Joint Winning Professor Zhao Haitao: Lenvatinib + immunotransformation therapy has significant benefits, bringing hope for survival to patients with unresectable liver cancer

*Only for medical professionals to read for reference.
Multidisciplinary overall management is to protect patients with rare irAEs in the combined treatment of liver cancer
.

This article introduces a real case of lenvatinib (Levima) combined with sintilimab as a conversion therapy.
The treatment is only 3 cycles, making patients with unresectable hepatocellular carcinoma resectable.
The important value of tinib-based system therapy in transformational therapy of liver cancer
.

The patient continued to receive adjuvant sintilizumab treatment after surgery, but immune-related fasciitis developed, but with the effective intervention of the multidisciplinary diagnosis and treatment (MDT) team, the patient's symptoms were controlled
.

Follow-up to the present, the patient’s progression-free survival (PFS) is 18 months, radiofrequency treatment after recurrence, and the tumor-free survival has been more than 29 months
.

This case adopts a comprehensive model of targeted + immune + local treatment, which is in line with the current development trend of liver cancer treatment and is consistent with the theory of immunotherapy 3.
0.
The patient finally achieved significant survival benefits
.

Case background Immune checkpoint inhibitors (ICIs) have been applied to many types of cancer treatments due to their significant clinical efficacy and acceptable safety [1]
.

However, the special anti-cancer mechanism of ICIs has caused side effects similar to autoimmune diseases (immune-related adverse events, irAEs) [2]
.

irAEs can involve multiple systems throughout the body, among which rheumatic irAEs have not been widely recognized or well described, especially in patients with liver cancer
.

Sintilimab is a fully human IgG4 monoclonal antibody that binds to the programmed death receptor (PD-1) and has been approved by China for the treatment of relapsed or refractory Hodgkin’s lymphoma [3]
.

In this case, it was used in the treatment of patients with unresectable hepatocellular carcinoma
.

Case review: A 64-year-old male liver cancer patient developed recurrence of the right lobe of the liver and intra-abdominal metastasis in 5 months after surgery.
The patient was subsequently treated with Lenvatinib combined with PD-1 inhibitor (Sintilimab)
.

After the third cycle of Sintilizumab treatment, the patient underwent abdominal mass resection.
Postoperative pathology revealed metastatic hepatocellular carcinoma with necrosis
.

Immunohistochemistry Ki-67 (index 60%)
.

Subsequently, the patient continued to receive targeted combined immunotherapy
.

After the fifth cycle of Sintilizumab treatment, the patient developed low back pain, focusing on the left side of the waist.
The pain was severe, and it was obvious when changing positions, exerting force, and stretching.
The local soft tissues were swollen and tender on physical examination
.

MRI showed flaky hyperintensity on the left psoas muscle
.

PET-CT indicated that the radioactivity uptake of the left waist muscle was increased, SUVmax4.
0
.

The clinical diagnosis was considered as possible myositis, and oral prednisone 50mg*3 days+25mg*10 days was given, and the symptoms of low back pain were relieved
.

After continuing to use Sintilizumab to the 8th cycle, the patient's low back pain recurred, mainly pain, no obvious muscle weakness, preferred fixed flexion position, restricted position change, position change and severe pain during exercise
.

On physical examination, the left side of the lumbar spine was swollen, local tenderness was obvious, and there was no obvious skin change
.

In laboratory tests, creatine kinase (CK) 75IU/L and creatine kinase MB (CKMB) 2.
6IU/L were in the normal range
.

High-sensitivity C-reactive protein (CRP) was 48.
15 mg/L, interleukin-6 (IL-6) was 22.
6 pg/mL, both of which were elevated
.

Alpha-fetoprotein (AFP) 4.
1ng/ml, sugar chain antigen 19-9 (CA19-9) 52.
9U/ml
.

Both antinuclear antibodies and myositis antibodies were negative
.

MRI showed that the flaky hyperintensity of the left waist muscle was higher than before
.

PET-CT indicated that the radioactivity uptake of the left waist muscle was increased, SUVmax 6.
9
.

Combined with the above examination results, the diagnosis is considered as musculoskeletal-related irAEs
.

Further puncture biopsy of the lumbar muscles revealed fibers and striated muscle tissue, but did not indicate tumor metastasis or muscle inflammatory infiltration
.

According to the patient’s clinical manifestations, imaging findings, and negative results of muscle pathology, considering that the cause of the back pain is immune fasciitis, the patient was given a 50mg prednisone shock, and the dose was gradually reduced.
The total course of treatment is 50mg*7 days+45mg* 7 days+40mg*7 days+37.
5mg*7 days
.

