Overview
Primary lung cancer (hereafter referred to as lung cancer) is one of the most common malignant tumors in China. Data released by the National Cancer Center in 2015 showed that the 5-year prevalence of lung cancer in China from 2006 to 2011 was 130.2 (1 per 100,000). Among them, 84.6(1/100,000) were men, ranking the 2nd in malignant tumors. Women 45.61/100,000), ranking the 4th in malignant tumors.
The International Association for the Study of Lung Cancer (IASL) developed the eighth edition of tumor-node-metastasis (TNM) staging for lung cancer in 2015. The U.S. Medicare Surveillance, Epidemiology, and End Results (SEER) database shows that 57% of lung cancer patients have already developed distant metastases at the time of initial diagnosis, so treatment of patients with advanced disease is an important part of the lung cancer treatment system and the part that has seen the most progress in recent years.
Pathological diagnosis is the gold standard for lung cancer diagnosis, meanwhile, molecular genetic research on lung cancer has made remarkable progress in recent years, and molecular typing based on genetic characteristics has brought the treatment of advanced lung cancer into the era of individualized molecular targeted therapy. It is in this context that the World Health Organization (WHO) published a new classification of lung tumor histology in 2015. One of the most significant changes from the 2004 classification is the emphasis on the role of molecular genetics in the individualized treatment strategy for patients with advanced lung cancer.
Clinical presentation
Patients with advanced lung cancer may present with symptoms such as irritating dry cough, hemoptysis, chest pain, fever, and shortness of breath. When the tumor spreads within the chest and invades the surrounding tissues, it may lead to hoarseness, superior vena caval obstruction syndrome, Hornersyndrome, pleural effusion and pericardial effusion. In case of distant metastasis to brain, bone, liver, adrenal gland and other organs, it may cause clinical manifestations of metastasis to the corresponding organs.
In addition, some patients may develop paraneoplastic syndromes, including Cushing syndrome, syndrome of inappropriate antidiuretic hormone (SIADH), hypercalcemia, carcinoid syndrome and secondary proliferative osteoarthrosis, etc.
Physical examination
Some patients with advanced lung cancer may show signs such as pestle-like fingers (toes), male breast enlargement, dark skin or dermatomyositis and ataxia. When physical examination reveals vocal cord paralysis, superior vena cava obstruction syndrome, Horner’s syndrome and other manifestations, it is necessary to be alert to local invasion and metastasis of lung cancer. The presence of subcutaneous nodules and supraclavicular lymph node enlargement should be excluded from distant metastasis.
Staging
1.NSCLC
The current staging of advanced NSCLC is based on the IASLC 2009 7th edition staging criteria or the 2015 8th edition staging criteria. In the 7th edition, M1a includes pleural/pericardial effusion, contralateral or bilateral pulmonary nodules or pleural nodules; M1b refers to distant metastases [9]. M1a in the eighth edition of staging criteria includes pleural/pericardial effusion, contralateral or bilateral pulmonary nodules or pleural nodules; M1b includes isolated metastases from a single organ; M1c includes multiple metastases from a single organ or multiple metastases from multiple organs.
2.SCLC Currently, the staging of extensive stage SCLC can adopt the limited disease (LD) and extensive disease (ED) staging methods proposed by Veterans Administration Lung Study Group (VALG). The extensive stage is when the lesion extends beyond the same side of the chest and includes malignant pleural effusion, pericardial effusion and distant metastases. In recent years, IASLC has recommended TNM staging for SCLC along with NSCLC, and patients with extensive disease are all stage IV (Tany, Nany, M1a/M1b; including T3 and T4 multiple pulmonary nodules).
Treatment
(I) Treatment principles
Advanced lung cancer should be treated with a comprehensive treatment based on systemic therapy, and individualized treatment strategies should be formulated according to the patient’s pathological type, molecular genetic characteristics and the patient’s organism status, in order to maximize the patient’s survival time, control the degree of disease progression and improve the quality of life.
1.Treatment of advanced NSCLC
The principle of treatment for advanced NSCLC is a comprehensive treatment based on systemic therapy. Before the first-line treatment, tumor tissues should be firstly obtained to clarify the pathological typing and molecular genetic characteristics, and the treatment plan should be decided according to the test results.
Systemic therapy for patients with advanced NSCLC.
(1) First-line treatment with EGFR-TKIs is recommended for advanced NSCLC patients with EGFR gene-sensitive mutations and no drug-resistant genes, and first-line treatment with crizotinib is recommended for ALK fusion gene-positive patients.
