Infect? Super progressive? Elderly lung cancer patients have high fever after immunotherapy, and the "culprit" is ...

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How to distinguish between high fever and imaging lesions after immunotherapy in elderly patients with multiple tumors? How is it diagnosed? What to do? Jinling Lung Cancer MDT Forum answers your questions
.

What are the special manifestations of lung cancer immunotherapy in the elderly? What are the additional risks of immunotherapy in elderly lung cancer patients? What causes fever after immunotherapy? How to deal with adverse reactions to immunotherapy?
On August 31st, the Jinling Lung Cancer Network Forum, which was attended by the MDT team of Professor Song Yong of Jinling Hospital affiliated to Nanjing University School of Medicine, the MDT team of Professor Zhang Dong of the Second Medical Center of the General Hospital of the People's Liberation Army of Chinese, the MDT team of Professor Zhao Yanqiu of Henan Provincial Cancer Hospital, and the MDT team of Professor Feng Jian of the Affiliated Hospital of Nantong University, had a wonderful discussion
on these issues.

Professor Wang Peng of the Second Medical Center of the General Hospital of the People's Liberation Army of Chinese shared the treatment of
an 83-year-old lung cancer patient.

Case situation

In April 2020, CT of the patient's lungs in the outer hospital found a nodular shadow
in the lower lobe of the right lung.
In June 2020, PET-CT of the outer hospital found abnormally high metabolic foci (2.
3*0.
9cm, SUV=5.
08) in the basal segment of the right lower lobe of the right lower lung, and abnormally high metabolic nodules at the top of the liver (1.
6*1.
4cm, SUV=7.
45).

The patient refuses pathological aspiration biopsy
.

Clinical diagnosis: lung cancer and liver metastasis?
Liver lesions have regressed, and lung nodule lesions have progressed?

June-July 2020

Gamma knife for lung nodule lesions at a dose of 30Gy/15F
.

2021-3-25

Thoracic CT: Lesions in the lower lobe of the right lung are significantly progressive
.

April 2021

Local hospital PET-CT: abnormally high metabolic lesions in the basal segment of the lower lobe of the right lung (size 3.
7*1.
5cm, SUV=9.
96, considering lung cancer, increased compared with 2020-6-18 examination
).
Abnormally high metabolic foci (size 3.
6*2.
2cm, SUV=18.
4) of the right lobe of the liver consider hepatic metastasis, which is new compared with the previous examination
.
The abnormally high metabolic nodules at the top of the liver disappear
from the previous examination.

2021-4-26

For the first time, he came to the Second Medical Center of the PLA General Hospital for treatment
.

2021-5-17

Perfect liver puncture biopsy, pathological results showed non-Hodgkin lymphoma, DLBCL non-GCB type IV phase B IPI 4 score
.

2021-5-27 to 11-10

With 6 courses of R-miniCHOP chemotherapy in the Department of Hematology, the liver lesions achieved complete remission, but the lung lesions continued to
increase.
2021-7-15Lung CT: solid patch shadow in the basal segment of the right lower lung, excluding malignant tumors, slightly enlarged
compared with 2021-4-26.

Progression of lung lesions

2021-8-19

PET-CT: 1.
Irregular soft tissue density shadow next to the lower lobe of the right lung with high metabolism, it is necessary to be alert to lymphoma invasion or the possibility of primary lung cancer; 2.
Increased metabolism of bis-atlanthalias, considering reactive changes
.
The nature of the paraspinal nodule in the basal segment of the right lower lung is unknown, the tumor is enlarged, and the tumor marker CA724 is gradually elevated, considering that a second tumor is more likely, and the patient agrees to puncture biopsy
.

2021-11-8

Pathology of lung puncture biopsy: pulmonary invasive mucous adenocarcinoma (intestinal type); Immunohistochemistry: TIF-1 (fos+), NapsinA (fos+), Alk-, CDX2+, Villil+, PD-L1 (TPS<1%)<b10>.
Molecular pathology test results show CD74-NRG1 fusion mutation
.
Non-Hodgkin lymph node chemotherapy was temporarily discharged and readmitted in January 2022
.

