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Is neoadjuvant therapy beneficial in pancreatic cancer?

Pancreatic cancer is the 7th deadliest cancer in the world. The high mortality rates are attributed to the spread of cancer to other parts of the body at the time of diagnosis. In patients having advanced pancreatic cancer, the first line of treatment is chemotherapy which controls the systemic spread of cancer. Following this, surgery and radiation therapy may be preferred to remove/destroy the tumor masses.

However, about 15-20% of pancreatic cancer patients are diagnosed at an early stage leaving them with multiple options for first-line treatment [1]. At an early stage, when the cancer cells have not left the primary site of origin, the tumor mass can be resected using conventional surgery and it is said to be resectable. Furthermore, when the cancer cells have only begun to move out of the pancreas, the tumor is called borderline resectable pancreatic cancer. It is wrapped around blood vessels so surgery is challenging but possible.

Therefore, both resectable pancreatic cancer and borderline resectable pancreatic cancer are amenable to upfront surgical removal but it is not clear if the patients will benefit more from chemotherapy prior to surgery (neoadjuvant chemotherapy).

What should be the first line treatment in pancreatic cancer?

Determining the first-line treatment for resectable and borderline resectable pancreatic cancer, which is best in terms of overall survival and progression-free survival, is an active area of research. Several clinical trials have explored the options of gemcitabine, modified FOLFIRINOX (a combination of chemotherapy drugs), and paclitaxel in the neoadjuvant setting. But these studies have used diverse methods and produced contradicting results [2].

Thus, the evidence regarding the use of chemotherapy as the first-line treatment in resectable pancreatic cancer is weak and no clinical decision can be made based on the results of individual clinical trials.

A meta-analysis to answer the pressing question

A meta-analysis (review of studies) was performed to provide some clarity about whether chemotherapy before the surgery is advantageous in resectable pancreatic cancer or should the conventional approach of upfront surgery be adopted in patients with localized pancreatic cancer [2]. To find out the answer to this pressing question, the authors of this meta-analysis filtered through 3229 relevant clinical studies and selected 6 studies that met their criteria.

Adjuvant chemotherapy for resectable pancreatic cancer

According to the findings of this meta-analysis, neoadjuvant therapy does not improve the clinical outcome including overall survival and disease-free progression in patients with resectable pancreatic cancer. But the silver lining is that it does facilitate the complete removal of the tumor (known as R0 resections) - the analysis found that neoadjuvant treatment improves chances of complete surgical removal by about 20%. So, while survival does not improve, neoadjuvant strategies may facilitate resection in this difficult-to-treat disease.

Adjuvant chemotherapy for borderline resectable pancreatic cancer

Clinical trials testing neoadjuvant chemotherapy or chemotherapy plus radiation have had mixed results. But some show improved resection rates and survival. One study found neoadjuvant chemotherapy plus radiotherapy before surgery improved overall survival to 17.6 months, versus 13.2 months with upfront surgery [3]. R0 resections were also better.

Another trial tested intense chemotherapy called mFFX in neoadjuvant settings [4]. A total of 8 cycles of mFFX without radiation did way better than 7 cycles plus radiation. About 57% of the patients had R0 resections and median survival was almost 30 months, versus only 17 months with chemotherapy plus radiation. However, the third study found that mFFX in the neoadjuvant setting only had 10-month median survival [5]. So the effectiveness and best neoadjuvant regimen is still unclear.

Therefore, neoadjuvant seems to improve R0 resections, even if survival benefit is still uncertain. More data is needed to optimize neoadjuvant therapy for borderline pancreatic cancer.

In a nutshell

A meta-analysis combined six clinical trials testing neoadjuvant chemotherapy or chemotherapy plus radiation for resectable pancreatic cancer to find out which first-line treatment holds the most clinical advantage in pancreatic cancer. It found no survival benefit from neoadjuvant treatment compared to upfront surgery for resectable pancreatic cancer. Upfront surgery should still be the standard approach for these patients.

However, there is some evidence to suggest a clinical benefit of neoadjuvant chemotherapy in borderline resectable pancreatic cancer, but more research is needed to arrive at a conclusion.