Chemoradiotherapy plus tislelizumab for mismatch repair proficient rectal cancer with supraclavicular lymph node metastasis: A case report

Abstract

BACKGROUND

According to the latest report, colorectal cancer is still one of the most prevalent cancers, with the third highest incidence and mortality worldwide. Treatment of advanced rectal cancer with distant metastases is usually unsatisfactory, especially for mismatch repair proficient (pMMR) rectal cancer, which leads to poor prognosis and recurrence.

CASE SUMMARY

We report a case of a pMMR rectal adenocarcinoma with metastases of multiple lymph nodes, including the left supraclavicular lymph node, before treatment in a 70-year-old man. He received full courses of chemoradiotherapy (CRT) followed by 4 cycles of programmed death 1 inhibitor Tislelizumab, and a pathologic complete response (pCR) was achieved, and the lesion of the left supraclavicular lymph node also disappeared.

CONCLUSION

pMMR advanced rectal cancer with preserved intact distant metastatic lymph nodes may benefit from full-course CRT combined with immunotherapy.

Key Words: Rectal cancer, Metastasis, Chemoradiotherapy, Immunotherapy, Prognosis, Case report

Core Tip: Rectal cancer is a clinically common malignancy and the mainstream treatment methods are chemoradiotherapy (CRT) and surgery. Advanced rectal cancer is often associated with distant organs and lymph node metastasis. We report a case of mismatch repair proficient rectal cancer with left supraclavicular lymph node metastasis. The patient received 4 cycles of CRT combined with immunotherapy and achieved pCR. This case provides a rare clinical experience for such patients.

INTRODUCTION

Clinical trials in the treatment of advanced solid tumors using programmed death 1 (PD-1) inhibitors are being conducted extensively. Recent results have shown that PD-1 blockade antibody has significant therapeutic efficacy in patients with mismatch repair deficient (dMMR) and microsatellite instability-high (MSI-H) colorectal cancer (CRC)[1,2], but these patients account for only 15% of all CRC patients[3]. In addition, clinical trials of immunotherapy for patients with mismatch repair proficient (pMMR) CRC are deficient. Here, we report a case of a pMMR rectal adenocarcinoma with metastases of multiple lymph nodes before treatment, including the left supraclavicular lymph node, in a 70-year-old man. He received full courses of chemoradiotherapy (CRT) followed by 4 cycles of PD-1 inhibitor Tislelizumab, a complete pathological response was achieved, and the lesion of the left supraclavicular lymph node also disappeared.

CASE PRESENTATION

Chief complaints

A 70-year-old Chinese man was admitted to our hospital complaining of difficulty in defecation for 1 month.

History of present illness

Upon admission, the patient underwent endoscopy, which detected a cyclo-intestinal luminal growth mass, which was diagnosed as a poorly differentiated adenocarcinoma by pathologic examination. ¹⁸F-FDG PET/CT was performed and metastasis to the left supraclavicular lymph node was found. The patient underwent enterostomy due to difficulty in defecation.

History of past illness

The patient had hypertension for more than 10 years, and kept taking medicine to control his blood pressure.

Personal and family history

The patient denied any family history of rectal cancer or psychological or genetic disorders.

Physical examination

All relevant physical examinations showed no significant abnormality and vital signs were stable.

Laboratory examinations

Tumor markers in serum including carcinoembryonic antigen, cancer antigen 199, CA125 and CA153 were all within the normal ranges, whereas the level of CA724 increased to 8.9 ng/mL (reference range 0-5.3 ng/mL).

Imaging examinations

¹⁸F-FDG PET/CT was performed to detect metastases (Figure 1A). It revealed metastases of multiple lymph nodes, including the left supraclavicular lymph node (Figure 1B) and a high uptake in the rectum (Figure 1C).

Figure 1 ¹⁸F-FDG PET/CT image before and after treatment. A: ¹⁸F-FDG PET/CT image before treatment. The number is time of examination; B: Metastatic lymph node in the clavicle before treatment. The orange arrow indicates the lymph node; C: The rectal lesion before treatment. The lesion is indicated by the blue arrows; D: ¹⁸F-FDG PET/CT image after treatment. The number is time of examination; E: Disappearance of the metastatic lymph node after treatment; F: The rectal lesion with reduced uptake after treatment.

Further diagnostic work-up

The immunohistochemistry demonstrated that the patient was positive for all four proteins associated with mismatch repair (MMR) status (Figure 2A-D), suggesting a pMMR rectal cancer, and the tumor proportion score of programmed cell death-ligand 1 was 8% (Figure 2E). We then compared the changes in CD8+ T cell/effector regulatory T cell (CD8/eTreg) ratio before and after treatment, and found that the ratio increased from 2.79 to 3.26 (Figure 3).