2022-1-11

PET-CT: compared with 2021-8-17 examination: 1.
Paraspinal lesions in the lower lobe of the right lung are enlarged compared with the anterior and metabolic are increased than before, considering the progression of lung lesions (72mm in length diameter, SUVmax 12.
8 vs 8.
0); 2.
The metabolism of the hilar lymph nodes of the double lung is higher than before, and the possibility of reactive changes is considered; Thickening of the right pleura; 3.
The two slightly low-density areas of the right lobe of the liver are similar to the previous ones, and no abnormally high metabolic signs are seen in the liver
.

Results of the in-hospital MDT discussion: Radiotherapy:
Considering that he has a previous history of radiotherapy to the lungs, the dose of radiation therapy is large, so it is not recommended that patients continue radiotherapy
.

Interventional radiology: considering that the patient's current lung tumor lesion is large, and involves the surrounding trachea and blood vessels, the scope is large, considering that the pleura may also have invasion, so it is not recommended that the patient undergo local treatment
such as particle implantation and thermal ablation.

Thoracic surgery: considering that the patient's tumor lesion is attached to the pulmonary vein and trachea, the risk is greater, and surgery is not recommended
.

Fever after immunotherapy, is it an infection? Or super progressive?

2022-1-21

Perform the first cycle of pabolizumab therapy
.

2022-2-5

(C1D15): fever begins, body temperature > 38 °C (38-39 °C), mild chills, chills, no cough, sputum production, no abdominal pain, no frequent urination, painful urination and other symptoms
.
Complete blood routine: CRP 11mg/dl, leukocytes 5.
9*10^9/L, neutrophils 0.
783, endotoxin assay (-), PCT normal
.
Blood cultures are negative
.
Lung CT: solid clump shadow of the basal segment of the lower right lung, compared with 2021-11-18 and 2022-1-15, gradually enlarged, no focus
on infection was seen.

2022-2-10

Blood count: CRP 10.
09mg/dl, leukocyte 4.
21*10^9/L, neutrophil 0.
587, negative blood culture
.

2022-2-11

Hepatobiliary, pancreatic and spleen ultrasound: hepatic right lobe hepatic hepatic lobe heterogeneous hypoechoic nodules, slightly reduced from the previous examination (2022-1-7), multiple small cysts of the
liver.
G test, GM test (-), rheumatoid factor (-), immunoglobulin set (-).


Anti-infective therapy: meropenem→ suprus, vancomycin, capofen
does not exclude infusion port catheter-related infection, anti-infection at the same time, 2-13 removal of the infusion port, body temperature did not improve
.
Catheter microbial culture (-).


Heat pattern map during anti-infection

2022-2-17

Human immunoglobulin 5-10 g qd*7d, transfusion of plasma
.

2022-2-18

Consult a respiratory specialist and recommend that all antibiotics
be discontinued.

Thermopattern before and after antibiotics are discontinued

Cover art

2022-2-25: Lung CT: solid clump shadow of the basal segment of the right lower lung is gradually enlarged compared with 2021-11-18, 2022-12-5, 2022-2-15, which is consistent with the consideration of malignancy, and the nodular shadow of the outer basal segment of the right lung is slightly larger than that of 2022-2-5, except for metastasis
.

Consider the diagnosis:
hyperprogression? Pseudo-progression?
Super progressive? Pseudo-progression? The main points of clinical differentiation and treatment are.
.
.
▌ Evidence of increasing hyper-progression
surfaces that 4% to 29% of all cancer patients with various histologies may suffer tumor outbreaks
after immunotherapy.
This new pattern of tumor response, known as hyperprogression, is a potentially harmful side effect of immunotherapy, accelerating disease progression
in a subset of patients.

There is currently no clear definition of tumor hyper-progression to show intention
, and it is more recognized that the following definition proposed by Kato et al.
in the 2021 CCR, after immunotherapy, tumor progression meets the following three conditions:
1.
In immunotherapy, the tumor progression time is less than two months;
2.
The tumor burden increases by more than 50% compared with the baseline;
3.
After immunotherapy, the tumor growth rate exceeds the previous rate by more than
2 times.

Hyperprogression factors include the following two aspects: 1.
Clinical factors:
age≥ 65 years old; Female; Higher LDH concentrations; Transfer of loads; Local recurrence
of cells in the radiotherapy area.

