Jiang-Xia Yin ,Yong-Jie Zhang ,Ai-Xiang Li ,Gui-Feng Chen ,Li-Ping Zhu ,Zi-Zhi Zhang*

1Department of Medical Oncology,Shouguang Hospital of Traditional Chinese Medicine,Shouguang,Shandong Province,China.

Abstract The patient was a 63-year-old female,who was diagnosed with advanced pancreatic cancer with mediastinal lymph node and lung metastases and pleural effusion in June 2019.First-line treatment with 6 cycles of gemcitabine plus tegafur with best response of partial response.Second-line treatment was 4 cycles of nab-paclitaxel monotherapy ended up with disease progression.Third-line treatment was sintilimab with anlotinib for 10 cycles.The patient's condition has achieved clinical complete remission so far.

Keywords:sintilimab;anlotinib;advanced pancreatic cancer;complete response

Background

Pancreatic cancer is a common gastrointestinal tumor with a very high degree of malignancy.The latest data showed that the 5-year survival rate of pancreatic cancer is only 9%,and the 5-year survival rate of patients with metastatic pancreatic cancer is 3%.In recent years,the incidence of pancreatic cancer has been increasing year by year [1].Pancreatic cancer is estimated to be the second leading cause of cancer death by 2030 [2].At present,the main treatment for pancreatic cancer is surgery,but the rate of metastasis and recurrence is high [3].Many other treatment options,such as radiotherapy and chemotherapy,are generally ineffective [4].Immunotherapy has achieved remarkable results in melanoma,lymphoma and lung cancer,however,immunotherapy in pancreatic cancer is still in its infancy.

Two studies have investigated the role of PD-1/PD-L1 inhibitor monotherapy in advanced pancreatic cancer.Brahmer et al.conducted a phase I clinical study of anti-PD-L1 antibody BMS-936559 in patients with advanced cancer,including 207 advanced patients with different cancer types,of which 14 patients with advanced pancreatic cancer did not respond to treatment [5].Another clinical study was a randomized phase II trial of 65 patients with metastatic pancreatic cancer who failed first-line gemcitabine or 5-FU treatment.The patients were randomized to receive either durvalumab monotherapy or durvalumab combined with tremelimumab,with median overall survival of 3.6 months and 3.1 months,respectively,and disease control rates were 6% and 9%,respectively [6].The above studies suggested that immunotherapy alone is not effective for pancreatic cancer,and current researches are trying to combine immunotherapy with other therapies to improve the anti-tumor efficacy.The effect of anti-PD-1 monotherapy is relatively slow but a longer duration of action.The advantage of targeted therapy is that it has a rapid onset of action,but the disadvantage is that it is prone to drug resistance.The combination of anti-PD-1 and targeted drugs is expected to become a new direction for the treatment of pancreatic cancer,and its therapeutic effect appears earlier and more durable than monotherapy.However,there is still difficulty of clinical application,and a lack of reference experience in the published literature.Our team used sintilimab combined with anlotinib in the third-line treatment of a patient with advanced pancreatic cancer of multiple metastases and achieved complete remission.This case is represented and discussed here.

Case presentation

The patient is a 63-year-old female patient with Karnofsky performance status of 90.In June 2019,he was admitted to a local hospital due to repeated abdominal pain and low back pain.Enhanced chest CT showed multiple lung metastases,mediastinal lymph node metastasis and pleural effusion.Abdominal CT scan indicated pancreatic lesions spreading to the fundus,spleen,left adrenal gland and left kidney.Lung biopsy suggested poorly differentiated metastatic adenocarcinoma,CK5/6(+),P40(-),P63(-),CK7(+),TTF-1(-),NapsinA(partial+),Vimentin(+).The final diagnosis was advanced pancreatic cancer.

First-line treatment was gemcitabine plus tegafur chemotherapy for 6 cycles,and grade 3 myelosuppression occurred after the 4th cycle.After chemotherapy,the patient's primary tumor was reduced from 8 cm to 2 cm,the enlarged mediastinal lymph nodes and pleural effusion disappeared,and the multiple lung metastases shanked significantly,and the efficacy evaluation was partial response.

