Anti-programmed death-1 immunotherapy-promising treatment for metastatic colorectal cancer: A case report

Abstract

BACKGROUND

Colorectal cancer (CRC) is the third most prevalent form of cancer worldwide. Among patients with CRC, colorectal liver metastasis (CRLM) is the foremost direct contributor to mortality. In recent years, immunotherapy has swiftly risen to prominence as a vital approach for treating a range of solid tumors, including CRC. We present a unique case of a patient suffering from CRLM, with the goal of offering an insightful example and relevant references for the treatment of CRLM.

CASE SUMMARY

We report a patient who experienced liver metastasis after undergoing successful surgical removal of CRC, with the postoperative pathological stage identified as pT4N2aM0. The patient has been receiving a combination treatment of Western and Traditional Chinese Medicine. Regular assessments of the patient’s condition have been conducted, encompassing evaluations of serum carcinoembryonic antigen levels, carbohydrate antigen 199, and observations of the tongue complexion and its coating. The patient achieved clinical remission after anti-programmed death-1 immunotherapy when various systemic therapies failed. Since the diagnosis of CRLM, the patient has survived for more than 6 years, surpassing the expected survival time for those with advanced CRC.

CONCLUSION

This case illustrates the considerable promise of anti-programmed death-1 immunotherapy in managing CRLM, especially in scenarios of drug resistance and disease progression.

Key Words: Colorectal cancer; Colorectal liver metastasis; Drug resistance; Immunotherapy; Anti-programmed death-1; Case report

Core Tip: The patient described in this report has survived for more than 6 years since the diagnosis of colorectal liver metastasis. The patient achieved clinical remission after anti-programmed death-1 (PD-1) immunotherapy when different systemic therapies failed. This case demonstrates the promising potential of holistic integrative medicine, combining anti-PD-1 immunotherapy with complementary and alternative treatments, for managing advanced malignancies amid drug resistance and disease progression.

INTRODUCTION

Globally, colorectal cancer (CRC) ranks the third among the cancers with the highest incidence and mortality rates[1]. Colorectal liver metastasis (CRLM) markedly reduces life expectancy and is the primary direct mortality factor in affected individuals[2]. The 5-year survival rate for patients with CRLM is less than 50%[3]. Traditional treatments such as surgery, chemotherapy, and radiotherapy, all come with their own set of constraints[4]. The national comprehensive cancer network guidelines suggest the use of bevacizumab in conjunction with chemotherapy for patients with CRC that may be surgically removed[5,6].

However, the emergence of drug resistance and disease progression narrows the therapeutic avenues. In such contexts, immunotherapy has swiftly ascended as a principal strategy against numerous solid tumors in recent years[7]. By blocking programmed death-1 (PD-1) with antibodies, its binding to programmed cell death ligand 1 and programmed cell death ligand 2 is hindered, which in turn disrupts their subsequent pathways and reactivates the T cells’ ability to combat tumors[8]. This method ranks as one of the most effective among clinically utilized checkpoint inhibitors[9].

We here report a special case of a CRLM patient treated with anti-PD-1 immunotherapy, who has survived for more than 6 years since the diagnosis of CRLM. Anti-PD-1 immunotherapy, as an innovative therapy, could provide a fresh strategy in the treatment of CRLM.

CASE PRESENTATION

Chief complaints

The patient was a 53-year-old male. He was admitted to our hospital for further treatment after colon cancer surgery 26 days ago.

History of present illness

Before admission to our hospital, the patient exhibited increased tumor markers: Serum carcinoembryonic antigen (CEA): 325.87 ng/mL, carbohydrate antigen (CA) 242: > 220 U/mL, and CA-199: 301.80 U/mL (Figure 1), during a routine health examination on August 23, 2018. Subsequently, on August 27, 2018, the patient underwent an abdominal computed tomography (CT) scan at Nanjing First Hospital. The scan revealed a lesion in the ileocecal region suggestive of CRC, accompanied by several enlarged peripheral lymph nodes; appendix thickening; emphysema adjacent to the right superior lobar septum; a pulmonary bulla; a nodule in the lower right lung; atherosclerosis; fatty liver; enhanced nodules in the left liver lobe indicative of hemangioma; and minor pelvic effusion. The following day, a gastrointestinal endoscopy was performed, revealing chronic gastritis, a duodenal ulcer, a lesion in the colorectal area, and several colorectal polyps. On August 31, 2018, the patient underwent comprehensive surgical removal of right-sided colon cancer at Nanjing First Hospital. The postoperative pathological examination showed moderately and poorly differentiated tubular adenocarcinoma in the ileocecal region of right colon cancer; tumor size 7.5 cm × 8.5 cm × 5.0 cm; invasion of cancer tissue outside the serosa; tumor thrombus in vessels; no nerve invasion; local invasion of cancer tissue into the appendix wall; no cancer involvement found at the upper and lower margins; peri-intestinal lymph nodes with cancer metastasis (6/10) (Figure 2). The pathology report following surgery indicated stage pT4N2aM0. Tumor-associated gene expression detection showed KRAS: NM-004985: exon2: c.G38A: p.G13D site mutation.