2.
Biological factors: upregulation of PD-1 + Tregs; T cell depletion; MDM2/4 amplification and EGFR mutation; The role of Fc receptors; Imbalance of immunosuppressive cytokines; Type 3 inherent lymphocytosis; The role of neoantigens; .
.
.
.
.
.

▌ Pseudo-progressive pseudo-progression (PP): refers to the initial increase in tumor size or new lesions after starting immunotherapy for a period of time, but this is not caused by the continued proliferation of tumors, the pseudo-progression
rate of patients receiving ICIs treatment does not exceed 10%, common in non-small cell lung cancer and melanoma, the incidence in NSCLC is about 1.
8%-6.
9%, and the incidence in melanoma is about 4.
6%-8.
3%
。
Pseudo-progression of tumors shows the intention of pseudo-progression due to more immune cells infiltrating into the stroma around tumor cells, causing the tumor to appear larger, and after a period of immunotherapy, the
"tumor" gradually shrinks
.

▌ Definitive diagnosis
of 2022-2-28: Secondary lung biopsy pathology: (right lower lung) differentiation of adenocarcinoma, and see necrosis, partial tumor cell degeneration, immunohistochemistry: ALK(-), TIF-1 (fos+), CK(+), P40(-), CK(-), CK7(+), NapsinA (fos+), P63(-).


The second pulmonary puncture versus previous puncture:
1.
Necrosis occurs in 50% of the area of the tumor bed, consistent with post-treatment changes;
2.
Lymphocytes and neutrophils infiltrate the tumor bed, fibrous tissue hyperplasia, and see exudation;
3.
Before treatment, lymphocytes are mostly around the tumor tissue, and the white blood cell infiltration inside the tumor bed is obvious
.

Diagnosis of pathological results of secondary lung biopsy: follow-up management of
pseudo-progression

2022-3-15

First cycle albumin-binding paclitaxel 100 mg;

2022-2-5

Second cycle albumin-binding paclitaxel 100 mg + anti-PD-1 therapy;
Adverse events (AE): degree III leukocyte suppression
.

2022-5-17

Fourth cycle anti-PD-1 therapy + second cycle alobinib

2022-6-8

Fifth cycle anti-PD-1 therapy + third cycle agonotinib

2022-6-8

CT of the lungs: lesions in the lower lobe of the right lung are anterior narrowed
.

The treatment effect can be achieved, and the patient is discharged from the hospital and returned to the local area to improve further treatment
.

After the discussion of the case sharing, Professor Wang Peng raised the following two questions:

1.
After the patient applied 1 anti-PD-1 treatment, there was a discontinual high fever, the site of infection was not identified, and the antibiotic treatment effect was not good, and the cause of fever was not good.

2.
Clinical experience sharing
on hyper-progression or pseudo-progression.

Professor Wang Zhanbo, Department of Pathology, Second Medical Center, General Hospital of the People's Liberation Army of Chinese: Comparing the pathological results of the two biopsies, it can be found that in terms of morphology, tumor type and immunohistochemistry, the two have great similarities, the difference is that in the second disease examination results, fibrous tissue proliferation is more obvious, there are large tumor tissue necrosis and metamorphosis, and lymphocyte infiltration is significant
.
Therefore, from a clinical point of view, it can be judged that false progression is more
likely.
Residual tumor cell changes, tumor stromal fibrosis and lymphocyte infiltration in the cancer bed all reflect the therapeutic effect
of immunotherapy.

As immunotherapy has become a hot spot in cancer treatment in recent years, false progression has received more and more attention, and it can also be seen in other cancer types receiving immunotherapy, such as melanoma, non-small cell lung cancer, kidney cell carcinoma, etc
.

In this case, it is worth noting that the patient's pathological type is enterotypic adenocarcinoma with mucus vacus type, while in gastrointestinal type mucoadenocarcinoma, after immunotherapy, it is not uncommon
for cases of pseudo-progression to occur.
Therefore, in the future, the next step can be to conduct in-depth analysis of some special subtypes of non-small cell lung cancer, and it may be that in some cancer types with mucus secretion function, neoadjuvant immunotherapy is more likely to produce imaging changes
of false progression after neoadjuvant immunotherapy.