At the same time, 240mg of Yamei Luo (a recombinant humanized anti-human IL-6 receptor monoclonal antibody) is used in combination
.

Later, the patient's back pain relieved
.

Re-examination of MRI left waist muscle flaky high signal is unclear than before
.

The patient subsequently resumed the 9th cycle of sintilizumab treatment, and no signs of recurrence or metastasis were found after re-examination
.

In addition, after 8 cycles of treatment, the patient developed thyroiditis and hypothyroidism, and was subsequently treated with thyroxine
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Follow-up to the present, the patient has PFS for 18 months, radiofrequency treatment after recurrence, and the tumor-free survival has been more than 29 months so far
.

Figure 1.
MRI (A) and PET-CT (B) when back pain occurs for the first time; MRI (C) and PET-CT (D) when back pain recurs; MRI (E) after back pain disappears
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Summary of treatment experience and reflections This study reports a case of recurrent liver cancer patients with new autoimmune fasciitis with myositis syndrome during the treatment of Sintilimab, and the effect is significant after receiving hormone treatment
.

Rheumatic irAEs have a wide spectrum of diseases, the most common manifestations are inflammatory arthritis, polymyositis and polymyalgia rheumatica (PMR), and fasciitis is rare [4]
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Among them, ICIs-induced myositis is characterized by proximal limb weakness, with or without myalgia
.

Plasma CK levels tend to increase before clinical manifestations appear
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Most patients with myositis are negative for autoantibodies, and a small number of patients are positive for one or more of anti-striated muscle antibodies and anti-nuclear antibodies [5]
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ICIs-induced PMR is characterized by pain, stiffness, and limited mobility in extremities and proximal trunk, without myositis
.

It can be seen that the myositis and PMR induced by ICIs are significantly different from the performance of this case
.

At present, there are only a few literature reports on ICIs-induced fasciitis, most of which are fasciitis of the lower extremities, accompanied by obvious edema, pain and local skin changes [6,7]
.

The imaging manifestations are mainly MRI suggesting diffuse edema of limb muscles and fascia
.

In this case, severe lumbar muscle pain was the main clinical manifestation.
The pain was aggravated during exercise, lack of muscle weakness, no peripheral joint involvement, repeated measurement of CK, no abnormality, full-thickness biopsy ruled out tumor metastasis and myositis
.

The abnormal MRI findings mainly focused on the parapsoas muscle and fascia of the lumbar spine, which further ruled out the possibility of PMR and finally confirmed the diagnosis of central fasciitis induced by ICIs
.

Although there is still a lack of FDG-PET/CT for the diagnosis of rheumatic irAEs system research [8]
.

In this case, we observed that when the patient developed ICIs-related fasciitis, PET/CT showed increased radioactivity uptake in the left waist muscle, which means that PET/CT has an important prompting role in the diagnosis of rheumatic irAE
.

Expert comment on expert profile Professor Wang Hanping, Peking Union Medical College Hospital Respiratory and Critical Care Medicine Doctor, associate chief physician, graduated from Chinese Peking Union Medical University, majoring in clinical medicine, eight-year program, Chinese Anti-Cancer Association Tumor Microcirculation Committee Member, China Lung Cancer Prevention Alliance, Lung Cancer Immunotherapy Committee member, Chinese Medical Education Association, Committee Member of Cancer Chemotherapy Committee, Beijing Cancer Prevention and Treatment Society Inhibition, activating anti-tumor T cell immunity, and killing tumors through the activated immune system, is the third systemic anti-tumor treatment method in addition to chemotherapy and targeted therapy.
In recent years, it has been extremely popular in various tumor types.
Big development
.

However, the activated immune system will inevitably damage the body's target organs and produce a series of irAEs
.

The potential toxicity spectrum of this type of irAEs is very broad.
In theory, various organs in the body may be affected by the immune system and produce adverse reactions.
With the widespread use of immunotherapy, more and more potential rare adverse reactions have been observed.
To
.

Rheumatic immune reactions involving joints and muscles are relatively rare.
Among them, myositis caused by muscle involvement, arthritis caused by joint involvement, and polymyalgia rheumatica are the relatively common rheumatic irAEs
.

Among them, ICIs-related myositis is clinically manifested as muscle weakness and muscle soreness, such as involving the neck muscles, respiratory muscles and other axial muscles.
It is often myositis gravis, and clinically mainly manifested as dysphagia caused by muscle weakness.
, Difficulty breathing or even type II respiratory failure and difficulty in erecting the neck
.

In laboratory tests, almost all patients will have an increase in creatine kinase
.

