An overview of the article: 2021 CSCO Small Cell Lung Cancer Guidelines Update Key Points

The 2021 CSCO Guide Conference kicked off in Beijing on April 23 with a combination of online and offline methods.

In the lung cancer session on the morning of the 23rd, Professor Liu Ying from Jilin Cancer Hospital, Professor Bi Nan from Chinese Academy of Medical Sciences Cancer Hospital, and Professor Liu Jiwei from the First Affiliated Hospital of Dalian Medical University respectively interpreted the diagnosis in the 2021 CSCO Small Cell Lung Cancer (SCLC) Diagnosis and Treatment Guidelines And internal medicine part, radiotherapy part, compound SCLC and transformative SCLC part.

Pathological diagnosis and molecular markers in diagnosis and internal medicine.
For pathological diagnosis, the level I recommendation is added: "For tumors that do not have neuroendocrine morphological features, neuroendocrine marker staining is not recommended"; deleted from the level II recommendation "CAM5.
2" comment added: For tissue specimen diagnosis principle 2, "When there is no histological morphology of neuroendocrine tumors, neuroendocrine marker staining is not recommended.

Definite squamous cell carcinoma or adenocarcinoma with neuroendocrine Differentiation does not affect treatment decision or prognosis” and “Diagnostic auxiliary examination items should be minimized to save specimens for follow-up treatment guidance examination”.

For the part of molecular markers, the level III recommendations for limited-stage and extensive-stage SCLC have added "serum sodium concentration" (category 2B).

Added note 7: Hyponatremia (blood Na <135mmol/L) is one of the common complications of SCLC.

A retrospective study found that the overall survival (OS) of SCLC patients with hyponatremia was significantly lower than that of patients with normal serum sodium; correcting hyponatremia may increase the survival benefit of SCLC patients.

Added note 8: Some studies have shown that for patients with limited-stage SCLC, the platelet/lymphocyte ratio (P/L ratio) before radiotherapy is significantly related to their OS.
Every increase in the P/L ratio by 1, the HR will increase by 1.
001, but it still Need further clinical verification.The initial treatment of limited-stage SCLC The initial treatment of limited-stage SCLC and the 2020 version of the guidelines are the same as the initial treatment of limited-stage SCLC.
The increasing exploration of immunotherapy in limited-stage SCLC is expected to change the treatment pattern of limited-stage SCLC.

The current exploration of immunotherapy for limited-stage SCLC mainly lies in the following two modes: immunoconsolidation therapy after radiotherapy and chemotherapy and concurrent immunotherapy with radiotherapy and chemotherapy.

The initial treatment of extensive-stage SCLC The initial treatment of extensive-stage SCLC is stratified according to symptoms, and different treatment strategies are recommended according to the PS score.

For patients with symptomatic brain metastases, the level II recommendation is that patients with complete remission (CR) or partial remission (PR) can be given chest radiotherapy (category 2A).

The initial treatment of extensive-stage SCLC combined immunotherapy has become the new standard for the first-line treatment of extensive-stage SCLC.

The IMpower133 study is the first milestone in immunotherapy in the field of SCLC in the past 30 years.
The subsequent CASPIAN study further confirmed the efficacy of combined immunotherapy.

Immune consolidation therapy also has potential value in extensive-stage SCLC immunotherapy.

The exploratory analysis result of IMpower133 was announced on the 2020 WCLC.

The study explored the efficacy of maintenance treatment with carboplatin + etoposide + atilizumab or placebo, followed by atilizumab or placebo.

The results showed that the median OS of the atilizumab group and the placebo group were 15.
7 months and 11.
3 months, respectively (HR=0.
67, P=0.
008).

The median progression-free survival (PFS) of the two groups were 5.
5 months and 4.
5 months (HR=0.
73, P=0.
008).

The analysis of the results showed that atelizumab + chemotherapy induction therapy and subsequent maintenance therapy all contribute to the benefit of OS.

Consolidation therapy enriched the benefited population, and atelizumab + chemotherapy enriched the population responding to immunotherapy.

Compared with the general population, people who have the opportunity to enter the consolidation treatment have more significant benefits from the use of atelizumab + chemotherapy.

