The most complete summary: Do you need adjuvant treatment after lung cancer surgery?

Author: Cause and Effect This article is authorized by the author to publish by Yimaitong, please do not reprint without authorization.

Lung cancer is one of the malignant tumors with the highest morbidity and mortality in my country.

According to statistics released by the National Cancer Center of my country in 2019, the incidence and mortality of lung cancer ranks first in malignant tumors, and its annual incidence and death toll are 787,000 and 631,000 respectively, nearly twice that of the second malignant tumor.
[1].

Among lung cancers, non-small cell lung cancer (NSCLC) accounts for about 85%, which is the main pathological type leading to the incidence and death of lung cancer, and about 30% of NSCLC patients are resectable early and mid-term NSCLC when they are first diagnosed.

NSCLC still has a high risk of recurrence and death after surgical treatment, so how to standardize and effectively carry out postoperative adjuvant treatment is particularly important.

1.
Adjuvant treatment of NSCLC patients, even if they have undergone complete tumor resection, there is still a risk of postoperative recurrence and metastasis.

More than 50% of tumor recurrence or metastasis occurs in the first 2 years after surgery, but the risk of recurrence and metastasis is still high in 3 to 5 years after surgery.
It is not until 5 years after surgery that the risk of tumor recurrence and metastasis is significantly reduced.
The later the stage is.
The risk of recurrence and metastasis is higher [2].

Therefore, drugs or other forms of treatment are needed after surgery to further improve long-term survival.
These postoperative treatments are collectively referred to as adjuvant therapy.

2.
Adjuvant treatment mode Adjuvant treatment mode mainly includes adjuvant chemotherapy, adjuvant targeted therapy, adjuvant radiotherapy, etc.

At present, stratification is based on EGFR mutation status.
For adjuvant treatment of patients with EGFR mutation-positive stage I~IIIB NSCLC after complete resection, adjuvant targeted therapy and adjuvant chemotherapy can be selected.
Compared with adjuvant chemotherapy, adjuvant targeted therapy has longer Disease-free survival (DFS) and overall survival (OS).

For NSCLC patients with EGFR mutation negative stage I~IIIB, adjuvant chemotherapy is the main treatment.

3.
Adjuvant chemotherapy 1.
Adjuvant treatment population and stratified adjuvant chemotherapy are currently the most widely used adjuvant treatment methods, but due to the limited benefits brought by adjuvant chemotherapy (the 5-year survival rate is increased by about 5%) [3], so The benefits and risks of adjuvant chemotherapy need to be comprehensively evaluated before adjuvant chemotherapy.
Adjuvant chemotherapy is not recommended for the following people: poor physical status: ECOG score> 2 or KPS <60, severe liver and kidney dysfunction (> 2ULN), severe comorbidities or Complications, active infections, persistent fever, severe bleeding tendency, abnormal hematopoietic function (hemoglobin<80g/L, neutrophils<1.
5×10^9/L, platelets<100×10^9/L) stage IA stage IA patients accepted Adjuvant chemotherapy does not benefit, so postoperative adjuvant chemotherapy is not recommended for patients with stage IA NSCLC [2].

Phase IB CALGB9633 [4], JBR10 clinical trials [5] and LACECG meta-analysis [3] found that patients with stage IB NSCLC have no significant survival benefit from postoperative chemotherapy, so adjuvant chemotherapy is not routinely recommended for this type of patients.

However, a retrospective study conducted by Park SY et al.
[6] in 2013 showed that some patients with stage IB NSCLC can benefit from postoperative adjuvant chemotherapy.

Therefore, the results of various clinical studies are inconsistent with regard to whether patients with stage IB should receive adjuvant chemotherapy.
At present, there is still controversy about whether to use adjuvant chemotherapy, and the recommendations of various guidelines are also different.

The current 2020 version of CSCO non-small cell lung cancer diagnosis and treatment guidelines [7] recommends: stage IB non-small cell lung cancer (including lung cancer with high-risk factors), due to the lack of high-level evidence support, adjuvant chemotherapy is generally not recommended.