Professor Huang Haili, Department of Respiratory and Critical Care Medicine, Second Medical Center, General Hospital of the People's Liberation Army of Chinese: First of all, there are some characteristics of the patient's pathology, the patient's lung tissue biopsy results are gastrointestinal differentiated mucous lung cancer, immunohistochemical CDX2+, Villil+, PD-1(+), NapsinA (foci+), TIF-1 (fos+), the histopathology is pointed to lung cancer, if NapsinA, TIF-1 are negative, Differentiation
between primary lung cancer and gastrointestinal tumor lung metastasis is required.
The pathological type of gastrointestinal differentiated mucous lung cancer was first reported in 1991, referred to as PEAC (pulmonary enteric adenocarcinoma), a rare subtype
of lung adenocarcinoma.

Second, the patient-driven gene showed a fusion mutation in CD74-NRG1, a neuroregulatory protein that is a member of the epidermal growth factor ligand family, with the most common fusion molecule being CD74
.
The mutation is also a rare mutation, with a reported incidence rate of about 0.
36%
in China.
This mutation has some suggestive implications for the choice of lung cancer treatment regimen, such as avatinib
.

Third, the patient is an 84-year-old patient with many underlying diseases, including lymphoma and hypertension
.
Therefore, after the patient's immunotherapy, high fever was immediately given, and strong anti-infective therapy was given immediately, and microbial metagenomics was added, but no obvious effect or meaningful results
were seen.
CT shows enlarged lesions of the lung with tracheal compression, and two main possibilities are considered: rapid tumor progression/pseudo-progression, or tumor progression with obstructive pulmonary infection
.
In addition, differential diagnosis of the etiology of fever has been carried out, including the absorption of necrotic lesions after immunotherapy, lymphoma, rheumatic diseases, etc
.
However, due to the poor cooling effect of anti-infective therapy, the cooling effect of immunoglobulins and NSAIDs drugs is obvious, so at this time, more consideration is given to immune or non-infectious inflammation-related fever, and the symptomatic treatment effect is obvious
.
Therefore, summarizing the patient's diagnosis and treatment ideas, when the lesion of lung cancer increases, the identification of progression or pseudo-progression needs to be considered the most
.
Pathological diagnosis, as the gold criterion for judging pseudo-progression or hyper-progression, fully supports the judgment
of "pseudo-progression" in this case.

In the standard guidelines for clinical trial response to iRECIST solid tumor immunotherapy, it is noted that confirmation of imaging tests for subsequent 4-8 weeks is required whether pseudo-progression is suspected or rapid
progression.

Although the tumor size of this case did not shrink from baseline on imaging in June 2022, there was a trend of lesion shrinkage, and the patient was generally in good condition and the lesion remained stable for a long time, so this can still indicate that immunotherapy is effective
.

In addition, it is also worth noting that some patients receiving immunotherapy have "new lesions" of patients, such as patients with sporadic lesions in both lungs after receiving immunotherapy, but the boundaries are blurred, and follow-up observations confirm that these lesions are not new lesions, but inflammatory reactions
after immunotherapy.
This situation should be identified carefully
.

There are also studies suggesting that in patients with progression who cannot make a biopsy pathological diagnosis, hyperprogression or pseudo-progression can also be used to help analyze
the patient's general condition, tumor markers, IL-8 (elevated to indicate progression, decreased to indicate good efficacy), ctDNA (elevated to indicate progression).

Professor Guo Xueguang, Department of Respiratory and Critical Care Medicine, Second Medical Center of the General Hospital of the People's Liberation Army of Chinese, shared a case of advanced pleural fibromatosis in response to tumor hyperprogression: the patient was admitted to the hospital with immunohistochemistry showing NDM2(+), so he temporarily did not consider double exemption treatment, recommended to improve NGS examination, and then gave chemotherapy
.

Professor Guo pointed out that the case suggests that in the actual clinical diagnosis and treatment process, when considering super-progression, close attention should be paid to the collection of information, including the patient's clinical data, the expression of hyper-progression-related genes, and immunohistochemistry, so as to avoid the rapid progression of tumors affecting the survival of patients and bringing losses to patients
.
Therefore, it is important
to screen out those who do not benefit from immunotherapy before choosing a treatment regimen.
However, immunotherapy is relatively slow to respond, and in this process, how to determine whether patients can benefit during the long period of clinical ineffectiveness is a huge challenge for clinicians
.

