Advanced pancreatic cancer treated with camrelizumab combined with apatinib: A case report

Abstract

BACKGROUND

The 5-year survival rate for patients with pancreatic cancer (PC) is 4%-12%. Surgery is the only treatment that offers curative potential, but only 15%-20% of patients are eligible for surgery. PC is prone to recurrence and metastasis, and the antitumor effect of chemotherapy is notably limited.

CASE SUMMARY

Histopathological analysis of a 53-year-old female PC patient who underwent Whipple surgery revealed poorly differentiated tumor cells infiltrating nerves, lymphatics, and blood vessels. The patient received two different first-line chemotherapy regimens consecutively; however, both regimens struggled to control disease progression. During this period, the patient underwent liver metastasis ablation surgery, Candida albicans liver abscess, and stereotactic body radiotherapy. With the addition of camrelizumab to the modified FOLFIRINOX regimen, tumor control was achieved. The patient subsequently refused to continue chemotherapy, and the antitumor regimen was changed to a combination of camrelizumab and apatinib. After patients received a combination of immunotherapy and targeted therapy, the length of hospital stay was significantly reduced. Furthermore, all side effects were within acceptable limits, leading to an improved quality of life and prolonged progression-free survival. Unfortunately, the pain associated with cancer, coupled with the side effects of opioid analgesics, has led the patient to reject all available anticancer treatment options. Approximately one month after camrelizumab and apatinib were discontinued without medical authorization, the PC recurred and rapidly progressed to widespread metastasis, ultimately leading to the patient's death approximately one month later. The overall survival was 2 years.

CONCLUSION

Immunotherapy and targeted therapy have the potential to increase both the quality of life and survival time of PC patients, particularly those whose tumor progression is not effectively controlled by chemotherapy alone. Nevertheless, further clinical trials are necessary to validate these findings.

Key Words: Advanced pancreatic cancer; Immunotherapy; Camrelizumab; Targeted therapy; Apatinib; Case report

Core Tip: Pancreatic cancer (PC) is among the most lethal malignancies worldwide, with minimal advancements in treatment over the past three decades. We report the case of a patient with highly malignant PC who demonstrated a poor response to chemotherapy. However, immunotherapy and targeted therapy extended the patient's progression-free survival and improved her quality of life. Immunotherapy and targeted therapy may offer new hope for PC patients.

INTRODUCTION

Pancreatic cancer (PC) is recognized as one of the most lethal malignancies worldwide. According to cancer statistics for China and the United States in 2022, as reported by Xing et al[1], PC represents 2.8% of all newly diagnosed cases and accounts for 4.1% of all cancer-related fatalities among 34 distinct types of cancer. The incidence of PC is increasing by 0.5% to 1.0% annually, and it is projected to become the second leading cause of cancer-related deaths by 2030[2]. Surgery is considered the optimal treatment option for PC. However, unfortunately, only approximately 15%-20% of patients with PC are eligible for pancreatic resection. This is because PC often presents with nonspecific symptoms in its early stages, resulting in a diagnosis of locally advanced stage (30%-35%) or metastatic disease (50%-55%) in the majority of patients[1]. The first-line chemotherapy regimens for PC encompass two primary options. The first regimen consists of gemcitabine in combination with albumin-bound paclitaxel. The second regimen consists of fluorouracil, calcium folinate, irinotecan, and oxaliplatin (FOLFIRINOX or modified FOLFIRINOX)[3]. Due to the challenges in early detection and the aggressive histological characteristics of PC, as well as its low sensitivity to chemotherapy, the 5-year survival rate for PC patients is only 4%-12%[1,2]. Despite extensive research by numerous medical experts over the past 30 years, there has been only minimal improvement in the effectiveness of PC treatment compared with other types of cancer. Consequently, there is an urgent need to identify more effective treatment regimens.

