Multiple metastases of advanced lung cancer, life is hanging by a thread; the combination of immunization and immunization, combined with two swords, will come to life from desperation

It is only for medical professionals to read and refer to the "Eastern Respiratory Alliance", and take you to explore wonderful cases~ 1.
The characteristics of the case Elderly men with previous history of hypertension, type 2 diabetes, diabetic nephropathy, CKD stage 3, gout, diagnosed as advanced Lung adenocarcinoma has multiple metastases (pleura, brain, bone), the driver gene is wild-type, and the expression of PD-L1 in tumor tissue is >50%.

After whole-brain radiotherapy, pembrolizumab single-agent treatment has obvious benefits, and there are no immune-related adverse reactions.

2.
Brief introduction of the case The patient, a 72-year-old male, was admitted to the hospital for "sudden weakness of the right limb for 10 days".

Ten days before admission, the patient had no obvious cause for weakness of the right limb.
He went to the external hospital on October 26, 2020.
Head CT showed that "bilateral fronto-parietal occipital lobes, brain stem occupying space, bilateral fronto-parietal lobe, lateral ventricle Possible para-ischemic focus, local calcification near the sickle, mild brain atrophy”, chest CT showed “the posterior basal segment nodule of the right lower lobe, which is larger than the previous film on July 25, 2019, and may be more malignant.

” The outside hospital gave it to you.
After valproate prevention of epilepsy, mannitol dehydration and lowering intracranial pressure and other symptomatic treatments, the patient was admitted to the neurology department of our hospital the next day.

After being admitted to the hospital, it was learned by inquiring about the medical history that the patient had a history of hypertension, type 2 diabetes, diabetic nephropathy, CKD stage 3, and gout.

Examination of the cardiopulmonary body was not special, the left limb muscle strength was grade V, the right upper limb muscle strength was grade IV, and the right lower limb was paralyzed (+).

Symmetrical acupuncture sensation on limbs.

Tendon reflexes in limbs (++).

The left finger nose test (-) and heel knee shin test (-) were not done on the right.

Pathological sign on the left (-), double stroke sign on the right (+).

Meningeal irritation (-).

You cannot walk in a straight line.

Blood pressure 154/84mmHg.

GCS 15 points.

The drinking water test of Watian's is Grade 1.

After admission, a complete lung CT showed "1.
The right hilar occupies space, obstructive inflammation in the lower lobe of the right lung; scattered inflammation in the right lung, and pleural effusion on the right.

2.
The seventh thoracic vertebral body and the eighth rib on the right side.
Bone destruction, mediastinal lymph node enlargement, consider metastasis.

3.
Aorta and coronary artery sclerosis” (Figure 1).

The enhanced MRI of the head indicates "1.
Multiple cerebral hemispheres and cerebellar hemispheres have multiple space-occupying areas.
If you consider metastasis, please refer to the clinical practice.
Further examination is recommended; 2.
Multiple ischemias in the bilateral basal ganglia, semi-oval center and under the frontal parietal cortex Focal; 3.
Elderly brain changes, white matter degeneration; 4.
Left maxillary sinusitis" (Figure 2).

PET-CT indicated that “the posterior basal segment nodules of the right lower lobe and abnormally increased FDG metabolism are considered to be malignant tumors; the right pleural fluid low-density shadow with increased FDG metabolism, consider pleural metastasis with pleural effusion; right neck Root and mediastinal lymphadenopathy with abnormally increased FDG metabolism is considered as lymph node metastasis; the 8th posterior rib, T7, L1, right iliac, right pubic bone, left femoral neck, etc.
have increased bone density with abnormal FDG metabolism Increased height, multiple bone metastases; multiple nodular high-density shadows on both frontal, parietal, temporal, occipital lobes, and brainstem with abnormal FDG metabolism.
Consider multiple brain metastases.
The initial consideration is "right lung cancer with multiple metastases throughout the body".
Into the respiratory medicine department for further diagnosis and treatment.

After the patient was transferred to our department, a perfect ultrasound bronchoscopy was performed immediately.
The enlarged lymph nodes in the 4R group and 7 groups underwent TBNA under EBUS under bronchoscope, and histopathological puncture initially suggested adenocarcinoma.

However, while waiting for the results of further pathological immunohistochemistry and molecular testing, the patient's right limb hemiplegia rapidly and progressively worsened, unable to get out of bed and walk independently, lying in bed all day, and experiencing intermittent headaches, nausea and jet-like vomiting.