In addition, the recommendations given by Professor Guo are not supported
on whether patients who do not benefit from screened immunotherapy can be added to immunotherapy after local radiotherapy, or whether patients with hyperprogression after the application of a PD-(L)1 inhibitor can switch to another immunotherapy.

For pseudo-progression, clinical judgment can be given 1-2 months of observation, if the tumor shrinkage occurs after a period of observation, or directly through pathological confirmation, it is not difficult to
confirm pseudo-progression 。 There is also a noteworthy situation that some patients have the same mechanism as pseudo-progression, that is, lymphocyte mobilization and infiltration of immune cells around cancer tissue, but the clinical outcomes are completely opposite, and the general condition of patients cannot support patients to safely pass through the pseudo-progressive stage of the tumor, such as cancer lymphangitis has cancer cell invasion, followed by further invasion of lymphocytes, aggravating obstruction, resulting in poor patient outcomes, and these conditions also require
。
Professor Zhang Dong, Department of Respiratory and Critical Care Medicine, Second Medical Center of the General Hospital of the People's Liberation Army of Chinese, summarized: For elderly patients, first of all, to identify progression or false progression, pathological biopsy as the gold standard, the status is unshakable
.
Second, the incidence of multiple tumors in elderly patients has increased significantly, so at the time of initial diagnosis, it is necessary to determine whether the lesion is metastatic or initial, which has a huge
impact on subsequent treatment choices and treatment effects.
Third, there are many adverse reactions in immunotherapy, and false progression is one of them, and the outcome is better, but the impact of other adverse reactions on elderly patients may be huge, and vigilance should be improved
.

In addition, immunoglobulins for immunotherapy-related fever are a class of drugs
that have a more reliable effect in addition to hormones.

In addition, the secondary pathological results of this case are not very consistent with the pathological characteristics of pseudo-progression that are generally believed, which is reflected in the low infiltration of lymphocytes, mainly manifested as fibrohyperplasia
.
Therefore, there may be different pathological features in different patients with pseudo-progression, and special attention
should be paid to subsequent case collection.

Finally, he pointed out that the "re-challenge of immunotherapy adverse reactions" exists on the premise that immunotherapy is effective, otherwise immunotherapy
should not be further attempted.

Professor Zhao Yanqiu of Henan Provincial Cancer Hospital evaluated this case on behalf of her team: the patient is an elderly multi-primary carcinoma, and the general condition is slightly worse after receiving lymphoma chemotherapy, so there is a greater
possibility of adverse reactions when receiving lung cancer immunotherapy.
For the patient's further diagnosis and treatment plan, due to the patient's advanced age, the degree of tolerance to chemotherapy may be limited, and the immunotherapy in one cycle has changed significantlyIn good cases, whether re-immunotherapy can be chosen in combination with a re-pulmonary biopsy or PTE-CT is an option
worth considering.

For the pseudo-progression of lung cancer, Professor Zhao also shared a case of small cell lung cancer patients who received immunotherapy drugs clinical trials managed by his team, and there was a lesion progression after receiving immunotherapy drugs for 1 year, which was generally good, so after full communication, he chose to continue to use drugs, and after 2-3 cycles, the target lesions of patients shrank
.
Although no focal biopsy was performed, improvement in symptoms and imaging confirmed that this was a pseudo-progression
.

Professor Zhao Hongyu of the Department of Tumor Chemotherapy of Professor Feng Jian MDT Team of Nantong University Hospital commented that first of all, if PET-CT suggests lung cancer and liver cancer, more consideration is given to diagnosing lung cancer liver metastases, and if lung puncture is confirmed as cancer, then liver puncture treatment
will generally not be considered.
However, if the liver does not change or gradually enlarge during the diagnosis and treatment, the liver biopsy
needs to be further improved.
At the time of biopsy, attention should be paid to the primordial or polygenic nature
of the tumor origin.
Second, in addition to pathology as the gold standard for diagnosing false progression, if it cannot be completed, the improvement of clinical symptoms, PET-CT shows that the lesion is enlarged but the SUV value is reduced have certain suggestive significance
for the diagnosis of pseudo-progression.
Third, from the patient's B ultrasound examination results, there are still some lesions remaining on the liver, and further treatment of lymphoma is also worth exploring
.