This case report describes a patient with highly aggressive PC who had multiple concurrent adverse prognostic factors, rendering disease progression challenging to control solely with chemotherapy. The combination of immunotherapy and targeted therapy not only extended her progression-free survival (PFS) but also significantly improved her quality of life, ultimately yielding an overall survival (OS) of 2 years. The anticancer regimens administered to the patient at different stages of the disease are depicted in Figure 1, while the imaging changes associated with the liver metastasis are illustrated in Figure 2.

Figure 1  Anticancer regimens and courses of treatment for the patient at different stages of the disease.

Figure 2 Imaging changes in liver metastasis in the patient receiving different anticancer regimens. Following treatment with camrelizumab in combination with apatinib, enhanced abdominal magnetic resonance imaging revealed no increase in size or enhancement of the liver metastasis.

CASE PRESENTATION

Chief complaints

A 53-year-old female patient was diagnosed with PC in April 2022 and was found to have a liver metastasis in November 2022.

History of present illness

In April 2022, the patient was incidentally diagnosed with PC during hospitalization for a right hand injury. At that time, she did not exhibit any symptoms such as abdominal pain or jaundice. Enhanced abdominal magnetic resonance imaging (MRI) revealed pancreatic head tumor with a diameter of approximately 2.2 cm × 2.0 cm, with no evidence of metastasis. The carbohydrate antigen (CA) 19-9 level was 45.3 U/mL (normal range ≤ 30 U/mL), while the carcinoembryonic antigen (CEA) level was within normal limits. She subsequently underwent Whipple surgery at West China Hospital of Sichuan University. Histopathological analysis revealed pancreatic adenocarcinoma with mucinous adenoma (comprising approximately 5%-10%, some of which exhibited signet ring cell carcinoma morphology), graded as G3/poorly differentiated. The tumor cells infiltrated nerves, lymphatics, and blood vessels, with no tumor cells detected at the resection margins. She was diagnosed with PC at stage T2N1M0. Genetic testing revealed mutations in the KRAS and TP53 genes, whereas no mutations were detected in mismatch repair genes or HER2. After surgery, the CA19-9 level decreased to within the normal range. The patient subsequently received chemotherapy consisting of gemcitabine in combination with albumin-bound paclitaxel at the hospital. From May to October 2022, the patient completed a total of 8 cycles of this chemotherapy regimen. During the entire treatment period, the patient experienced bone marrow suppression, gastrointestinal reactions, numbness in both feet, hair loss, and elevated liver enzymes.

One month after the completion of chemotherapy, the patient's CEA level increased to 9.39 ng/mL (normal range ≤ 5 ng/mL), whereas her CA19-9 level remained within the normal limit. A follow-up enhanced abdominal MRI revealed a nodular lesion in the right lobe of the liver, showing enhancement and a maximum cross-sectional diameter of approximately 2.0 cm × 1.9 cm (Figure 3A). We organized a multidisciplinary consultation for the patient and subsequently performed computed tomography (CT)-guided ablation surgery to treat the liver metastasis. In December 2022, the patient was admitted to the hospital for chemotherapy. CEA and CA19-9 levels were within normal ranges. The patient underwent chemotherapy with modified FOLFIRINOX. Following chemotherapy, the patient gradually experienced fever, abdominal pain, and decreased appetite. Abdominal CT and real-time polymerase chain reaction confirmed the presence of a liver abscess and coronavirus disease 2019. The patient subsequently underwent CT-guided percutaneous catheter drainage to treat the liver abscess. The culture of the pus revealed Candida albicans. The patient recovered after receiving a 5-week course of fluconazole and azvudine treatment. In February 2023, follow-up enhanced MRI revealed a reduction in the diameter of the liver metastatic lesion to 1.2 cm × 0.9 cm with enhancement (Figure 3B). She continued to undergo a modified FOLFIRINOX regimen. During the treatment, the patient experienced bone marrow suppression, gastrointestinal reactions, and elevated liver enzymes. However, the numbness in both feet decreased, and the patient’s hair began to regenerate gradually.

