Immunotherapy has made some progress in the treatment of esophageal cancer. But overall, there is no immunotherapy approach that has been officially approved for esophageal cancer. The only way to try immunotherapy is to participate in a clinical trial. Also, immunotherapy is not a “cure-all,” and it can lead to some serious side effects.
In this article, we take a look at a real-life example of the possible risks of immunotherapy for esophageal cancer.
Mr. Wang, 49 years old, began having difficulty swallowing in January 2017, with progressively worse symptoms.
First visit
Diagnosis:
In February 2017, he visited a local hospital, where gastroscopy revealed: a mass growing on the esophagus 32-37 cm from the incisors, causing a narrowing of the lumen, about 5 cm in length. subsequent pathology and imaging suggested: esophageal squamous cell carcinoma with mediastinal lymph node metastasis.
Surgical resection:
On February 24, Mr. Wang underwent esophagectomy for esophageal cancer. The postoperative pathology biopsy suggested a moderately differentiated squamous carcinoma with tumor invasion of the esophageal epithelium and metastasis to nearby groups of lymph nodes; the surgical specimen had negative margins, indicating a “clean cut”.
Postoperative adjuvant radiotherapy:
Because the postoperative pathology report showed lymph node metastases, Mr. Wang continued to receive adjuvant radiation therapy from March 20 to May 9.
After radiation therapy, he was evaluated by his doctor and received 2 weeks of “docetaxel + cisplatin + capecitabine” chemotherapy on June 14 and July 7, respectively.
Recurrent disease
In September 2017, Mr. Wang came to Peking University Cancer Hospital to have a review of his first visit.
PET-CT examination suggested multiple enlarged lymph nodes in the left mediastinal region, behind the left diaphragm.
Thoracic CT suggests possible recurrence and metastasis in the surgical anastomosis, mediastinum, and other areas.
The doctor said:
Based on the results of the examination, it is initially determined that you have a postoperative recurrence of metastasis. You have recently received radiotherapy at an outside hospital, but the results are clearly poor and are a failure of first-line treatment. There is no standard second-line treatment option for esophageal squamous cancer in China. There are only two options available now: 1. try other chemotherapy regimens; 2. participate in clinical studies of immunotherapy (such as PD-1 monoclonal antibody).
Here, Mr. Wang had some doubts: What is PD-1 monoclonal antibody and is it effective for esophageal cancer? “The company’s main goal is to provide the best possible service to its customers.
In the clinic, many patients have similar confusion. The PD-1 monoclonal antibody is a type of immune checkpoint inhibitor, and its mechanism of action is very different from chemotherapy and targeted therapy. It prevents tumors from “escaping” in the immune chain, which activates the autoimmune system and enhances the ability to kill tumors.
Currently, these drugs are approved abroad for the treatment of malignant melanoma, lymphoma, lung cancer, and so on. The company’s main goal is to provide the best possible support for the development of a new product. The clinical trials are designed to get this data for the drugs to be approved for marketing and to benefit more patients.
For you, if you have the opportunity to participate in a clinical trial, you may want to give it a try. Of course, clinical trials are not for everyone. Doctors will run a series of tests to determine if you are a “potential beneficiary” of an immunotherapy treatment, and you will have to give your informed consent before you can join the trial.
Trying immunotherapy
After careful consideration, Mr. Wang enrolled in a clinical trial for 6 cycles between September 28, 2017, and January 11 2018. During the dosing period, his condition was relatively stable, with no new rash, chest tightness, palpitations, cough, dizziness, headache, abdominal pain, bloating, weakness, or other common adverse effects.
At the end of cycles 3 and 6, he had two efficacy assessments, both of which indicated that “the masses were smaller and stable”.
Adverse events
However, after the sixth cycle of treatment, Mr. Wang’s skin and sclera of his eyes appeared “yellowish”. The results of his blood chemistry indicated that his liver function indicators, such as bilirubin and transaminases, were high. The abdominal enhancement CT showed that the density of the liver was not uniform, suggesting abnormal changes.
According to the “Common Criteria for the Evaluation of Adverse Events (CTCAE 5.0)” published by the U.S. Department of Health and Human Services, Mr. Wang’s transaminases were elevated at level 4, direct bilirubin was elevated at level 3, and indirect bilirubin was elevated at level 2, and the cause of the abnormal liver function needed to be determined as soon as possible.
The doctor immediately gave him symptomatic treatment such as liver protection and anti-yellowness, and also perfected several tests such as viral hepatitis screening and autoimmune liver disease antibodies, all of which came back negative. After comprehensive consideration, the doctor determined that he was experiencing immunotherapy-related liver toxicity.
Stopping immunotherapy
Due to the severity of the adverse effects, the doctors immediately stopped the PD-1 monoclonal antibody and put him on glucocorticoids.
From February 2018 1 onwards, Mr. Wang received methylprednisolone 1 mg/kg intravenous infusion. After 7 days of medication, transaminases and bilirubin basically decreased to normal. Subsequently, he changed to oral methylprednisolone and gradually reduced and stopped the dosage.
Despite the return of normal liver function, he could no longer use immunotherapy. His doctors adjusted him to a third-line chemotherapy regimen to try to control disease progression.
Summary
Common adverse effects of immune checkpoint inhibitors include immune-related skin toxicity, hepatotoxicity, endocrine toxicity, gastrointestinal toxicity, lung injury, and in a few cases, cardiotoxicity may occur.
Hepatotoxicity most often occurs 6 to 12 weeks after treatment and is manifested by elevated transaminase and bilirubin levels, which are usually not apparent in patients themselves. Therefore, liver function needs to be monitored closely during treatment.
If you are participating in a clinical trial of immunotherapy, it is recommended that you follow your doctor’s instructions to review regularly and tell your doctor if you develop yellowing of the skin or eyes to determine if it is a toxic reaction to the liver caused by immunotherapy and to treat it promptly.
The American Society of Clinical Oncology (ASCO)/National Comprehensive Cancer Network (NCCN) guidelines state that a grade 3 to 4 elevation in transaminases and a grade 1 elevation in bilirubin requires permanent discontinuation of immunotherapy; depending on the grade of toxicity, corticosteroids may be added to suppress the immune response; and if efficacy is poor within 3 days, other immunosuppressants (such as morte-macro, for example) should be added. If efficacy is poor within 3 days, other immunosuppressive agents (e.g., morte-macrolide) should be added.
Disclaimer:
Tumor disease and treatment options are extremely complex and treatment should be fully individualized, and this case does not represent a “like patient” treatment decision. Please seek professional advice from a competent physician regarding your specific treatment plan.
Co-written by:
Peking University Cancer Hospital Department of Gastrointestinal Oncology Liu Chang