Figure 2 Histopathological analysis and immunohistochemical staining of the biopsy specimen. A: MLH1 is positive in tumor cells; B: MSH2 is positive in tumor cells; C: MSH6 is positive in tumor cells; D: PMS2 is positive in tumor cells; E: High expression of programmed cell death-ligand 1 in the specimen.

Figure 3 Immunohistochemical staining of CD8+ T cell and effector regulatory T cell before and after treatment. A: CD8+ T cell in tumor cells before treatment; B: effector regulatory T cell (eTreg) in tumor cells before treatment; C: CD8+ T cell in tumor cells after treatment; D: eTreg in tumor cells after treatment.

FINAL DIAGNOSIS

Combined with the medical history, the patient was diagnosed with rectal cancer with the left supraclavicular lymph node metastasis, which was staged as cT3N2bM1a (c-stage IVA), according to the AJCC 8^th TNM staging system.

TREATMENT

The patient received 4 cycles of CRT with capecitabine and radiotherapy at a dose of 50.4 Gy, followed by PD-1 inhibitor Tislelizumab 200 mg once every three weeks.

OUTCOME AND FOLLOW-UP

The patient did not have any adverse effects related to the PD-1 inhibitor during the follow-up. After finishing the last treatment, the patient was admitted to the hospital for re-examination, unexpectedly, there was no significant uptake of the previous metastases of the multiple lymph nodes, including the left supraclavicular lymph node (Figure 1D and E) and no uptake of the rectal lesion could be seen on the ¹⁸F-FDG PET/CT (Figure 1F). He then underwent radical resection of the rectal lesion, and no tumor cell was found under microscope, which suggested that the patient achieved a pCR.

DISCUSSION

The 5-year survival rate of CRC patients is still low in spite of various treatments used[4,5]. Based on the mutation patterns, CRC can be categorized into two distinct groups: the patients with dMMR, which tends to have high overall tumor mutation burden, and the patients with pMMR, with much lower tumor mutation burden[6]. dMMR tumors can be certified by the lack of immunohistochemical staining of the MMR proteins MLH1, MSH2, MSH6, or PMS2, which tend to have a high density of immune cell infiltration, known as "hot tumor", thus these patients have a better prognosis generally, but the number of the patients was low[7].

Currently, many phase 2 and 3 clinical trials have been carried out in the treatment of various solid tumors, including CRC, using PD-1 inhibitors. In a phase 2 clinical trial by Cercek, 100% dMMR/MSI-H rectal cancer patients, who received PD-1 inhibitor treatment and standard CRT followed by surgery, achieved clinical complete response, and no patient had disease progression or recurrence[8]. The KEYNOTE 016 study[9] evaluated the efficacy of pembrolizumab in metastatic CRC patients. All patients with dMMR/MSI-H metastatic CRC displayed favorable antitumor activity with an objective remission rate (ORR) of 40% (4/10), while none of the patients with pMMR or microsatellite stable tumor achieved ORR. The latest PANDORA trial[10] also indicated the efficacy of a neoadjuvant therapy with PD-1 inhibitor following CRT in patients with locally advanced rectal cancer (LARC), and 34.5% (19/55) of the patients achieved pCR. The above trials have shown positive therapeutic effects in dMMR/MSI-H CRC patients treated with PD-1 inhibitor alone or combined with other treatments, but pMMR CRC patients showed little benefit from immunotherapy. The main reason for this phenomenon is the “cold” characteristic of pMMR tumor. Therefore, how to induce pMMR tumor to be “hot” has been a major concern.

As observed in the VOLTAGE-A study[11], 37 patients received 5 cycles of CRT and Nivolumab and about 30% of the patients achieved pCR. Similarly, the study by Gao et al[12] confirmed the effectiveness of immunotherapy for pMMR LARC. One possible explanation is that the induction of tumor cell death after radiotherapy increases the release of tumor antigens and pro-inflammatory mediators which promote infiltration of tumor-infiltrating lymphocytes at the primary site and triggers anti-tumor responses[13,14]. Simultaneously, according to recent studies, maintaining the integrity of the lymph nodes is significant to immunotherapy efficiency[15,16], which suggested that immunotherapy induces activation of migratory dendritic cell in tumor-draining lymph node and increases anti-tumor capacity by decreasing Treg and activating effector T cells in the sentinel lymph node and peripheral blood, increasing anti-tumor capacity.

CONCLUSION

We presented a rare case of pMMR advanced rectal cancer with distant lymph node metastasis treated with CRT and Tislelizumab with good efficacy. Immunotherapy combined with standard CRT as a conversion therapy might be a promising treatment in the advanced rectal cancer.

ACKNOWLEDGEMENTS

We appreciate the cooperation of patient and his family during the treatment.