Figure 1 Tumor markers. A: Carcinoembryonic antigen; B: Carbohydrate antigen 199. CEA: Carcinoembryonic antigen; CA-199: Carbohydrate antigen 199.

Figure 2 Pathological examination of the ileocecal region of the resected right colon mass specimen (hematoxylin and eosin staining). A: Original magnification, × 10; B: Original magnification, × 40.

History of past illness

The patient denied any medical history of chronic illnesses or infection.

Personal and family history

The patient denied notable family history of cancer.

Physical examination

The patient was 185 cm tall and weighed 90 kg. His physical examination was unremarkable except for a longitudinal incision approximately 12 cm long in the middle of the right abdomen, which healed well.

Laboratory examinations

Serum tumor markers, including CEA and CA-199, were above the normal ranges (Figure 1). Other laboratory test results, including routine blood tests, blood biochemistry and coagulation function, were unremarkable.

Imaging examinations

Chest and abdominal CT (Figure 3A) showed the change after radical resection of right colon cancer; a high possibility of metastasis in the left lateral lobe and right posterior lobe of the liver; minor pelvic effusion; pulmonary emphysema adjacent to the right superior lobar septum; a ground-glass nodule in the right lower lung; coronary atherosclerosis; thoracolumbar degeneration (September 28, 2018).

Figure 3 Radiologic images of computed tomography and magnetic resonance imaging. A: September 28, 2018 computed tomography (CT) imaging [colorectal liver metastasis (CRLM) 27 mm]; B: October 12, 2018 CT imaging (CRLM 23 mm × 13 mm); C: December 7, 2018 CT imaging (CRLM 20 mm × 12 mm); D: January 11, 2019 CT imaging (CRLM 23 mm × 16 mm); E: February 13, 2019 magnetic resonance imaging (CRLM 25 mm); F: June 26, 2019 CT imaging (CRLM 24 mm × 27 mm); G: September 18, 2019 CT imaging (CRLM 25 mm × 30 mm); H: October 11, 2022 CT imaging (CRLM not observed). R: Right; L: Left; A: Anterior; P: Posterior; S: Superjacent; I: Inferior.

FINAL DIAGNOSIS

The patient was diagnosed with CRC and CRLM based on the pathological examination and imaging examinations.

TREATMENT

The patient received bevacizumab combined with FOLFOX treatment [bevacizumab 300 mg day 1 + oxaliplatin 150 mg day 1 + calcium folinate 200 mg day 1 + fluorouracil (5-FU) 0.5 g day 1, 5-FU 2.0 g continuous intravenous infusion (civ) 46 hours] on September 28, October 30, November 13, November 27, and December 11, 2018. The liver metastases were shown to be smaller than before from October 12, 2018 to December 07, 2018 (Figure 3B and C).

The patient intended to undergo surgical treatment. It was recommended by the Department of Surgical Oncology that bevacizumab should be stopped 4 weeks before surgery. The patient received FOLFOX treatment (oxaliplatin 150 mg day 1 + calcium folinate 200 mg day 1 + 5-FU 0.5 g day 1, 5-FU 2.0 g civ 46 hours) on December 25, 2018, January 10, and January 26, 2019. On January 11, 2019, abdominal CT (Figure 3D) indicated a slight progression (small lymph nodes around the operative area similar to CT findings on December 07, 2018; the liver metastases were slightly larger compared with CT findings on December 07, 2018). The patient was admitted to the Department of Surgical Oncology for preoperative assessment on February 11, 2019. On February 13, 2019, abdominal magnetic resonance imaging (Figure 3E) showed a high possibility of multiple intrahepatic metastatic tumors; thus, metastases could not be excluded. Department of Surgical Oncology suggested that the surgical indication was still uncertain. It was recommended that radiofrequency ablation (RFA) of the liver metastases should be performed by the Intervention Therapy Department. On February 18, 2019, the patient underwent RFA of the liver metastases, with 2 targets in total.