At the same time, the patient's mental state is poor, poor appetite, lethargy, and other emotions such as world weariness, bone pain at night is obvious, night sleep is extremely poor, and physical strength drops rapidly to 3 points.

Re-examination showed that the left upper limb muscle strength was grade IV, the left lower limb muscle strength was grade III, the right upper limb muscle strength was grade II, and the right lower limb muscle strength was grade II.

Pathological sign on the left (-), double stroke sign on the right (+).

Meningeal irritation (-).

Considering the rapid progress of the patient’s condition, after consultation with the radiotherapy department, whole-brain radiotherapy will be performed from November 4, 2020, with a total dose of 30Gy/10f.
During this period, bevacizumab 200 mg intravenously and glycerol fructose intravenously daily To reduce the edema and exudation of intracranial lesions.

Considering that the patient has multiple bone metastases throughout the body, 120 mg of desulumab was injected subcutaneously for bone protection treatment.

After radiotherapy, the patient's right limb hemiplegia improved slightly, and he still could not get out of bed to walk.
The frequency of paroxysmal headaches, nausea, and jet vomiting decreased.

Physical examination revealed that the left upper limb muscle strength was grade IV, the left lower limb muscle strength was grade V, the right upper limb muscle strength was grade III, and the right lower limb muscle strength was grade III.

Pathological sign on the left (-), double stroke sign on the right (+).

Meningeal irritation (-).

At this time, the results of immunohistochemistry and genetic testing were clear.
The final diagnosis of the patient was: 1.
Right lower lobe adenocarcinoma cT1bN3M1c, stage IVb (pleura, bone, brain), EGFR/ALK/ROS1 wild type, PD-L1> 50%, PS 3 points; 2.
2 type diabetes, diabetic nephropathy, CKD stage 3; 3.
hypertension grade 3 (very high-risk group); 4.
gout; 5.
old cerebral infarction.

Considering that the patient had a poor PS score, diabetic nephropathy and proteinuria at the same time, although the driver gene expression was negative, there was a high expression of PD-L1.
Therefore, on the 6th day after the end of whole brain radiotherapy, the patient received pembrolizumab Monoclonal antibody 200mg q3w intravenous infusion of anti-tumor immunotherapy, combined with disulumab 120mg q4w subcutaneous injection for bone protection therapy, while receiving symptomatic support such as controlling blood pressure and blood sugar, improving renal function, and regulating intestinal flora.

After 2 cycles of immunotherapy, the patient's hemiplegia on the right side of the body improved significantly compared with before, and he could get out of bed and walk with support without obvious headache, dizziness, nausea, etc.

Good mental state, appetite and night sleep are significantly improved compared with before.

The physical examination showed that the left upper limb muscle strength was grade V, the left lower limb muscle strength was grade V, the right upper limb muscle strength was grade IV, and the right lower limb muscle strength was grade IV.

Bilateral pathological signs (-), meningeal irritation signs (-).

At present, the patient is regularly receiving pembrolizumab immunotherapy and desulzumab bone protection treatment.

During the treatment, the patient's blood pressure and blood sugar can be controlled, and the kidney function is not significantly impaired.
He can walk independently, take care of himself basically, have a good mental state, appetite, sleep at night, and no special complaints.

The physical examination showed that the left upper limb muscle strength was grade V, the left lower limb muscle strength was grade V, the right upper limb muscle strength was grade V, and the right lower limb muscle strength was grade V-.

Bilateral pathological signs (-), meningeal irritation signs (-).

After 4 months of treatment, the assessment of the patient’s lungs (Figure 3) and intracranial lesions were significantly smaller than the baseline period (Figure 4), and the serum tumor index carcinoembryonic antigen was also significantly lower than before (Figure 5).
The preliminary efficacy assessment is PR.

3.
Questions and answers 1 The effect and timing of radiotherapy combined with immunotherapy? With the clinical application of immune checkpoint inhibitors (ICIs), the clinical treatment strategy for lung cancer patients has been changed.

Although PD-1, PD-L1 and CTLA-4 antibodies have improved the treatment mode of NSCLC patients, the response rate of ICIs alone is only 19%-47%.
Therefore, in order to enhance the anti-tumor ability, ICIs and radiotherapy have been started Joint exploration.

Recent studies have found that radiotherapy can increase the expression of PD-L1 in the tumor microenvironment.
Combined anti-PD-L1 therapy can not only effectively control the growth of local tumors, but also delay the growth of distant tumors by activating cytotoxic T cells and reducing the accumulation of MDSCs.
[1].

