Pancreas lift and pancreatic movement|Professor Fu Deliang Interpretation of Major Research in the Field of Pancreatic Cancer Chemotherapy: Exploring New Options for Pancreatic Cancer Chemotherapy

*Only for medical professionals to read for reference.
What is the current status of advanced pancreatic cancer treatment and locally advanced pancreatic cancer neoadjuvant treatment? See Professor Fu Deliang interpreting relevant research progress for us.

Pancreatic cancer has a high degree of malignancy and a poor prognosis, and the comprehensive treatment model of multidisciplinary collaboration has become the main clinical treatment method.

As an important medical treatment, chemotherapy occupies an important position in the treatment of pancreatic cancer.

In response to hot issues such as chemotherapy options for advanced pancreatic cancer and neoadjuvant treatment of pancreatic cancer, the "medical community" specially invited Professor Fu Deliang from the Huashan Hospital of Fudan University to conduct in-depth exchanges and discussions.

Professor Fu Deliang’s wonderful video The overall treatment effect of metastatic pancreatic cancer is not good, and there is a far unmet clinical need for treatment.
Pancreatic cancer treatment includes surgical treatment and non-surgical treatment.
Patients with early, clear diagnosis and resection can be treated with radical (R0) resection.
.

For part of resectable pancreatic cancer, borderline resectable pancreatic cancer, and locally advanced pancreatic cancer, preoperative neoadjuvant therapy has become the standard treatment.

However, the incidence of pancreatic cancer is hidden, and the early diagnosis rate is low.
About 60% of patients have metastasized when they are first diagnosed, and often have lost the opportunity for surgical treatment.
For these patients, chemotherapy-based treatment will be adopted.

The first-line chemotherapy for advanced pancreatic cancer needs to be selected according to the patient's physical status.

Professor Fu Deliang said, “At present, the mainstream domestic first-line chemotherapy regimen is a combination of fluorouracil (5-FU) or gemcitabine.
The two classic regimens are the FOLFIRINOX regimen (oxaliplatin+irinotecan+5-FU+ Folic acid calcium) and the AG regimen (gemcitabine + albumin-bound paclitaxel).
The
AG regimen is widely used in China, and the physical requirements of patients are relatively low, and it is also suitable for elderly patients.

The FOLFIRINOX program has a good effect, but its side effects are very severe, and the incidence of grade 3 to 4 adverse events is high, which requires special attention.

In addition to these two combined regimens, there are also some chemotherapy regimens that are also under clinical exploration, such as gemcitabine combined with tigeo or platinum-containing regimens.

In addition, molecular targeted drugs have not yet obtained clear and good therapeutic effects.

"For pancreatic cancer that has progressed after first-line chemotherapy, non-overlapping drugs can be selected as second-line chemotherapy based on the drugs that have been used, patient comorbidities, and adverse reactions.

If the patient has disease progression after first -line chemotherapy based on gemcitabine, second-line treatment 5-FU drugs are often used, but the efficacy of this program is very small; if patients use FOLFIRINOX in the first-line regimen, clinicians may choose albumin-bound paclitaxel for second-line treatment, but there is currently no corresponding research evidence to prove its benefit .

Professor Fude Liang pointed out that "the treatment of metastatic pancreatic cancer is still facing a huge unmet clinical need, especially in second-line and subsequent treatment options are limited, affecting the overall survival of patients with urgent need for us to conduct more clinical research Provide more effective treatment options.

"Irinotecan liposomes bring a new solution to break the dilemma of second-line treatment of metastatic pancreatic cancer.
In response to the dilemma of "almost no drugs available" in the second-line treatment of metastatic pancreatic cancer, a large number of relevant clinical studies have been carried out at home and abroad in recent years.

Among them, SEQUOIA The study and the NAPOLI-1 study are two large-scale clinical studies that have received more attention.
The
SEQUOIA study [1] is a randomized, global phase III clinical study that compares the FOLFOX regimen (5-FU + oxaliplatin) with FOLFOX + polyethylene Efficacy and safety of the glycated interleukin 10 (PEG) regimen in the second-line treatment of gemcitabine-resistant metastatic pancreatic ductal adenocarcinoma (PDAC).

The 567 patients included in the study were randomly assigned to receive the FOLFOX regimen or the FOLFOX+PEG regimen at 1:1 Treatment, 94.
7% of patients had previously received AG regimen treatment.

The primary endpoint is overall survival (OS), secondary endpoints include progression-free survival (PFS), objective response rate (ORR) and safety assessed by RECIST 1.
1 standards, and exploratory analysis includes biomarkers related to immune activation .