 The 2021.
V4 edition of the NCCN NSCLC guidelines [8] recommends adjuvant chemotherapy for high-risk patients.

  Among them, high-risk factors include: poorly differentiated tumors (including lung neuroendocrine tumors, but not well-differentiated neuroendocrine tumors), vascular invasion, wedge resection, T>4cm, visceral pleural invasion, Nx, etc.

   In the recently released guidelines for adjuvant treatment after complete resection of stage I~IIIB non-small cell lung cancer (2021 edition) [2], it is recommended that patients with stage IB NSCLC who are negative for EGFR mutations should be treated with adjuvant chemotherapy after complete tumor resection.
For patients with high-risk factors, a multidisciplinary comprehensive evaluation is recommended.
Combined with the evaluation opinions and patient wishes, postoperative adjuvant chemotherapy can be considered (Class 1 evidence, recommendation).

Among them, high-risk factors include: poorly differentiated tumors (including micropapillary adenocarcinoma, neuroendocrine tumors, but not well-differentiated neuroendocrine tumors), visceral pleural invasion, vascular invasion, and air cavity dissemination.

   Therefore, for patients with high risk factors after stage IB, a multidisciplinary comprehensive evaluation is recommended.
After the evaluation results and the patient's wishes, postoperative adjuvant chemotherapy can be considered.

Phase IIA CALGB9633 clinical trial [4] showed that for patients with N0 stage NSCLC with tumors larger than 4cm, postoperative chemotherapy can still reduce the risk of death by 31%.

In the JBR10 study [5], postoperative adjuvant chemotherapy for stage IIA NSCLC patients can reduce the risk of death by 34%.

Therefore, it is still recommended to consider postoperative adjuvant chemotherapy for NSCLC patients with EGFR mutation-negative stage IIA complete resection.

Among them, the 2020 CSCO Guidelines for the Diagnosis and Treatment of Non-Small Cell Lung Cancer is a Class III recommendation of Class 2B evidence, and the 2021.
V4 version of the NSCLC Guidelines is a Class 2A recommendation.

The 2008 LACE Collaborative Group meta-analysis of phase IIB-IIIB showed that the risk of postoperative chemotherapy death in patients with phase IIB~III NSCLC can be reduced by 17% [3].

A 2010 meta-analysis of 26 clinical studies showed that postoperative chemotherapy for stage II-III NSCLC patients can increase the 5-year survival rate by 5%.

The 2010 phase III clinical study JBR10 also found that postoperative chemotherapy in patients with phase II NSCLC can reduce the risk of death by 32% [4-5].

Based on the above evidence, for NSCLC patients with stage IIB to IIIB EGFR mutation negative, routine adjuvant chemotherapy is recommended after complete tumor resection.

2.
The first choice for adjuvant chemotherapy is a two-drug regimen based on cisplatin.
Its combination drugs include vinorelbine, gemcitabine, docetaxel, paclitaxel, albumin-bound paclitaxel, and pemetrexed (only for non-squamous cancer )Wait.

For patients who cannot tolerate cisplatin, a carboplatin-based two-drug regimen can be used.

3.
Starting time of adjuvant chemotherapy The physical condition of patients after the operation has basically returned to normal, and adjuvant chemotherapy can be started, generally 4 to 6 weeks after the operation, and it is recommended that it be no later than 3 months after the operation.

4.
Adjuvant chemotherapy cycle After adjuvant chemotherapy is routinely recommended 4 cycles, more chemotherapy cycles will not increase the benefit of patients, but may increase adverse reactions.

IV.
Adjuvant Targeted Therapy 1.
Targeted therapy stratification stage IA Most studies of EGFR-TKI as adjuvant targeted therapy did not include stage IA NSCLC patients, and there is currently no sufficient evidence-based basis to support the EGFR mutation-positive stage IA Adjuvant targeted therapy is used in NSCLC patients, so adjuvant targeted therapy is not recommended for stage IA patients.