The patient was subsequently admitted to our department for further treatment. On February 23, 2019, the patient received targeted therapy combined with chemotherapy (bevacizumab 300 mg day 1 + oxaliplatin 150 mg day 1 + raltitrexed 5 mg day 1). The tumor markers were higher than before (CEA: 9.01 ng/mL, CA-242: 103.60 U/mL, CA-199: 182.57 U/mL) (Figure 1) on March 9, 2019. Treatment was changed to bevacizumab combined with FOLFIRI (bevacizumab 300 mg day 1 + irinotecan 200 mg day 1 + calcium folinate 200 mg day 1 + 5-FU 0.5 g day 1, 5-FU 2.0 g civ 46 hours) on March 9, March 23, April 6, April 20, and May 11, 2019. Chest and abdominal CT (Figure 3F) indicated the progression of CRLM [soft tissue shadow in front of the right psoas major muscle, considered to be metastasis; the liver metastases were larger compared with previous CT findings (January 11, 2019); multiple enlargements of hepatic hilum lymph nodes were larger than before, considered to be metastasis (June 26, 2019)]. Treatment was changed to irinotecan 200 mg day 1 + capecitabine 1.5 g day 1-day 14 on June 29, July 26, and August 16, 2019. On September 18, 2019, chest and abdominal CT (Figure 3G) showed suspicious thickening of the anastomosis; a soft tissue shadow in front of the right psoas major muscle, considered to be metastasis, slightly larger compared with previous CT findings (June 26, 2019); multiple metastatic tumors of the liver larger than before; multiple enlargement of hepatic hilum lymph nodes larger than before, considered to be metastasis; patch shadow on L3 vertebral body, which indicated progression of the disease. It was recommended that the patient receive interventional therapy. However, the patient refused and requested to continue the original chemotherapy for one more cycle. On September 19, 2019, he received irinotecan 200 mg day 1 + capecitabine 1.5 g day 1-day 14.

OUTCOME AND FOLLOW-UP

The disease continued to progress rapidly after first-, second- and third-line treatments. The patient sought further evaluation at Jiangsu Cancer Hospital, where next-generation sequencing revealed the tumor’s microsatellite instability-high status. Subsequently, the patient received anti-PD-1 immunotherapy (toripalimab 240 mg day 1) from October 2019 to October 2021. The tumor markers were normal when reassessed at Jiangsu Cancer Hospital on May 24, 2022. On October 10, 2022, the patient was admitted to our department for further re-examination. Chest and abdominal CT (Figure 3H) indicated a clinical cure of CRLM [change after radical resection of right colon cancer; review after treatment of liver metastasis, multiple mild enhanced liver lesions shown in the previous film were not seen this time; small cystic focus in the liver; multiple enlarged lymph nodes in the liver hilum and the soft tissue mass in front of the right psoas major muscle shown in the previous film was not seen this time; multiple nodules in both lungs; slight fibrosis of the right lower lung; coronary arteriosclerosis; thoracolumbar degeneration; mild instability of lumbar vertebral bodies 2 and 3; patch shadow on L3 vertebral body (October 11, 2022)]. Over the past year to six months ago, the patient gained 15 kg, with no significant weight changes observed in the past six months. Chest and abdominal CT indicated a stable condition on February 6, 2023; October 31, 2023; May 21, 2024 and September 20, 2024. The treatments received by the patient and the subsequent outcomes are listed in Table 1.

Table 1 Timeline of treatments received by the patient and the subsequent outcome.

