.


"In my opinion, the major takeaway from this study is that it seems [that] even if a patient is given chemotherapy before surgery and then receives surgery, if the patient is fit and in good condition, it is probably worth still giving more chemo after the surgical resection," said Del Chiaro. "For example, age [may be a factor] because normally aged people potentially can be sicker. Then, they may potentially be less keen to receive more chemotherapy after getting every chemotherapy followed by surgery. This becomes even more of a factor if a tumor is aggressive, as oncologists would then need to be aggressive in their treatment."


In general, the study reported that adjuvant chemotherapy was associated with better overall survival in patients with any pathological N stage and margin status. Another notable finding from the research showed that adjuvant chemotherapy after NAC and resection regardless of node and margin status is recommended.


"[We also found that if] the patient is extremely tired or has complications from surgery, this method of treatment may not be a good fit and should not be recommended," Del Chiaro explained. "I would say that, for patients who received chemo followed by surgery, considering adjuvant chemo could be recommended."


Additionally, he noted that, as humans are not machines, there will always be some level of unpredictability when it comes to the effects of treatment and, therefore, also so for studies conducted on the topic. He used the example of COVID-19, where some patients contracted the virus, had worse outcomes, and even died, while others had very minimal symptoms.


"The same applies to chemotherapy and treatment of pancreas cancer. We know that chemotherapy works in some patients but not in everyone. After we give chemotherapy and surgery, some will respond better than others," Del Chiaro said. "Then, when you give chemotherapy again, patients may continue to respond differently. There are so many variables we cannot control, but this is why studying a large dataset is so important."


Overall, this retrospective matched-cohort study helped provide important information on PDAC survival rates that can now be used to work toward improved long-term outcomes. The sheer number of patient data studied in combination with the use of multiple Cox regression models helped the study's authors gain insight that can be dismantled to physicians and patients to determine optimal treatment plans. Moving forward, additional randomized controlled trials to evaluate the true benefit of adjuvant chemotherapy would assist in researchers' ability to provide thorough, evidence-based recommendations.


"My personal opinion is yes; I think that giving chemotherapy before and after is probably the best modality, but that's based on experience," Del Chiaro explained. "This is based on my personal idea of how pancreas cancer works and not based solely on the paper, because [in the paper] we didn't include the patient that didn't receive a neoadjuvant before surgery. Mostly, we did not demonstrate that chemo before surgery is the gold standard for any stage of pancreas cancer."


Del Chiaro further explained that the next step is to fully understand if chemotherapy before surgery should be included for all pancreatic cancer patients, instead of only borderline and locally advanced PDAC patients. He added that chemotherapy before surgery, in his opinion, could have advantages, even if it's not yet the official "gold standard" for primary resectable.


"PDAC is a systemic disease that means your CT scan shows the tumor independently from other cells in your body. [Oncologists] want to control those cells before a patient goes into surgery with chemotherapy," Del Chiaro said. "Other important points to try to understand [using adjuvant chemotherapy] are the roles of chemotherapy before surgery in every patient and how we can detect if the chemotherapy works."


Yet, if chemo and then surgery is performed, and the tumor returns quickly (meaning that the chemo didn't work), the surgery was potentially of no benefit. Being a systemic disease, surgery alone will not dramatically increase overall survival and prevent a recurrence in pancreas cancer patients.


He noted that normally pancreas cancer doesn't respond radiologically to chemotherapy (it does in only about 20% of cases), even if there is a biological response. For this reason, his team wants to become better able to understand the response, the length, how much should be administered, and which patients are ideal for chemotherapy both before and after surgery.


"These are reasons this study was so difficult to randomize. We still have so many questions," Del Chiaro shared. "We want to develop new and better treatments for pancreatic cancer, which is unpredictable and can happen in a relatively short or instead a long period of time. Our group is already investigating some subsequent questions, trying to determine the best possible treatment package for a patient with pancreatic cancer."


Lindsey Nolen is a contributing writer.


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1. Identify results from a study by the University of Colorado Cancer Center related to the treatment of patients with pancreatic ductal adenocarcinoma (PDAC).


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