Figure 3 Magnetic resonance imaging of liver metastasis during different anticancer treatment regimens. A: On November 23, 2022, an enhanced abdominal magnetic resonance imaging (MRI) revealed a nodular lesion in the right posterior lobe of the liver, with a maximum cross-section of 2.0 cm × 1.9 cm. The lesion exhibited annular enhancement, indicative of a metastatic lesion; B: On February 21, 2023, follow-up MRI revealed a decrease in the size of the nodular lesion to 1.2 cm × 0.9 cm, with persistent annular enhancement; C: On April 11, 2023, MRI revealed an increase in the size of the lesion to 2.0 cm × 1.9 cm, maintaining annular enhancement; D: On July 5, 2023, the lesion was observed to have decreased in size again, measuring 1.4 cm × 1.0 cm, with annular enhancement still present; E: On October 18, 2023, the MRI showed a further reduction in lesion size to 0.9 cm × 0.6 cm, and no enhancement was noted; F: On January 12, 2024, the final MRI revealed no change in lesion size, remaining at 0.9 cm × 0.6 cm, and no enhancement was observed.

The patient was readmitted to the hospital for chemotherapy.

History of past illness

She had no other known medical conditions.

Personal and family history

Her father died of an unknown cancer at the age of 49, and her uncle died of PC at the age of 68.

Physical examination

The patient's vital signs were stable, and her skin and sclera showed no signs of jaundice. There was no tenderness or palpable masses in the abdomen.

Laboratory examinations

The results of the routine blood, renal function, coagulation, and CA 19-9 assays were all within the normal ranges. However, the CEA level increased to 9.89 ng/mL (normal range ≤ 5 ng/mL). Additionally, there was a mild elevation in liver transaminase levels.

Imaging examinations

Enhanced abdominal MRI revealed a ring-enhancing lesion in the right lobe of the liver, with a maximum cross-sectional diameter of approximately 2.0 cm × 1.9 cm, indicating the recurrence of the ablated liver metastasis (Figure 3C).

FINAL DIAGNOSIS

Advanced PC.

TREATMENT

After recurrence of the liver metastasis was detected, the patient underwent 6 consecutive sessions of stereotactic body radiotherapy targeting the metastasis (GTV 10Gy). The patient subsequently continued modified FOLFIRINOX chemotherapy and received a 200 mg dose of camrelizumab every 3 weeks. One month after initiating camrelizumab treatment, the patient developed scattered reactive capillary proliferation on the head, face, neck, trunk, and upper arms, with a maximum diameter of approximately 0.5 cm. These reactive capillary proliferations are prone to rupture and bleeding, but the bleeding stops spontaneously. Reactive capillary proliferation recurred repeatedly over a period of more than one month before gradually resolving without further recurrence. During this period, the patient experienced bone marrow suppression, gastrointestinal reactions, elevated liver enzymes, and subclinical hypothyroidism.

In July 2023, contrast-enhanced MRI revealed an enhancing nodular lesion in the right lobe of the liver, with a maximum cross-sectional diameter of approximately 1.4 cm × 1.0 cm (Figure 3D). The patient refused to undergo chemotherapy, so the anticancer regimen was modified to a combination of camrelizumab (200 mg, iv, every 3 weeks) and apatinib (500 mg, oral administration, once daily). Approximately 3 months later, the follow-up abdominal enhanced MRI revealed a reduction in the size of the liver metastasis without enhancement, with a diameter of approximately 0.9 cm × 0.6 cm (Figure 3E). The patient experienced bone marrow suppression, elevated liver enzymes, subclinical hypothyroidism, fatigue, and grade 1 hypertension.