The final results of the SEQUOIA study were announced at the American Society of Clinical Oncology Gastrointestinal Oncology Symposium (ASCO-GI) in 2020.

The results of the study showed that OS (median OS: 5.
8 months vs 6.
3 months) and PFS (median PFS: 2.
1 months vs 2.
1 months) were not statistically different between the FOLFOX+PEG group and the FOLFOX group.
The ORR of the two groups Also similar, they are 4.
6% and 5.
6% respectively.

The safety results of the FOLFOX+PEG group are similar to previous research data, and the safety of the combined regimen is tolerable.

The results of this study indicate that PEG+FOLFOX does not improve the efficacy of advanced PDAC patients after the first-line gemcitabine-containing regimen has progressed.

The exploratory analysis of the study showed that with the addition of PEG, the total amount of IL-18, IFN-γ and granzyme B increased, while TGF-β decreased.

In this regard, Professor Fu Deliang explained, “This reflects that the addition of PEG activates an active immune state, which may bring survival benefits.

” At the same time, an analysis of the correlation between IL-18 levels and efficacy in 214 patients found that, In the FOLFOX+PEG group (N=183), the patients whose IL-18 levels increased the most from baseline achieved the longest OS and PFS, but this correlation was not found in the FOLFOX group (N=31).

Professor Fu Deliang pointed out, "The reason why the correlation was not found in the FOLFOX group may be due to the small sample size.

I hope that in the future, when we screen subjects, we can find relevant patients for clinical research based on this phenomenon, so as to obtain better research.
in conclusion.

"The NAPOLI-1 study [2] is a global multicenter (14 countries, 76 centers), non-blinded, randomized, phase III clinical trial, which aims to compare irinotecan liposomes (nal-IRI), 5 -The effectiveness and safety of FU+leucovorin (5-FU/LV) and the combination of the two in the treatment of metastatic PDAC (mPDAC) patients who have previously received gemcitabine-based chemotherapy regimens.

The main results of the study were in 2016 Published in "The Lancet" magazine (impact factor: 60.
392), the results showed that compared with the 5-FU/LV group, the median OS of the nal-IRI+5-FU/LV group was prolonged by 1.
9 months, and the median PFS was extended by 1.
6 months, ORR (16% vs 1%) and CA19-9 response rate (29% vs 9%) were significantly improved.

NAPOLI-1 included 13 Asian centers (5 in South Korea and 8 in Taiwan) A) A total of 132 Asian patients, accounting for about 32% of the overall population.

The results of the Asian population subgroup analysis announced in 2020 show that [3], the nal-IRI+5-FU/LV group has a median of the 5-FU/LV group OS was extended by 5.
2 months (8.
9 months vs 3.
7 months; HR=0.
51, P=0.
025) (Figure 1), median PFS was extended by 2.
6 months (4.
0 months vs 1.
4 months, HR=0.
48, P=0.
011 ), ORR increased (8.
8% vs 0%, P=0.
114), and the response rate of CA19-9 was significantly increased (32.
0% vs 7.
7%, P<0.
001) (Figure 2).

In this regard, Professor Fu Deliang pointed out, “nal The -IRI+5-FU/LV regimen is more effective in subgroups of the population, and provides a new idea for the second-line treatment of patients with metastatic PDAC in Asia.

Irinotecan liposomes have not yet been approved for marketing in China.
It is hoped that irinotecan liposomes will be able to add a new and powerful therapeutic weapon to my country's clinics in the near future.

"Figure 1.
NAPOLI-1 study Asian population nal-IRI+5-FU/LV group and 5-FU/LV group OS results Figure 2.
NAPOLI-1 study Asian population nal-IRI+5-FU/LV group and 5 -The overall result of the FU/LV group is that neoadjuvant therapy for locally advanced pancreatic cancer has not yet been satisfactory, and further exploration is needed in the future.
In recent years, the role of neoadjuvant therapy in improving the prognosis of pancreatic cancer patients has received increasing attention.

The value of neoadjuvant therapy Professor Fu Deliang pointed out, “For operable pancreatic cancer, the value of neoadjuvant therapy is still controversial, and its R0 resection rate may not be significantly improved.

For borderline resectable pancreatic cancer, neoadjuvant therapy can help control tumor progression and even reduce tumor burden, increase R0 resection rate, and improve patient prognosis.

For locally advanced pancreatic cancer, neoadjuvant therapy may downgrade the tumor to a marginal resectable pancreatic cancer, or even resectable pancreatic cancer, in order to obtain a chance of surgical resection.

At the same time, neoadjuvant therapy can also assess the effect of chemotherapy in advance, as a screening measure, to prevent patients with extremely poor prognosis from receiving meaningless surgery.