(2) Patients with advanced NSCLC with EGFR-sensitive mutations and ALK fusion gene negativity or unknown mutation status should start systemic chemotherapy with a platinum-containing two-drug regimen as soon as possible if the Eastern Cooperative Oncology Group (EOCG) performance status (PS) score is 0 to 1 (see Table 1 for recommended chemotherapy regimens). For patients who are not suitable for platinum-based therapy, a non-platinum-based two-drug combination regimen chemotherapy may be considered. For appropriate patients, combination angiogenesis inhibitor therapy may be considered.
(3) Patients with advanced NSCLC with an ECOG PS score of 2 should be given single-agent chemotherapy, and chemotherapy with cytotoxic agents is not recommended for patients with an ECOG PS score ≥ 3. Best supportive care is recommended.
(4) Second-line treatment options include doxorubicin, pemetrexed and EGFR-TKIs. patients with EGFR gene-sensitive mutations and no combined drug-resistant mutations, if EGFRTKIs are not applied at first-line and maintenance therapy, EGFR-TKIs should be given priority at second-line therapy; for patients with negative EGFR gene-sensitive mutations, chemotherapy should be given priority.
Based on systemic treatment, appropriate local treatment can be chosen to improve symptoms and quality of life.
2.Treatment of extensive stage SCLC
Extensive SCLC should be treated with chemotherapy-based combination therapy. EP (etoposide combined with cisplatin), EC (etoposide combined with carboplatin), IP (irinotecan combined with cisplatin) and IC (irinotecan combined with carboplatin) are recommended for first-line treatment. Prophylactic cranial irradiation (PCI) may be considered in chemotherapy-naïve patients. If chemotherapy is effective and the distant metastases are controlled, radiotherapy of the chest lesion is feasible if the general condition is still good.
(II) Internal medicine treatment
1, chemotherapy for advanced NSCLC
(1)First-line chemotherapy
In China, vincristine, gemcitabine, docetaxel and paclitaxel combined with platinum are the most common platinum-containing two-drug combination chemotherapy regimens. For non-squamous NSCLC, pemetrexed in combination with cisplatin regimen is significantly more effective and better tolerated than gemcitabine in combination with cisplatin regimen. on May 4, 2014, CFDA approved pemetrexed in combination with cisplatin for the treatment of patients with locally advanced or metastatic non-squamous NSCLC.
Tegeo (S-1) in combination with cisplatin or carboplatin is a new first-line chemotherapy regimen for the treatment of advanced NSCLC. The results of the SC-103 trial conducted in China showed that the progression-free survival (PFS) and overall survival (OS) of the S-1 combined with cisplatin (SP) group were non-inferior to those of the docetaxel combined with cisplatin (DP) group for the first-line treatment of advanced NSCLC. The incidence of 3rd/4th degree neutropenic fever and neutropenia in the SP group was significantly lower than that in the DP group, but the drug has not yet been approved by the CFDA in China for the treatment of patients with advanced NSCLC.
The results of the phase III clinical trial showed that the overall efficiency of paclitaxel (albumin-bound) in combination with carboplatin was significantly higher than that of paclitaxel in combination with carboplatin in patients with advanced squamous lung cancer, while the overall efficiency of the two regimens was similar in patients with non-squamous NSCLC. The total efficiency of both regimens was similar in patients with non-squamous NSCLC. Subgroup analysis showed that for elderly patients aged >70 years, paclitaxel (albumin-bound) combined with carboplatin significantly improved OS compared with paclitaxel combined with carboplatin regimen.
In addition to this, the incidence of severe peripheral neurotoxicity and neutropenia was significantly lower in the paclitaxel (albumin-bound) than in the paclitaxel group. Therefore, on October 11, 2012, the US FDA approved the combination of paclitaxel (albumin-bound) and carboplatin for the treatment of patients with advanced NSCLC, but at present, China’s CFDA has not approved the drug for the treatment of advanced NSCLC.