The patient was reexamined at Shandong Cancer Hospital on November 27,2019.CT showed that the primary tumor of the pancreas,lung metastases and mediastinal lymph nodes were enlarged.Considering the progression of the disease,he was switched to second-line chemotherapy with nab-paclitaxel.The first intravenous infusion of the patient after 200mg of albumin-paclitaxel resulted in grade 3 myelosuppression,fatigue and anorexia.The first re-examination after the first cycle of second-line chemotherapy,the efficacy evaluation was partial response,the second CT re-examination on March 26,2020 showed that the lung metastases and mediastinal lymph nodes were enlarged compared with before,the lung metastases increased from 2 cm to 4 cm,and the mediastinal lymph nodes increased to 3 cm,the tumor marker CA125 increased from 34.35U/ml to 84.64U/ml,considering that the disease progressed again.

Third-line treatment was sintilimab 200mg day 1 and anlotinib 8mg daily two weeks on/one week off,every 3 weeks.The regiment went smoothly without obvious adverse reactions.After 10 cycles,the patient achieved clinical complete remission,and 20 cycles of treatment have been completed so far,without recurrence and new lesions.

Discussion and Conclusions

The combination therapy of tumor immunotherapy and anti-angiogenesis has synergistic effect based on the mechanism of inhibiting tumor growth and metastasis.The major cell components of the tumor microenvironment are endothelial cells,which provide the tumor with nutritional support and play a role in immunosuppression.The second major component are immune cells,which promote tumor metastasis and suppress anti-tumor immune mechanisms and responses [7].Therefore,the research of tumor microenvironment has focused on two major branches:tumor immune microenvironment and tumor neovascularization [8].

In the tumor immune microenvironment,tumor-associated macrophages (TAMs) support primary tumor growth,angiogenesis,and invasion by secreting numerous tumor-promoting proteases,cytokines,and growth factors such as EGF.As tumors grow,immunosuppressive cells,including myeloid-derived suppressor cells(MDSCs) and Treg cells,are mobilized into the circulation and infiltrate into growing tumors,which inhibit antitumor immune processes,disrupt immune surveillance,and enable tumor immune escape [9].Abnormal pro-angiogenic signals in the tumor microenvironment result in a lack of endothelial cells,reduced pericyte coverage,disruption of endothelial cell connections,and non-functioning blood vessels,which results in the difficulty of leukocytes to adhere to blood vessels and infiltrate tumor tissue.These vessels are also unable to recruit tumor-targeting leukocytes into the tumor tissue,exacerbating the immunosuppressive tumor microenvironment [10].Antiangiogenic therapy with appropriate dose and duration can normalize the abnormal vascular structure and function of tumors,which could produce normal perfusion and mature vascular distribution,improve drug delivery efficiency,increase tumor tissue oxygen partial pressure,and sensitize radiotherapy.This would facilitate the recruitment and infiltration of effector T cells,reduce the accumulation of immunosuppressive regulatory T cells,relieve the immunosuppressive state,and improves the efficacy of immunotherapy [11].Reduced immunotherapy efficacy is associated with immunosuppressive cells in the tumor microenvironment.For example,MDSCs are associated with adverse effects of immunotherapy,and higher regulatory T cells are associated with reduced immune efficacy [12].

The team used immunotherapy combined targeting drug for third-line treatment of pancreatic cancer.Satisfactory effect has been achieved after 2 cycles of treatment,and complete remission has been achieved after 10 cycles of treatment.At present,20 cycles of treatment have been completed.The patient is in good physical condition and well tolerated.The hypertension caused by anlotinib is well controlled by valsartan,and the blood pressure is stable.In the past 2 months,the patient developed proteinuria (+-++) and urinary tract infection,and he was given anti-infection drugs,etc.After supportive treatment,the symptoms disappeared.There were no other significant adverse events.For patients who are well tolerated,vigilance should still be maintained and adverse events should be dealt with in a timely manner.

Currently,the patient is in complete clinical remission,but the subsequent treatment strategy is not clear,which include drug holiday,targeted therapy alone,immunotherapy alone,or immunotherapy plus targeted therapy as maintenance.There is still no clear evidence-based guidance for further treatment plans after remission.The Multidisciplinary Team (MDT) recommended immunotherapy plus targeted maintenance therapy.MDT plays an important role in tumor treatment decision-making,especially in challenging cases.With the advancement of the concept of multidisciplinary comprehensive treatment,an optimized combination of various treatment methods such as surgery,radiotherapy and chemotherapy,interventional therapy,targeted therapy,and immunotherapy has been adopted to exert the best curative effect and ultimately translate into survival benefits for patients.

Table 1 Treatment process

Figure 1 The primary focal point of the pancreas

Figure 2 Lung metastases

Figure 3 Meterastinal lymph node metastases