The Phase IB ADAURA study [9] showed that the adjuvant treatment of osimertinib for 3 years after complete tumor resection of EGFR mutation-positive stage IB patients can reduce the risk of disease recurrence or death by 61%.
For such patients, osimertin may be considered.
Adjuvant therapy.

Currently 2021.
V4 NCCN guidelines recommend ossitinib as an adjuvant treatment for patients with NSCLC after complete stage IB surgery.

The Phase II-IIIB EVAN study [10] is a multicenter randomized phase II clinical study comparing the efficacy and safety of erlotinib and chemotherapy as an adjuvant treatment for patients with stage IIIA NSCLC with EGFR mutations.

The results showed that the 2-year DFS in the erlotinib group was significantly better than that in the chemotherapy group (81.
35% vs44.
62%, P<0.
001), and the median DFS was extended from 21.
0 months to 42.
4 months (HR=0.
27, 95%CI: 0.
14~0.
53, P<0.
001). At the same time, the erlotinib group is also better than the chemotherapy group in terms of safety.

In-depth analysis found that most of the patients enrolled were IIIA (N2 stage), suggesting that IIIA (N2 stage) EGFR-mutant NSCLC patients are most likely to benefit from postoperative adjuvant targeted therapy.

ADJUVANT study [11] compares the efficacy and safety of gefitinib versus chemotherapy for adjuvant therapy in completely resected stage II~IIIA (N1~N2) EGFR-mutant NSCLC patients.
The results show that the median DFS in the gefitinib group It was significantly better than the traditional chemotherapy group (28.
7 months vs 18.
0 months, P=0.
0054), and significantly prolonged the disease recurrence time by about 10 months.

The EVIDENCE study [12] showed that adjuvant treatment with icotinib for 2 years can reduce the risk of disease recurrence or death by 64% in patients with stage II-IIIA NSCLC.

The ADAURA study [9] included 682 patients with stage IB~IIIA EGFR mutation-positive NSCLC after complete resection, and they were randomized to receive adjuvant treatment with osimertinib or placebo for 3 years or until disease recurrence or intolerable toxicity Compared with placebo, osimertinib significantly prolonged the median DFS of patients with stage II~IIIA.
The median DFS of the two groups was not reached and 19.
6 months (HR=0.
17, P<0.
001), which decreased 83% risk of disease recurrence or death.

The median DFS of the osimertinib group was also significantly better than that of the placebo group, which were not reached and 27.
5 months (HR=0.
20, P<0.
001).

The 2-year DFS rates of the two groups were 89% and 52%, respectively.

Therefore, for patients with EGFR mutation-positive stage II-IIIB NSCLC, EGFR-TKI (osimertinib, gefitinib or icotinib) adjuvant therapy is recommended after complete tumor resection.

2.
Targeted drug selection is based on current clinical research design and guideline recommendations [2,7-8].
After complete resection of EGFR mutation-positive NSCLC patients: stage IB patients: osimertinib may be considered as adjuvant therapy (Class 1A evidence) ). Stage IIA and IIB patients: choose osimertinib (type 1A evidence), gefitinib (type 1B evidence) or icotinib (type 1B evidence).

Stage IIIA and IIIB patients: choose osimertinib (type 1A evidence), gefitinib (type 1B evidence), icotinib (type 1B evidence) or erlotinib (type 2 evidence), with priority Adjuvant treatment with osimertinib is recommended (unanimous recommendation).

It should be noted that patients with stage III NSCLC have a higher risk of brain metastasis, and adjuvant osimertinib therapy can reduce the risk of brain metastasis or death by 82%.
For stage III patients, adjuvant osimertinib therapy is preferred.

3.
The start time of adjuvant targeted therapy The time to start EGFR-TKI adjuvant therapy is determined based on the postoperative physical recovery of the patient, and it should not exceed 10 weeks after surgery.

For EGFR mutation-positive patients who have received adjuvant chemotherapy, they can continue to receive third-generation EGFR-TKI osimertinib adjuvant therapy, and the start of adjuvant osimertinib therapy is usually no later than 26 weeks after surgery.