At present, a number of domestically-made PD-1/PD-L1 inhibitors are currently undergoing validation studies for the first-line treatment of extensive-stage SCLC.
It is hoped that these studies will bring more data for immune combination therapy.

The second-line treatment of relapsed SCLC is added.
Note 5: "New exploration of second-line treatment for relapsed SCLC: Adding the PASSION study and the description of the related research results of adding rubicardine.

" The PASSION study is a multi-center, two-phase phase II conducted in China The purpose of this study is to evaluate the efficacy and safety of carrelizumab + apatinib in the second-line treatment of patients with extensive-stage SCLC.

The results showed that the objective response rate (ORR) of the combination therapy was 34%, and the disease control rate (DCR) was 68.
1%.

Subgroup analysis showed that the ORR of chemotherapy-sensitive and drug-resistant patients were 37.
5% and 32.
3%, respectively.

The results of the study provide a basis for further exploration of immunization combined with anti-vascular treatment for recurrent SCLC.

Third-line treatment For the third-line and above treatment of SCLC, based on the ALTER1202 study, anlotinib's standard treatment status has been established.

Added note 3: "Nivolumab's Phase III CheckMate-331 study for SCLC second-line treatment and CheckMate-451 Phase III study for maintenance treatment after first-line treatment both ended in failure.
BMS has already failed on December 30, 2020.
It was decided to withdraw the indication for SCLC approved by Nivolumab in the United States on the same day.
The 2021 V2 NCCN guidelines changed the recommendation of Nivolumab from category 2A to category 3 recommendation as the follow-up systemic treatment option for relapsed SCLC within 6 months.

”Added note 4: “Because the phase III confirmatory study KEYNOTE-604 only reached one of the joint primary endpoints of PFS, but did not reach the other primary endpoint of OS, pembrolizumab was actively withdrawn in March 2021.
Indications for SCLC.
The
2021 V3 NCCN guidelines changed pembrolizumab from a category 2A recommendation to a category 3 recommendation.

"The ALTER1202 study update at the ASCO conference in 2020 shows that Anlotinib can significantly improve the PFS and OS of patients with relapsed SCLC within 3 months of second-line treatment.

The updated results announced by ESMO in 2020 show that Anlotinib can also significantly improve second-line treatment.
PFS in SCLC patients with post-baseline liver metastases.

In addition, the exploration of
anlotinib combination therapy has been ongoing.
A PD-L1 inhibitor (TQB2450) combined with anlotinib for the treatment of advanced solid tumors (including SCLC) The arm phase Ib study shows that the combination therapy has good anti-tumor activity.

Another phase III study of TQB2450+anlotinib+carboplatin+etoposide for the first-line treatment of extensive-stage SCLC is also underway, and we look forward to the announcement of the research results .

radiotherapy part limited SCLC limited SCLC in radiotherapy for limited (T1-2, N0) patients suitable for surgical patients, the I-level recommended: for patients after N1, mediastinal lymph nodes may be employed adjuvant chemotherapy ± radiotherapy (2A class ); For postoperative N2 patients, adjuvant chemotherapy + mediastinal lymph node radiotherapy (category 2A) can be used.

Level II recommendation: PCI (category 1).

In patients with limited stage (T1-2, N0), for patients who are not suitable for surgery or not For patients who are willing to undergo surgery, level I recommendation: Stereotactic radiotherapy (SBRT/SABR) post-chemotherapy (category 2A) and chemotherapy + simultaneous/sequential radiotherapy (category 1) can be used; level II recommendation: patients with CR or PR can use PCI (1 class)
in limited stage (over T1-2, N0) patients, patients in PS 0 ~ 2, the I-level recommended chemotherapy may employ synchronous / sequential radiotherapy (category 1); recommended class II: CR or PR patients PCI (Class 1).

For PS 3~4 patients, chemotherapy±radiotherapy can be used; Level II recommendation: PCI (Class 1) for CR or PR patients.

Extensive-stage SCLC Radiotherapy for extensive-stage SCLC has no local symptoms and no brain For patients with metastasis, PS 0~2 or PS 3~4 (due to SCLC), level II recommendation: CR or PR patients can be given chest radiotherapy (category 2A) and preventive brain radiotherapy (category 2A).