OUTCOME AND FOLLOW-UP

In January 2024, the patient gradually began to experience intermittent abdominal pain at night. The CEA level was 8.7 ng/mL (normal range ≤ 5 ng/mL), and the CA19-9 Level was 22.1 U/mL (normal range ≤ 30 U/mL). A follow-up enhanced MRI revealed no recurrence of PC, no changes in the liver metastasis, and no other metastases (Figure 3F). Gastrointestinal endoscopy ruled out immune-mediated enteritis, and mesenteric CT angiography excluded mesenteric thrombosis. Initially, the patient managed the abdominal pain with oral loxoprofen, but the pain progressively worsened. Oral morphine or oxycodone resulted in persistent constipation and vomiting. The patient unilaterally discontinued the use of camrelizumab and apatinib, and steadfastly refused any form of anticancer therapy. In February 2024, the patient was hospitalized at a local hospital and diagnosed with recurrent PC. The cancer had metastasized extensively to the abdominal lymph nodes, liver, and multiple sites in both lungs (as reported by the patient's family; no imaging or relevant reports were provided). She died at home 1 month after discharge.

DISCUSSION

PC is among the most lethal malignancies worldwide. The incidence of PC is increasing by 0.5% to 1.0% annually, and it is projected to become the second leading cause of cancer-related deaths by 2030[2]. Surgery remains the most effective treatment for PC. However, PC often presents with an insidious onset, and by the time patients experience symptoms such as abdominal pain and jaundice, the disease has typically progressed to an advanced stage. Consequently, only approximately 15%-20% of PC patients are eligible for surgical intervention. Moreover, even among those who undergo pancreatic resection, approximately 60% will experience recurrence or metastasis within one year after surgery[1]. For patients who have undergone surgery for pancreatic ductal adenocarcinoma, the 5-year OS rate is approximately 20%-25%[4]. Overall, the 5-year OS rate for PC patients is only 4%-12%[1,2]. Patients with PC who have positive resection margins, poorly differentiated tumors, large tumors size, lymph node involvement, and KRAS and TP53 mutations have a lower 5-year survival rate[5]. Consequently, there is an urgent need to identify effective treatments for PC.

Currently, there are two first-line chemotherapy regimens for PC: Gemcitabine in combination with albumin-bound paclitaxel, and either FOLFIRINOX or its modified version[3]. The study revealed that, for patients with resected pancreatic ductal adenocarcinoma, those who received modified FOLFIRINOX regimen presented a longer median disease-free survival (DFS) (21.6 months vs 12.8 months), higher 3-year DFS rate (39.7% vs 21.4%), longer median OS (54.4 months vs 35.0 months), and higher 3-year OS rate (63.4% vs 48.6%) than did those in the gemcitabine group. In terms of drug safety, grade 3 or 4 adverse events were more common in the FOLFIRINOX group than in the gemcitabine group (75.9% vs 52.9%). However, treatment-related deaths were more common in the gemcitabine group than in the FOLFIRINOX group (2.07% vs 0.58%)[6]. Considering the potential adverse events, the patient in our study received gemcitabine in combination with albumin-bound paclitaxel 2 weeks after undergoing Whipple surgery. Throughout the entire course of treatment, there was no evidence of tumor recurrence or metastasis. However, one month later, during the first follow-up examination, a metastatic lesion was discovered in the right lobe of the liver following the completion of 8 cycles of chemotherapy. Fortunately, there was no recurrence of PC. The DFS duration was 7 months, which was significantly shorter than the previously reported DFS duration of 12.8 months. This shorter DFS was associated with several adverse prognostic factors, including low differentiation of the tumor, tumor cell invasion of blood vessels, nerves and lymphatic vessels, and the presence of KRAS and TP53 mutations. For patients with metastatic PC, the FOLFIRINOX regimen demonstrated superior median PFS (6.4 months vs 5.6 months) and median OS (11.1 months vs 9.2 months), as well as a higher 12-month OS rate (48.4% vs 39.5%) than the gemcitabine regimen[7,8]. The patient we reported was diagnosed with PC with liver metastasis. She received modified FOLFIRINOX regimen, with more severe bone marrow suppression and gastrointestinal reactions than did gemcitabine in combination with albumin-bound paclitaxel regimen. Fortunately, the patient's hair gradually regenerated, and the numbness in her feet decreased gradually. However, after 4 months of modified FOLFIRINOX chemotherapy, there was an increase in tumor size at the site of previous liver metastasis. This short PFS of only 4 months highlights the highly aggressive nature of PC, and suggests that chemotherapy alone is not sufficiently effective.

