case_images: PMC10756898_01
case_images: Representative images, pathological features and clinical courses of this patient. (A) PET/CT shows that the patient has multiple liver metastases and pyramidal metastases at initial diagnosis, indicating stage IV intrahepatic cholangiocarcinoma. (B) Hematoxylin-eosin staining images of the pathological section show a small amount of tumor tissue with the concentrated distribution of active foci, and most of the edges are mucous tissue. (C) Patient's clinical courses and treatment response assessment: The patient entered second-line therapy in January 2022, and achieved SD-PR 3 months after the end of radiotherapy. The best response was SD-PR, and the second-line PFS reached 12 months.
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case_images: IV intrahepatic cholangiocarcinoma in April 2021. Imaging examinations showed a huge liver mass on enhanced CT and multiple slightly low-density lesions in the liver on positron emission tomography-computed tomography (PET-CT), with the largest lesion measuring 16.5x11.6 cm in the right liver lobe and T12 vertebral body destruction (Figure 1A). Pathology examination showed a large amount of mucin in the puncture tissue, with a few poorly differentiated adenocarcinoma cells visible (Figure 1B). From April to July 2021, the patient first received 4 cycles of chemotherapy of GP regimen (gemcitabine 1000 mg/m2, day1 and day8; cisplatin 75 mg/m2, day1, every 3 weeks), accompanied with radiotherapy to the 12th thoracic vertebra (Figure 1C). Tumors (version 1.1) (Figure 1C), while serum AFP and CA125 were slightly decreased. Consideration of the limited efficacy of chemotherapy alone, Sintilimab, a PD-1 inhibitor, was added to the treatment regimen in July 2021(200 mg every 3 weeks). The patient received a combination of the PD-1 inhibitor and GP regimen for 7 cycles from July to December 2021 in further. Subsequent treatment response evaluation still showed SD based on CT image; but further confirmation by magnetic resonance imaging revealed an increase in solid lesions in the tumor, suggesting local disease progression, with PFS for first-line treatment of 8 months (Figure 1C). Based on MRI imaging which revealed the massive low-density regions within the tumor area, and only solid cancer foci were identified near the blood vessels at the margin of the tumor (Figure 1C). Apatinib and Sintilimab until January 2023, when imaging evaluation showed an increase in the solid lesion at the tumor edge, indicating disease progression. At that time, the PFS of radiation therapy combined with targeted immunotherapy was 12 months, and the patient's overall survival (OS) reached 25 months from the time of initial diagnosis (Figure 1C).
case_images: Dose distributions and comparison of treatment response before and after radiotherapy. (A) Dose distribution of transverse, coronal and sagittal view. Based on MR images, the radiation treatment plan for the patient's parenchymal tumor lesion was 25 Gy in 5 fractions, presented as yellow line, and the plan for the overall tumor area was 5 Gy in 5 fractions, presented as blue line. (B) Coronary and transverse image changes of the tumor before and after radiotherapy, the best response was PR after radiotherapy.
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case_images: A low-dose radiation of 5Gy/5F was delivered to PTV-tumor, while, a high-dose radiation of 25Gy/5F was administered to the PTV-high area (Figure 2A). In April 2022, imaging evaluation showed a significant reduction in the tumor size, with a stable disease close to partial response (SD-PR) achieved (Figure 2B), with normalized AFP and CA125 levels.
case_images: Changes in immuno-related indicators of patient response during treatment. The treatment plans for patients at different time periods are marked on the horizontal axis. Black arrows indicate the time point to radiotherapy (from January 16, 2022, d1-5). When the anti-PD-1 therapy was combined with chemotherapy, the change of killer T lymphocytes with anti-tumor effect was not obvious as shown in (A) IL-2/TNF-alpha/IL-4 rises rapidly and then decreases significantly as shown in (B-D) Anti-PD-1 therapy after radiotherapy can significantly increase the level of killer T lymphocytes as shown in A, IL-2/TNF-alpha/IL-4 was maintained at high levels for a long time from 2 months after radiotherapy as shown in (B-D).
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case_images: During the course of immunotherapy, we concurrently monitored lymphocytes and inflammatory cytokines (Figure 3). T cells also decreased to a low point. This result suggests that radiation therapy can increase the distribution and ratio of CTL in the blood circulation, and is closely related to the synergistic effect of immunotherapy (Figure 3A). In addition to monitoring the distribution of lymphocytes during treatment, we also monitored the change in inflammatory cytokines levels (Figure 3). After radiation therapy was administered in January 2022, serum levels of IL-2 and IL-4 decreased again and remained low for nearly 10 months (Figures 3B, C). TNF-alpha increased again, peaked three months after radiation therapy, and then decreased to a low point after 8 months of treatment. The overall duration of maintaining a high level was longer than the earlier immunotherapy combined with chemotherapy (Figure 3D). This suggests that radiation therapy combined with immunotherapy is more favorable for the release of the antitumor inflammatory cytokine TNF-alpha.