"The commonly used neoadjuvant chemotherapy regimens for patients with locally advanced pancreatic cancer are the FOLFIRINOX regimen and the AG regimen, but the effective rate of treatment (surgical conversion rate) is limited.

Professor Fu Deliang explained, "From the imaging point of view, it is 5% to 15%.
In fact, The clinical summary of the major centers is about 10%, and the meta-analysis of the tumor database shows that it is 7% to 8%.

"How to further improve the surgical conversion rate has become the focus of attention in the field.
The
NEOLAP-AIO-PAK-0113 study [4] is a multi-center, open-label, multi-center, randomized phase II study conducted in Germany, and included the ECOG score as 0 or 1, untreated locally advanced pancreatic cancer (confirmed by histology or cytology) adult (18-75 years old) patients, aiming to compare AG regimen with AG regimen sequential FORFRINOX regimen as multi-drug induction of locally advanced pancreatic cancer The efficacy and safety of chemotherapy regimens.
The
main endpoint of the study is the surgical conversion rate.

The 130 patients included in the study were randomly divided into the AG group or the AG sequential FOLFIRINOX group at 1:1.

The main results of the study will be published in the journal "Lancet Gastroenterol Hepatol" in 2021 (impact factor: 14.
781).

The results showed that the surgical conversion rates of the AG group and the AG sequential FOLFIRINOX group were 35.
9% and 43.
9% (OR 0.
72, 95% CI 0.
35-1.
45; p=0.
38), and the median OS was 18.
5 months and 20.
7 months, respectively (HR 0.
86, 95% CI 0.
55-1.
36; p=0.
53) (Figure 3).

Figure 3.
NEOLAP-AIO-PAK-0113 Study OS Outcomes All other secondary endpoints of the study, such as investigator-assessed PFS, imaging response rate, CA19-9 response rate, and R0 resection rate, between the two treatment groups There was no significant difference, but the histopathological degradation of the evaluable resectable specimens in the AG sequential FOLFIRINOX group improved.

In terms of safety, during induction chemotherapy, the incidence of adverse events (TEAE) in the AG group and AG sequential FOLFIRINOX group 3 or above treatment was 55% and 53%, respectively; no treatment-related adverse events were found death.

In this regard, Professor Fu Deliang pointed out, “This study has brought dawn to the clinic, but the AG regimen and the AG sequential FOLFIRINOX regimen have a higher incidence of adverse events, especially after many Chinese patients receive the FOLFIRINOX regimen, the drug side effects The occurrence of this makes the patient’s quality of life poor, so the patient’s tolerance to the treatment still needs to be considered.

” Professor Fu Deliang further added, “We can also try to use chemotherapy combined with radiotherapy, radiofrequency therapy, nanoknife therapy, etc.
, which may be The patient is helpful.

The results of a phase III clinical trial PREOPANC study in the Netherlands [5] showed that for patients with resectable or border-resectable PDAC, the R0 resection rate of gemcitabine combined with neoadjuvant radiotherapy was significantly higher than that of direct surgical treatment.
Improved (71% vs 40%), but the neoadjuvant treatment regimen failed to bring significant OS benefits.

Therefore, the treatment of locally advanced pancreatic cancer is still a clinical problem, and we still need to further explore in the future.

"Expert Profile Professor Fu Deliang Director of Pancreatic Surgery, Huashan Hospital Affiliated to Fudan University Director of Pancreatic Cancer Center, Huashan Hospital Affiliated to Fudan University Director of the Institute of Pancreatic Diseases, Fudan University Shanghai Medical Leader, Shanghai Excellent Subject Leader Shanghai Medical Association General Surgery Branch Secretary, Chairman, Pancreatic Disease Committee, Shanghai Association of Integrated Traditional Chinese and Western Medicine, Vice Chairman, Pancreatic Cancer Committee, Shanghai Anti-Cancer Association, Deputy Director, Pancreatic Oncology Group, Chinese Medical Association Oncology Branch, Member of Pancreatology Group, Chinese Medical Association General Surgery Branch, China Anti-Cancer Vice Chairman of the Pancreatic Cancer Professional Committee of the Cancer Society Vice Chairman of the Pancreatic Cancer Expert Committee of the Chinese Society of Clinical Oncology (CSCO) Member of the Standing Committee of the Pancreatic Disease Branch of the Chinese Medical Promotion Association and Leader of the Rapid Rehabilitation and Nutrition Group Chinese Medical Education Association Abdominal Tumor Professional Committee Rapid Rehabilitation Servier, the deputy chairman of the academic group, is the second largest pharmaceutical company in France and one of the top 30 pharmaceutical companies in the world .

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