4.
Adjuvant targeted therapy course Regarding the duration of postoperative TKI medication for EGFR mutation-positive patients, existing studies mostly use 2 years of maintenance therapy, while the ADAURA study is 3 years.
There is no randomized controlled study evidence to provide the best maintenance medication time.

5.
Adjuvant radiotherapy For postoperative adjuvant radiotherapy, in view of the results of a meta-analysis of 9 randomized studies in 1998 [13], postoperative adjuvant radiotherapy has an effect on N0 (no regional lymph node metastasis) and N1 (ipsilateral bronchial or Hilar lymph node metastasis) NSCLC patients have the effect of reducing survival, while N2 [ipsilateral mediastinal and/or subcarinal lymph node metastasis] patients have no significant benefit, and subsequent data updates published in 2005 and 2013 have similar results Therefore, postoperative adjuvant radiotherapy is not recommended for patients with N0 and N1 NSCLC in stages I to IIIB.

At present, the main controversy lies in N2 patients.

Corso et al.
[14] retrospectively analyzed 6979 patients with pN2 postoperative adjuvant radiotherapy in the NCDB database.
The results showed that the 5-year overall survival rates of the PORT group and the control group were 34.
1% and 27.
8%, respectively (P<0.
001).
PORT makes the survival rate.
The absolute value increased by 6.
3%. Urban et al.
[15] analyzed 4773 pN2 patients in the SEER database and showed that the risk of death in the PORT group was significantly reduced (HR=0.
9, P=0.
026), and the conclusion was consistent with the above study.

In addition, Mikell[16], Robinson[17] and others analyzed the effects of PORT on the NCDB database of pN2 patients who received radiotherapy from 2004 to 2006 and 2006 to 2010.
The results also showed that PORT significantly improved the median survival, and multivariate analysis showed PORT is an independent prognostic factor.
The results of the above studies all show that PORT may improve the overall survival of patients with stage III-N2 NSCLC, but its benefit is small.

Europe has initiated a large-scale randomized controlled phase III clinical study (Lung ART) since 2007.
The study uses three-dimensional conformal radiotherapy technology.
The sample size is estimated to be 700 cases.
The results of the phase III randomized clinical study were reported at the ESMO meeting in 2020.
The results of Lung ART [18] showed that for patients with N2 NSCLC after complete tumor resection, adjuvant radiotherapy did not significantly improve the recurrence rate and survival rate of patients after surgery, but it would significantly increase cardiotoxicity.

Therefore, the recently released guidelines for adjuvant treatment after complete resection of stage I~IIIB non-small cell lung cancer (2021 edition) clearly pointed out that adjuvant radiotherapy is not recommended for patients with NSCLC (N0~N2) after complete tumor resection.

In general, postoperative adjuvant therapy is an important component of treatment for reducing recurrence, prolonging survival and improving quality of life after complete resection of early and mid-term NSCLC.
From postoperative adjuvant chemotherapy to EGFR-TKI adjuvant targeted therapy, adjuvant therapy brings early There are increasing clinical benefits for patients with mid-stage NSCLC.

Among the various known NSCLC-driven gene mutations, EGFR mutations are the most important type of mutation.

Studies have shown that the positive rate of EGFR mutations in Asian patients with early and mid-stage lung adenocarcinoma is similar to that of late-stage lung adenocarcinoma, which is about 50%.
According to the current evidence-based basis, EGFR gene mutation testing is recommended for early- and mid-stage NSCLC patients, and based on EGFR mutation status.
Formulate adjuvant treatment strategies with tumor staging [19-20]. However, there are still many issues worthy of further exploration, such as the course of adjuvant targeted therapy, determination of the best adjuvant therapy plan, TKI toxicity management, etc.
We look forward to more studies to further optimize adjuvant therapy strategies for patients with early and mid-term resectable NSCLC Bring more clinical benefits. References: [1] Zheng Rongshou, Sun Kexin, Zhang Siwei, et al.
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