For patients with local symptoms of superior vena cava syndrome, level I recommendation: radiotherapy + chemotherapy (category 2A) can be given to patients with severe clinical symptoms, chemotherapy + radiotherapy can be given to patients with mild clinical symptoms (category 2A); level II recommendation: CR or Prophylactic brain radiotherapy for patients with PR (Class 2A).

For patients with spinal cord compression symptoms, level I recommendation: local radiotherapy to control compression symptoms + EP/EC/IP/IC chemotherapy (Class 2A).

For patients with local symptoms of bone metastases, I recommend: EP/EC/IP/IC regimen chemotherapy + local palliative external beam radiation therapy (Class 2A).

For asymptomatic patients with brain metastases, I recommend: ateliizumab+EC ​​regimen first, followed by whole brain radiotherapy (Class 1A evidence) or EP/EC/IP/IC regimen first, followed by whole brain radiotherapy (Class 1A Evidence); Level II recommendation: give chest radiotherapy to patients with CR or PR (category 2A); Level III recommendation: first varizumab + etoposide + carboplatin or cisplatin regimen, followed by whole brain radiotherapy (category 1A) .

For symptomatic patients with brain metastases, I recommend: whole brain radiotherapy first, atelizumab + EC regimen after the symptoms are stable (Class 1A evidence) or whole brain radiotherapy first, and EP/EC/IP/IC after the symptoms are stable Protocol (Class 2A evidence); Level II recommendation: give CR or PR patients chest radiotherapy (Class 2A); Level III recommendation: first whole brain radiotherapy, followed by duvalizumab + etoposide + carboplatin or cisplatin (Category 1A).

Compound SCLC and transforming SCLC compound small cell lung cancer Compound small cell lung cancer (C-SCLC) refers to a mixture of SCLC and non-small cell lung cancer (NSCLC) components.

Compound SCLC accounts for about 10% of small cell lung cancer.
Pathologically, the components of small cell lung cancer are accompanied by varying amounts of other non-small cell cancer components.

The clinical features are about 50% of peripheral lung cancer, and about 70% of limited stage (stage I-II).
Compared with pure SCLC surgical treatment, it has greater benefits, is relatively insensitive to radiotherapy and chemotherapy, and is potentially effective for EGFR-TKI.

The treatment of compound SCLC still lacks large-sample prospective randomized controlled clinical research data, most of which are small-sample retrospective analysis and case reports.

Therefore, the current major guidelines classify compound SCLC into the SCLC category and adopt the same treatment model.

Compound small cell lung cancer in the treatment of transforming small cell lung cancer In the course of NSCLC disease, the histological type can be transformed into SCLC, which is collectively referred to as transforming SCLC.

Transforming SCLC and classic SCLC are similar in pathological morphology and molecular characteristics, but they cannot be completely classified into classic SCLC, and can be classified as a new SCLC subtype.

Tumor tissue biopsy must be performed again.
Pathological diagnosis is the gold standard.
Gene characteristics and plasma testing alone cannot reliably determine whether a patient has undergone SCLC transformation.

The 2021 version of the CSCO Small Cell Lung Cancer Diagnosis and Treatment Guidelines introduces the mechanism of transforming SCLC, including the tumor cell heterogeneity hypothesis, tumor stem cell hypothesis, molecular mechanism hypothesis and molecular mechanism hypothesis.

The new version of the guideline gives recommendations for the treatment of transformative SCLC.
In addition, the new version of the guideline also updates one of the resistance mechanisms of NSCLC targeted therapy "transforming SCLC".

Previous studies have shown that SCLC transformation is the drug resistance mechanism of EGFR-TKI.
There are case reports suggesting that transforming SCLC can also occur in patients with NSCLC who have received TKI treatment with ALK or ROS1 fusion gene positive, and after receiving immune checkpoint inhibitor treatment.
NSCLC.

Most transforming SCLC retain the original lung adenocarcinoma gene mutations (about 84% to 88%) and SCLC gene features (such as TP53 and RB1 deletion mutations); these features may be related to PIK3CA, NOTCH, and ASCL1 gene pathways.

Once a patient undergoes SCLC transformation, the disease progresses quickly and the overall prognosis is poor.
The median OS is 6 to 10.
9 months.