It has also been confirmed in mouse models of non-small cell lung cancer that radiotherapy combined with PD-1 antibody can enhance anti-tumor activity through the infiltration of CD8+ T cells [2-3].

Radiotherapy can activate immune neoantigens.
After the neoantigens are activated, more lymphocytes can be recruited to gather around the tumor at the same time, change the microenvironment, and exert anti-tumor effects.
At this time, with immune checkpoint inhibitors, it may reach 1+1 The effect of >2.

Although the combination of radiotherapy and ICIs is currently considered to be an effective treatment mode, the optimal timing and sequence of radiotherapy combined with immunotherapy is unclear.

The PACIFIC study [4] showed that adjuvant duvalizumab administration 1-42 days after radiotherapy and chemotherapy can improve PFS and OS.

Regardless of the length of time to complete radiotherapy, the PFS of the duvalizumab group was longer than that of the placebo group (<14 days: NR vs.
4.
8 months, HR=0.
39; ≥14 days: 14.
0 vs.
5.
6 months, HR= 0.
63).

And the overall safety is good, and it does not increase the probability of pneumonia.

Multivariate analysis showed that the use of duvalizumab within 14 days was associated with better OS.

Another retrospective study [5] explored the best time to start immunotherapy after radiotherapy.

The analysis showed that compared with patients who received immunotherapy within 21 days after the start of SBRT, patients who received immunotherapy at least 21 days after the start of SBRT had a longer OS (19 vs.
15 months; P=0.
0335).

In combination with this case, we added immunotherapy within 1 week after the end of radiotherapy, and the patients benefited significantly.

Therefore, the effect of radiotherapy on immunotherapy response may be two-sided, which is related to the separation mode of radiotherapy and the biological characteristics of the tumor.
The optimal time for immunotherapy after radiotherapy still needs to be explored through large randomized clinical trials.

In addition, the comprehensive effect of radiotherapy and immunotherapy is not only related to the interval between the two, but also closely related to the sequence of combined treatment, different immunotherapies, different radiation doses and division schemes.

Therefore, we look forward to more clinical evidence to further guide precise clinical applications in the future.

2 The final immunohistochemistry of the patient showed PD-L1>50%.

For this type of PD-L1 high expression population, is it possible to consider immune checkpoint inhibitor monotherapy? The results of KEYNOTE-024 showed that [6] the median OS of pembrolizumab compared with platinum-containing chemotherapy first-line treatment group was 26.
3 (18.
3~40.
4) months and 13.
4 (9.
4~18.
3) months, respectively, HR=0.
62 (95%) CI: 0.
48~0.
81), because crossover is allowed, up to 55% of the patients in the control group crossover to the pembrolizumab group in the later period, and an additional 11% are subsequently treated with other PD-1/PD-L1 monoclonal antibodies.
The risk of death was reduced by 38%; the 60-month OS rate was 31.
9% and 16.
3%, respectively.
The 5-year OS rate of the pembrolizumab group was nearly twice that of the platinum-containing chemotherapy group, that is, nearly 1/ 3 patients are still alive at 5 years.

The results of the KEYNOTE-024 study also put immunotherapy on the stage of first-line treatment of tumors for the first time, and it is a "de-chemotherapy mode.
"
The KEYNOTE-042 study [7] further explored the OS after pembrolizumab monotherapy in patients with PD-L1 TPS ≥ 1%, and found that different TPS stratification groups benefited significantly.

The primary study endpoint was OS in the TPS ≥ 50%, TPS ≥ 20%, and TPS ≥ 1%.

The results showed that pembrolizumab has no EGFR sensitive mutations or ALK fusion in the first-line treatment, and the efficacy of advanced NSCLC patients with PD-L1 TPS≥1% is better than platinum-containing chemotherapy.

These data show that pembrolizumab can significantly prolong overall survival whether it is expressed at 50%, 20%, or 1% or more in PD-L1, which further establishes the status of pembrolizumab as a first-line treatment.

Combining this case, although the patient had severe intracranial metastases at the initial stage of treatment, and the general condition was not good, but from the overall treatment effect, this patient with high PD-L1 expression can obviously benefit from immune checkpoint inhibitor monotherapy , And the additional damage is small, simple and effective, the general condition of the patient is significantly improved after just 2 weeks of treatment, and it also suggests that once the immune checkpoint inhibitor is effective, it can quickly take effect.