In the past 30 years, despite extensive research by medical experts, there has been minimal improvement in the effectiveness of PC treatment compared with other types of cancer. However, recent studies have demonstrated the potential of immunotherapy to improve the prognosis of PC patients. The tumor microenvironment induces high expression of programmed cell death protein 1 (PD-1) on infiltrating T cells, whereas tumor cells express high levels of the PD-1 ligands, PD-L1 and PD-L2. PD-L1 binds to PD-1 on T cells, inhibiting their proliferation and activation, which results in T cells being unable to kill tumor cells. To overcome this, camrelizumab, a humanized monoclonal antibody, specifically binds to PD-1 and blocks its interaction with PD-L1. This allows T cells to regain their ability to fight against tumor immune responses[9]. In the present case, the patient experienced a recurrence of liver metastasis despite undergoing modified FOLFIRINOX chemotherapy for 4 months. However, the tumor was subsequently controlled by the administration of camrelizumab. After more than a year of chemotherapy, the patient expressed a reluctance to continue with further treatments. Consequently, we were compelled to seek a new anti-cancer regimen for this patient. Published studies have demonstrated that immunotherapy and targeted therapy can prolong PFS and OS in patients with PC. However, some trials have failed to observe any beneficial effects of either monotherapy or combination therapy in PC patients. Additionally, others have reported severe side effects, including bone marrow suppression and immune enteritis. These outcomes are significantly influenced by individual patient differences and the specific drugs used[10]. The aggressiveness of PC is based mainly on its ability to form extensive new blood vessels. Apatinib, a targeted antiangiogenic drug, inhibits the tyrosine kinase receptor VEGFR2, thereby reducing tumor angiogenesis. A published study has reported that combination therapy with camrelizumab and apatinib altered the tumor microenvironment in several ways. Specifically, it increases the infiltration and activation of CD8+ cytotoxic T cells. Additionally, this combination therapy alters the M1/M2 ratio of tumor-associated macrophages and decreases the infiltration of T regulatory cells and the presence of chemokine receptor 2-positive monocytes in cancer tissues. Dual anti-PD-1/VEGFR-2 treatment has a durable vascular strengthening effect in hepatocellular carcinoma, which reduces drug resistance to either treatment alone and improves OS[11]. Numerous studies have demonstrated that the combination of camrelizumab and apatinib offers promising efficacy and manageable safety in patients with hepatocellular carcinoma. Additionally, apatinib is effectively inhibits the reactive capillary proliferation induced by camrelizumab[11,12]. After discussion with the patient and her family, the anticancer regimen was modified to incorporate camrelizumab and apatinib. Patient treated with camrelizumab in combination with modified FOLFIRINOX or camrelizumab in combination with apatinib experienced a prolonged PFS and improved quality of life. Unfortunately, the patient unilaterally discontinued the anticancer regimen because of the pain caused by cancer and the adverse effects of opioid analgesics. Furthermore, the patient refused any further anticancer therapeutic regimens. The OS was 2 years.

CONCLUSION

Immunotherapy and targeted therapy have the potential to increase both the quality of life and survival time of PC patients, particularly those whose tumor progression is not effectively controlled by chemotherapy alone. Nevertheless, further clinical trials are necessary to validate these findings.

ACKNOWLEDGEMENTS

Grammar consulting and writing assistance were kindly provided by Ying Liu.