Time period	Treatment and dose	Results
From September 28, 2018 to December 11, 2018	Bevacizumab + FOLFOX treatment (bevacizumab 300 mg day 1 + oxaliplatin 150 mg day 1 + calcium folinate 200 mg day 1 + fluorouracil 0.5 g day 1, fluorouracil 2.0 g civ 46 hours)	Stable disease
From December 25, 2018 to January 26, 2019	FOLFOX treatment (oxaliplatin 150 mg day 1 + calcium folinate 200 mg day 1 + fluorouracil 0.5 g day 1, fluorouracil 2.0 g civ 46 hour)	Progressive disease
February 18, 2019	RFA	Progressive disease
February 23, 2019	Bevacizumab 300mg day 1 + oxaliplatin 150 mg day 1 + raltitrexed 5 mg day 1	Progressive disease
From March 9, 2019 to May 11, 2019	Bevacizumab + FOLFIRI treatment (bevacizumab 300 mg day 1 + irinotecan 200 mg day 1 + calcium folinate 200 mg day 1 + fluorouracil 0.5 g day 1, fluorouracil 2.0 g civ 46 hours)	Progressive disease
From June 29, 2019 to September 19, 2019	Irinotecan 200 mg day 1 + capecitabine 1.5 g day 1-day 14	Progressive disease
From October 2019 to October 2021	Anti-PD-1 immunotherapy (toripalimab 240 mg day 1)	Stable disease
From October 2021 to September 2024	Single Traditional Chinese Medicine treatment	Stable disease

Civ: Continuous intravenous infusion; RFA: Radiofrequency ablation; PD-1: Programmed death-1.

DISCUSSION

CRLM significantly impacts the prognosis of patients with CRC[10]. We report the special case of a patient with CRLM (Figure 4). The disease continued to progress rapidly following first-, second- and third-line treatments. The patient failed different systemic therapies, such as chemotherapy, targeted therapy and interventional therapy. Subsequently, the patient underwent anti-PD-1 immunotherapy (toripalimab 240 mg day 1) after the development of multiple metastases of CRC. Surprisingly, he achieved clinical remission, as confirmed by tumor markers and CT scans. Researches showed that anti-PD-1 immunotherapy exhibits anti-tumor efficacy in metastatic CRC[11,12].

Figure 4 The entire treatment process in this patient. RFA: Radiofrequency ablation; PD-1: Programmed death-1.

The patient has survived for more than 6 years since the diagnosis of CRLM, which is a long course of CRC disease. At present, there is a lack of treatment methods for CRLM. This patient’s clinical cure demonstrates the significant potential of anti-PD-1 immunotherapy for treating CRLM. It is essential to follow up patients to observe their outcome and prognosis, as this can contribute to improving clinical diagnosis and treatment strategies. However, this can be particularly challenging, especially in China, where the high patient volume and low staff-patient ratio often lead to difficulties in doctor-patient communication. Clinicians are burdened with heavy workloads and have limited time to conduct thorough follow-ups with each patient. In China, patients often compare hospitals and select the one they prefer. Consequently, some patients may not receive treatment at a single hospital for an extended period, thereby complicating the follow-up process. Despite the numerous challenges, establishing an effective patient follow-up system is crucial. This allows for the observation of outcomes and prognosis, providing valuable clinical data for further research.

The present patient has consistently undergone Traditional Chinese Medicine (TCM) treatment in our department. Modified Liujunzi Decoction was administered and was adjusted based on the patient’s symptoms at different times. The patient’s condition, including complexion and tongue coating, was constantly assessed. Patients with Chinese background tend to seek TCM treatment[13], which has been shown to alleviate clinical symptoms, prolong survival time, and reduce the adverse effects of conventional therapy[14]. The pathogenesis theory of cancerous toxin is a TCM innovative theory for the differentiation and treatment of tumors[15]. Research has indicated that TCM decoctions[16], such as Xian-Lian-Jie-Du decoction[17], formulated based on the pathogenesis theory of cancerous toxin, exhibit anticancer effects on CRC and CRLM. Tumorigenesis is a multistep process, and its occurrence and development mechanisms are still not fully explored. Single therapy may have little or no effect, necessitating holistic integrative medicine[18]. The combination of multiple therapies, including conventional therapy, targeted therapy, immunotherapy, and complementary and alternative medicine, such as TCM, represents a novel approach to treating tumors and metastases.

CONCLUSION

We report a rare case where the patient’s overall survival has been more than 6 years, even though CRLM occurred. This case demonstrates the promising potential of holistic integrative medicine, combining anti-PD-1 immunotherapy with complementary and alternative treatments, for managing advanced malignancies amid drug resistance and disease progression.

ACKNOWLEDGEMENTS

The authors thank the patient for his kind consent for the anonymized publication of this case report and accompanying images.