Professor Feng Jian pointed out that first of all, after the pseudo-progression of immunotherapy, whether continuing immunotherapy belongs to the treatment of side reactions after symptomatic treatment "re-challenge" or whether to take pseudo-progression as the embodiment of the treatment effect and the next few cycles as the follow-up continuation of treatment, how to clearly grasp this concept, still needs follow-up discussion
.
Secondly, regarding the fever of patients after receiving single immunotherapy, the absorption heat caused by tumor necrosis still exists, and it is recommended to improve bronchoscopy to further clarify it
.

Subsequently, Professor Zhang Dong analyzed and answered the above questions
.
First of all, for the diagnosis of pseudo-progression, the elderly patient is generally in a poor condition after persistent fever, and it is difficult to directly determine whether it is tumor progression or pseudo-progression
from clinical symptoms.
From the perspective of PET-CT, it is also difficult to distinguish between tumor and verified imaging findings, so pathology is still the most important means of
judgment.

Second, regarding the cause of the patient's fever, in the process of fever, the patient has the performance of mild inflammation, including chills, chills and other manifestations, and after a slight decrease in body temperature, there is a high fever, so the presence of
infection cannot be completely excluded.
Therefore, for fever after immunotherapy, in addition to considering adverse reactions, we must not forget to consider the possibility
of infection and other diseases.

The MDT team of Professor Song Yong of Jinling Hospital Affiliated to Nanjing University School of Medicine spoke highly
of Professor Zhang Dong's MDT team's report.

Professor Shen Qin of the Department of Pathology proposed that first of all, intestinal lung adenocarcinoma has strict diagnostic criteria, many types of tumor cells will appear abnormal phenotypes such as intestinal type in the process of degeneration, so it is difficult to judge the tumor tissue as a gastrointestinal source with great certainty only through the marker, so it is necessary to combine clinical evidence to consider the primary source of
lung cancer after excluding the gastrointestinal mass area.
Second, the tumor necrosis observed in the secondary biopsy, in addition to false progression, in the process of tumor development and development, it can also occur some inflammatory necrosis, which also needs to be judged
in combination with clinical information.
Third, in addition to morphology, we can also pay attention to the before and after comparison of lymphocyte CD4 and CD8 expression, and the re-detection of PD-(1)L will have some guiding significance
for follow-up treatment.

Professor Yin Jie raised some doubts about the choice of treatment plan for this case: for elderly patients, the adverse effects of pemetrexed will be much smaller than white blood cells binding to paclitaxel, why not choose pemetrexed in second-line treatment?
Professor Zhang Dong responded: First of all, the patient's poor tolerance to chemotherapy is a feature
of elderly patients.
Second, white-purple is relatively more convenient and safer
to use than pemetrexed.

Professor Zhu Xixu of the Department of Radiotherapy pointed out that the patient had a history of low-dose radiotherapy in the outer hospital, and for fever after immunotherapy, it can also be considered that low-dose radiotherapy can trigger immune memory, and immunotherapy triggers an immune response, which may be a potential mechanism
of pseudo-progression.

Professor Song Yong commented that first of all, for the cause of the patient's fever, from the etiological point of view, it is defined as the lack of evidence of infection; From a therapeutic point of view, anti-infective combined immunoglobulin therapy overlaps with a decrease in body temperature, so there is also a lack of evidence for the complete exclusion of infection; From the perspective of clinical treatment, it is more inclined to non-infectious fever
.

In addition, for the tumor enlargement after immunotherapy, for this patient, the clinical manifestations are difficult to judge, and imaging including molecular imaging auxiliary diagnosis is also very difficult, which can be considered from three aspects: First, the baseline tumor markers and the level of inflammatory indicators before treatment are in what kind of changes occur after comparative treatment; Second, changes in ctDNA are important clinical indicators; Third, some new technologies can help diagnose false progression, such as immune polystaining, such as CD8+ T cells, which are most likely to be false progression; If Treg is dominant, hyperprogression
should be suspected.
For patients who cannot undergo a secondary biopsy, labeling technology can help provide diagnostic aids, the principle is to label CD8+ T cells with fluorescence, by scanning the fluorescence intensity in the tumor bed, if the fluorescence intensity in the tumor bed is significantly increased after treatment, it is likely to be false progression
.

Finally, for CD74-NRG1 fusion mutation, avatinib can indeed achieve good results, but follow-up observation and research
are still needed.