Some recent studies [8] have concluded that after analyzing the efficacy of immune single-drug vs.
immune combination in the population with PD-L1 expression ≥50% in existing trials, the advantage of immune combination is mainly reflected in the tumor remission rate compared with single-drug immunity The improvement and the reduction of early treatment failure rate.

The study proposes that for patients with symptoms, high tumor burden, or expected and worried about rapid disease progression, a combination strategy is the first choice.
These factors are independent of PD-L1 expression (including ≥50%).

Therefore, due to the extreme heterogeneity of patients with advanced driver gene-negative NSCLC, it is not appropriate to consider only the cut-off value of PD-L1 expression ≥50% to select the best strategy for first-line treatment.
More biomarkers are expected to be used.
It is used as a guide for clinical immunotherapy.

3 What is the therapeutic effect of immune checkpoint inhibitors on patients with lung cancer and brain metastases? Brain metastasis (BM) is the most common mode of distant metastasis in patients with lung cancer.
Once brain metastasis is found, it means that the disease has advanced to an advanced stage.

About 20% of small cell lung cancers are found to have brain metastases when they are first diagnosed.

About 30% of NSCLC patients develop brain metastases during treatment, especially lung cancer patients with positive driver genes are more likely to develop brain metastases during treatment.

The prognosis of patients with lung cancer and brain metastasis is extremely poor.
Without any treatment, the average survival time is only 1-2 months.

The traditional treatment options for patients with NSCLC brain metastases include surgery and craniocerebral radiotherapy [for example, whole brain radiotherapy (WBRT) + stereotactic radiotherapy (SRS) combined system chemotherapy].

So, what is the effect of immunotherapy on lung cancer brain metastasis?
The molecular size and fat solubility of the drug play a vital role in its anti-tumor activity in the central nervous system.
Therefore, the traditional view is that monoclonal antibodies cannot penetrate the blood-brain barrier due to their large molecular weight and cannot effectively treat patients with BM.

There is also a view that “the brain is an immune-exempt organ, and there are no lymphatic vessels in the central nervous system.
” Theoretically, BM patients receive poor immunotherapy. However, the current academic circles believe that lymphocytes in the meninges, cerebrospinal fluid, and lymphocytes residing in the meninges will form a relatively mature network, which provides physical conditions for antigens in the cerebrospinal fluid to initiate the development and activation of T cells.

T lymphocytes activated by PD1/PD-L1 inhibitors in extracranial lesions can enter the central nervous system (CNS) through deep cervical lymph nodes, which is a key element for the immune effect of brain metastases.

At the same time, CD4+ T cells produce gamma interferon, which helps PD1/PD-L1 inhibitors to enter the central nervous system.

All these provide important breakthroughs in the mechanism and treatment strategies of tumor brain metastasis.

Hendriks’ study [9] analyzed 1025 cases of PD-(L)1 with/without CTLA-4 and other immunotherapies, excluding patients with meningeal metastasis or previous chemotherapy.
A total of 24.
9% of patients had brain metastases at baseline.
100 patients (accounting for 39.
2% of brain metastases) had untreated active brain metastases or progressed after treatment with glucocorticoids.

In patients with active brain metastases, the intracranial ORR was 27.
3% (37.
5% of patients with tumor PD-L1 expression ≥ 1%, while only 11.
1% of PD-L1 negative patients).

12.
7% of patients with intracranial and extracranial tumors did not respond to immunotherapy.

The median OS of patients with brain metastases was 8.
6 months, while that of patients without brain metastases was 11.
4 months.

A study [10] included 409 patients with asymptomatic brain metastases who received nivolumab monotherapy.

The results showed that the ORR of brain metastases patients and the whole group of patients were 17% and 18%, DCR were 40% and 44%, PFS were 3.
0 months, OS was 8.
6 months and 11.
3 months, and 1-year OS The rates were 43% and 48%, respectively.
There was no significant difference between the brain metastasis population and the whole group in all the main survival indicators.

OAK study [11] showed that compared with chemotherapy, atezolizumab has a tendency to prolong the survival time of patients with brain metastases, and prolong the occurrence of brain metastasis progression (especially for patients with a history of brain metastasis, the effect is more obvious).

The KEYNOTE-189 study [12] included the largest number of first-line brain metastasis treatment groups so far, with a total of 109 cases, accounting for 17.
5% of the total population, and in the intracranial metastasis subgroup, the overall survival of the immune combined chemotherapy group was significantly longer than that of the intracranial metastasis subgroup.
Chemotherapy monotherapy.