(2) Maintenance therapy
Maintenance therapy can be chosen for patients with advanced NSCLC who have achieved disease control [complete remission (CR) + partial remission (PR) + stable disease (SD)] with first-line chemotherapy. Maintenance therapy is divided into same-drug maintenance therapy and maintenance therapy with drug changes according to whether or not the drug in the first-line chemotherapy regimen is followed. Pemetrexed can be used for maintenance treatment of non-squamous NSCLC with the same drug;
In addition, gemcitabine can also be used for co-drug maintenance therapy in NSCLC. Drugs used for maintenance therapy with drug exchange are docetaxel and pemetrexed for non-squamous NSCLC. Studies of pemetrexed for maintenance therapy in advanced NSCLC with switch showed that pemetrexed maintenance therapy after first-line platinum-containing regimen chemotherapy prolonged PFS and OS, and pemetrexed maintenance therapy after pemetrexed combined with cisplatin chemotherapy in patients with advanced non-squamous NSCLC significantly prolonged OS compared with placebo. studies of docetaxel for maintenance therapy only showed benefit in PFS and did not obtain prolongation of OS.
(3) Second-/third-line chemotherapy
Second-line chemotherapy options include docetaxel and pemetrexed for non-squamous NSCLC. Third-line treatment can be enrolled in clinical trials or given as best supportive care.
2.Chemotherapy for extensive stage SCLC
Because the biology of SCLC is different from other histological types, the extensive stage accounts for 2/3 of the diagnosis. chemotherapy is the most important treatment for extensive stage SCLC and is the first-line standard treatment for patients with extensive stage SCLC. For those with an ECOGPS score of 0-2, the recommended first-line chemotherapy regimens are EP, EC, IP or IC regimens. Clinical trials have demonstrated that IP regimens are not inferior to EP regimens in terms of efficacy in untreated patients with extensive stage SCLC.
For patients with extensive stage SCLC and ECOG PS score of 3-4, treatment regimens can be carefully selected based on the best supportive therapy and a comprehensive analysis of the patient’s tumor condition, organism condition, and the wishes of the patient and family, weighing the pros and cons. After first-line chemotherapy, if there are few systemic disseminated lesions, good disease control after treatment, ECOG
PS score of 0-2, selected patients can undergo chest radiotherapy; those who achieve CR with first-line treatment and ECOG PS score of 0-2 can be considered for PCI.
Patients with extensive stage SCLC with disease progression after or during first-line chemotherapy are selected for second-line chemotherapy or enrolled in clinical trials. Patients with relapse are clinically classified into 3 categories.
①Refractory relapse: disease progression during first-line chemotherapy;
②Resistant relapse: disease progression within 3 months after the end of first-line chemotherapy;
③Sensitive relapse: disease progression after 3 months after the end of first-line chemotherapy.
The efficacy of second-line chemotherapy is related to the patient’s response to first-line chemotherapy and the time from first-line chemotherapy to disease recurrence. Overall, second-line chemotherapy is less effective and in remission than first-line chemotherapy. those with effective first-line chemotherapy are more likely to benefit from rechemotherapy after disease progression. patients with refractory or drug-resistant relapses have poor efficacy to most drugs, with an efficacy rate of ≤10%, and those with sensitive relapses have an expected efficacy rate of approximately 25%. patients with disease relapse progression within 3 months are recommended to participate in clinical trials.
Topotecan, irinotecan, gemcitabine or paclitaxel are recommended for relapses within 3 months-6 months. chemotherapy regimens for initial treatment are available for those with disease progression after 6 months.
3.Anti-angiogenic drug therapy
(1) Recombinant human vascular endothelial inhibitor (rh-endostatin, Endo): The results of the phase I I clinical trial showed that combining Endo with first-line chemotherapy with vincristine and cisplatin significantly prolonged the efficiency and median time to progression (TTP) of patients with advanced NSCLC, with no significant difference in toxic side effects between the two groups. approved Endo in combination with chemotherapy for the treatment of patients with stage III/IV NSCLC.
(2) Bevacizumab: The results of both the ECOG 4599 study [19] and the BEYOND study showed that combination chemotherapy with bevacizumab followed by maintenance treatment with bevacizumab on top of first-line chemotherapy with paclitaxel in combination with carboplatin regimen significantly prolonged OS and PFS in advanced non-squamous NSCLC. the AVAPERL study The results showed that pemetrexed combined with cisplatin and bevacizumab chemotherapy followed by 4 cycles of two-drug maintenance with pemetrexed combined with bevacizumab significantly prolonged PFS compared to bevacizumab monotherapy maintenance.
On July 9, 2015 CFDA approved bevacizumab in combination with carboplatin and paclitaxel for the first-line treatment of patients with unresectable advanced, metastatic or recurrent non-squamous NSCLC.