Pancreatic cancer is a highly malignant tumor of the digestive system, and the 5-year survival rate of patients is less than 5%. However, due to the insidious onset of pancreatic cancer and the difficulty of early diagnosis, most patients are already in advanced stage when they are diagnosed and lose the chance of surgery, so drug therapy becomes the main treatment. Even for patients who have undergone surgical resection, their recurrence and metastasis rates are as high as 80% 2 years after surgery, and their survival rates are only 15%-20% 5 years after surgery, and most patients lose their lives because of recurrence or metastasis after surgery. Therefore, active exploration of postoperative adjuvant drug therapy may be an important way to inhibit recurrence and metastasis and thus prolong the survival of patients. Next, we will introduce the therapeutic drugs for pancreatic cancer and the latest progress one by one.
1.Gicitabine-based chemotherapy
Gemcitabine is the first-line drug for pancreatic cancer treatment. Compared with other drugs, gemcitabine has less side effects and is well tolerated by patients, while maintaining similar efficacy. Patients with all stages of pancreatic cancer have benefited from gemcitabine-based combination chemotherapy.
(1) Postoperative adjuvant therapy for resectable pancreatic cancer.
For patients with resectable pancreatic cancer, surgery is undoubtedly the best option. However, even if the tumor is completely removed, the prognosis of such patients is still not satisfactory. Studies have confirmed that postoperative chemotherapy with 5-fluorouracil + gemcitabine or folinic acid (previously used in the treatment of unresectable pancreatic cancer) in patients with resectable pancreatic cancer can effectively improve the prognosis of patients.
It is worth mentioning that our department is conducting a clinical trial of adjuvant therapy with metformin combined with gemcitabine, and this type of unique treatment regimen is likely to make adjuvant therapy more effective.
(2) Preoperative neoadjuvant therapy for critical resectable pancreatic cancer.
For those critical resectable pancreatic cancer that has developed localized venous infiltration, we can still reduce the tumor stage and increase the surgical resection rate through preoperative neoadjuvant therapy. The preoperative neoadjuvant therapy and preoperative re-evaluation around gemcitabine currently carried out in our hospital have improved the outcome of such patients to some extent.
(3) Standard medication for palliative treatment of unresectable pancreatic cancer.
In palliative treatment, the effective response rate of gemcitabine monotherapy is only about 15% and the median survival does not exceed 1 year. In contrast, gemcitabine in combination with oxaliplatin/cisplatin/erlotinib/capecitabine has a slightly improved efficacy, but also a greatly increased side effect profile.
5-Fluorouracil was the key drug in the treatment of pancreatic cancer before the introduction of gemcitabine, and recent studies have shown that the “FOLFIRINOX” quadruple combination of gemcitabine, oxaliplatin, and irinotecan has better efficacy than gemcitabine alone in metastatic pancreatic cancer, but its application is limited by the aggravation of toxic side effects.
2. Novel drugs for adjuvant gemcitabine chemotherapy
Although gemcitabine-based chemotherapy is the standard treatment for pancreatic cancer, its limited efficacy and unavoidable toxic side effects have prompted us to search for new drugs in the hope of improving the efficacy by combining with gemcitabine.
(1) Drugs for pancreatic cancer debulking therapy.
Pancreatic cancer contains abundant tumor interstitium with few blood vessels, making it difficult for chemotherapeutic drugs to reach the tumor localization, which in turn affects the efficacy. It has been shown that anti-angiogenic drugs such as sorafenib and sunitinib are basically ineffective, and drugs with potential pro-vascular normalization effect such as metformin may improve the efficacy of gemcitabine, but the actual effect needs to be evaluated. In contrast, de-interstitialization therapy can effectively promote the arrival of gemcitabine and other drugs to the tumor localization by destroying the interstitium. Albumin-conjugated paclitaxel has been used clinically for the adjuvant treatment of progressive pancreatic cancer with good results. In addition to the inhibition of tumor cell growth, the interstitial effect of this drug is likely to be the key to the increased efficacy. In addition, new drugs like hyaluronidase inhibitors, CD40 agonists, Notch pathway inhibitors, Hedgehog pathway inhibitors and other drugs targeting interstitialization of pancreatic cancer are under development and are believed to be new options for combination therapy of pancreatic cancer in the near future.
(2) Molecularly targeted drugs.
Intracellular tyrosine kinase phosphorylation is an important link in the survival and proliferation of tumor cells. Inhibition of tyrosine kinase phosphorylation can effectively inhibit the growth of tumor. The representative drugs are erlotinib, sunitinib, etc. Clinical trials have been conducted on sunitinib for the treatment of pancreatic neuroendocrine tumors.
”Monoclonal antibodies” are drugs that use immunological principles to identify tumor cell-specific antigens, allowing cancer inhibiting drugs or immune cells to concentrate at the lesion to kill tumor cells more effectively. Such drugs include SB408075, erbitux, etc., but their efficacy needs to be evaluated.
(3) Emerging biological therapies for pancreatic cancer – immune-related therapy, gene therapy.
Traditional chemotherapeutic drugs mainly kill tumor cells directly, however, with the increasing understanding of pancreatic cancer, it has been found that the development of pancreatic tumors is not only the continuous proliferation of tumor cells themselves. Tumor-related inflammation, human immunity and genetic mutations are all deeply related to it.
”Immunomodulatory mobilization” has been proposed as an emerging concept in the treatment of pancreatic cancer in recent years. Drugs such as thymidine (Nitazen) have been used with some success in the treatment.
Mutations in the K-ras gene have been found in the majority of pancreatic cancers, and many studies have suggested that mutations in this gene may be key to the development of pancreatic cancer. Although the relevant drugs are still in the experimental stage (our department will soon conduct a related trial program), it is possible that they will enter the clinic in the near future and become a blessing for pancreatic cancer patients.
Although many of these emerging therapies have not yet entered the clinic and their effects are not as ideal as expected, these new ideas and therapeutic entry points are based on a profound understanding of pancreatic cancer, and some of them may be transformed into effective treatments in the near future.
In conclusion, the current effective response rate of gemcitabine monotherapy is only about 15%, which is still far from the “standard therapy” in oncology, which means that there is still a long way to go to launch the “optimal” regimen. This means that there is still a long way to go before the “optimal” regimen is available! But at the same time, we are constantly searching for new drugs and combination chemotherapy regimens. It should be noted that the invention and launch of new drugs in pancreatic cancer drug therapy does not mean the elimination of the “old” drugs, but the fundamental purpose of these new drugs, new therapies and new ideas in pancreatic cancer clinical treatment is to improve the effectiveness of gemcitabine-based chemotherapy. Through the application of new drugs and combination therapy protocols, we believe that the effectiveness of adjuvant treatment for pancreatic cancer will continue to increase and improve.