There are still many problems that need to be resolved, including finding a population of brain metastases that are more suitable for ICIs treatment, whether there are more suitable biomarkers other than PD-L1, and possibly effective combination treatment options.

In addition to radiotherapy combined with ICIs that have been initially explored clinically, research on the treatment of brain metastases with antivascular drugs combined with ICIs is also underway.

 Expert profile Yin Qi, deputy chief physician of the Department of Respiratory and Critical Care, Dongji University Affiliated Hospital, doctor of medicine, lecturer of Tongji University School of Medicine.

Member of the Respiratory and Lung Cancer Group of the Shanghai Medical Association, member of the Lung Cancer Professional Committee of the Shanghai Women's Physician Association, member of the Young Respiratory Endoscopy Physician Committee of the Endoscope Branch of the Chinese Medical Doctor Association, and member of the Shanghai Association of Integrated Chinese and Western Medicine Respiratory Diseases.

Presided over and in charge of many projects of Shanghai Municipal Science and Technology Commission, Shanghai Municipal Health Bureau, Shanghai Medical Association, and Tongji University.
Participating projects won the first prize of Pudong Science and Technology Progress Award.

Published more than 10 core journals and SCI papers, participated in the compilation of 2 monographs, and obtained 3 patents.

 Expert profile Lu Jingjing Attending physician in the Department of Respiratory and Critical Care Medicine, Shanghai Dongfang Hospital, Shanghai Dongfang Hospital, PhD student, lecturer participated in 3 national natural and provincial scientific research projects, presided over 1 hospital-level project, first author published 5 SCI papers and long-term engagement Reference materials for individualized and precise treatment of lung cancer clinical frontline and teaching work: [1] Xia WY, Feng W, Zhang CC, et al.
Radiotherapy for non-small cell lung cancer in the immunotherapy era: the opportunity and challenge-a narrative review .
Transl Lung Cancer Res, 2020; 9(5): 2120-2136.
[2] Herter-Sprie GS, Koyama S, Korideck H, et al.
Synergy of radiotherapy and PD-1 blockade in Kras-mutant lung cancer.
JCI Insight, 2016;1(9):e87415.
[3]Gong X, Li X, Jiang T, et al.
Combined Radiotherapy and Anti-PD-L1 Antibody Synergistically Enhances Antitumor Effect in Non-Small Cell Lung Cancer.
J Thorac Oncol , 2017; 12(7): 1085-1097.
[4] Antonia SJ, Villegas A, Daniel D, et al.
Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC.
N Engl J Med, 2018; 379(24): 2342-2350.
[5] Wegner RE, Abel S, Hasan S, et al.
Time from stereotactic body radiotherapy to immunotherapy as a predictor for outcome in metastatic non small cell lung cancer.
J Clin Oncol, 2019;37(15):abstr 9024.
[6]JRBrahmer, D.
Rodriguez-Abreu, AGRobinson, et al.
LAB51 KEYNOTE-024 5-year OS update: First-line (1L) pembrolizumab (pembro) vs platinum-based chemotherapy (chemo) in patients (pts) with metastatic NSCLC and PD-L1 tumour proportion score (TPS) ≥50%.
ESMO 2020.
[7]Mok TSK, Wu YL, Kudaba I, et al.
Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised , Open-label, controlled, phase 3 trial.
Lancet, 2019; 393(10183): 1819-1830.
[8]Di Federico A, De Giglio A, Parisi C, et al.
PD-1/PD-L1 inhibitor monotherapy or in combination with chemotherapy as upfront treatment for advanced NSCLC with PD-L1 expression≥50%:Selecting the best strategy.
Crit Rev Oncol Hematol.
2021;160:103302.
[9]Hendriks LEL, Henon C, Auclin E, et al.
Outcome of Patients with Non-Small Cell Lung Cancer and Brain Metastases Treated with Checkpoint Inhibitors.
J Thorac Oncol, 2019;14(7):1244-1254.
[10]Crino L, Bronte G, Bidoli P, et al.
Nivolumab and brain metastases in patients with advanced non-squamous non-small cell lung cancer.
Lung Cancer, 2019;129:35-40.
[11]Rittmeyer A, Barlesi F, Waterkamp D, et al.
Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial.
Lancet, 2017;389(10066):255-265.
[12]Rodríguez-Abreu D, Powell SF, Hochmair MJ, et al.
Pemetrexed Plus Platinum With or Without Pembrolizumab in Patients With Previously Untreated Metastatic Nonsquamous NSCLC :Protocol-Specified Final Analysis From KEYNOTE-189.
Ann Oncol, 2021.