This patient is mainly muscle pain and weakness, and it is easy to draw conclusions about muscle involvement from the location.
However, the clinical manifestations are very special, including abnormally severe pain, limited postural changes, and slow relief after hormone therapy, but creatine kinase However, there was no significant increase, muscle biopsy was also negative, and the diagnosis of conventional myositis was questioned.
Clinically, the true irAEs in patients can be diagnosed as immune-related fasciitis, which is a very rare rheumatic irAEs
.

In addition, the patient's PET-CT and MRI also have very special manifestations, which play an important role in diagnosis
.

The patient’s PET-CT showed obvious diffuse hypermetabolism of the psoas major muscle.
On the one hand, tumor metastasis needs to be excluded, on the other hand, it also prompts very active local inflammation.
Combined with negative biopsy and low CK, it plays an important role in the diagnosis of fasciitis The prompting role of MRI; muscle swelling and fascial edema presented by MRI also have very important prompting significance, so both PET-CT and MRI can play an important role in the diagnosis of these inflammatory diseases
.

At the same time, the patient’s hormone therapy has a very characteristic effect.
Unlike general myositis, the pain will be quickly relieved after hormone therapy.
The pain of fasciitis can continue for a long time after hormone therapy, and the relief is relatively slow.
Therefore, for In patients with fasciitis, in addition to hormone therapy, analgesia can be strengthened to relieve symptoms
.

At the same time, this is also a case in which ICIs treatment was successfully restarted after the fasciitis was relieved.
The patient finally achieved a complete remission, and there was no recurrence of fasciitis
.

This example suggests that when the patient’s irAEs are manifested as fasciitis, although the painful symptoms are prominent, they will not involve important organs and cause a life-threatening situation.
Therefore, after the successful outcome of irAEs, ICIs treatment can be restarted as much as possible.
Maximize patient efficacy
.

The emergence of irAEs may itself suggest a better therapeutic effect of immunotherapy
.

Expert Profile Professor Zhao Haitao, Department of Liver Surgery, Peking Union Medical College Hospital, Chief Physician, Doctoral Supervisor, Chinese Society of Clinical Oncology (CSCO), Standing Committee Member of the Liver Cancer Expert Committee, Secretary-General and Deputy Chairman of the Chinese Society of Microcirculatory Hepatology Committee, Director, Peking University Alumni Association, Peking University Alumni Association Physician Deputy Secretary-General of the Association, Chairman of the Youth Committee of the European and American Alumni Association of Physicians, Secretary-General of the Hepatobiliary Branch of the European and American Alumni Association of Physicians, and Deputy Chairman of the Ministry of Science and Technology Major Project Review Expert HBSN (SCI included IF: 7.
293) ) Associate editor of the magazine WJG (SCI included IF: 5.
742), editor of the magazine China Social Welfare Foundation-Tumor Precision Immunotherapy Public Welfare Fund Founder, National Ten Thousand Talents Program Expert (Leading Talent) published 122 SCI academic papers as the corresponding author, total impact The factor is 978.
805 points, the total number of citations exceeds 5300, and the H-index is 35
.

The immunotherapy 3.
0 (stereotactic therapy) we proposed is expected to enable inoperable hepatocellular carcinoma patients to achieve down-stage and further obtain the opportunity for transformational resection [11]
.

For patients with extrahepatic metastases, short-term immunotherapy combined with targeted and local therapy is currently in the trial stage.
According to our experience, immunotherapy for a period of time after surgery can help prevent recurrence
.

This patient has developed irAEs that are very difficult to judge.
If they cannot be clarified and dealt with, the patient’s symptoms will continue to aggravate, which may lead to the discontinuation of immunotherapy
.

Following the principle of maximizing the benefit of patients, we hope not only to treat patients' current symptoms, but also to continue immunotherapy
.

The patient in this case received strong support from the Concord irAEs MDT team throughout the entire process after the symptoms appeared after the operation.
The irAEs were evaluated as an extremely rare central fasciitis and received effective treatment interventions.
, The patient's symptoms were relieved, and later resumed ICIs medication, no similar symptoms reappeared, so that the patient can obtain a relatively long-term tumor-free survival after the operation
.

irAEs can appear in any part in any form, and it is very difficult to judge.
This puts higher requirements on our clinical treatment team.
We must have full patience, immediate communication, and full monitoring for each patient.
And the support of the whole discipline
.

In addition to continuous learning, the clinical treatment team also needs to spend a lot of time to interact with patients in real time, in order to find and solve problems in the first time, so as to achieve the individualized optimal treatment effect and transform more patients with advanced liver cancer into The tumor survives and works towards the cure
.

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