I. Incidence The most common, oncology-related cause of death in Europe in 2006 was lung cancer (estimated 334,800 deaths). Lung cancer was the second most common neoplasm in men after prostate cancer, with age-specific incidence and mortality rates of 75.3 and 64.8/100,000/year for men and 18.3 and 15.1/100,000/year for women, respectively, in 2006. Small-cell lung cancer (SCLC) accounts for 15%C18% of all lung cancers, and the incidence of SCLC has gradually decreased in recent years. the occurrence of SCLC is highly correlated with smoking.
Second, the diagnosis should be made pathologically according to the WHO classification criteria. According to the location of tumor, bronchoscopy, mediastinoscopy, endoscopic ultrasonography, transthoracic needle aspiration biopsy and thoracoscopy can be chosen for biopsy. Metastasis biopsy can replace primary tumor biopsy. It is recommended to choose the least invasive examination method for biopsy.
Staging and risk estimation Staging evaluation items include medical history, physical examination, chest radiograph, routine blood, liver, kidney and lung function, lactate dehydrogenase, electrolyte testing, and CT scan of the chest and abdomen (including liver and adrenal glands). For patients with metastatic signs or symptoms, the following tests should be added: bone ECT, head-enhanced CT or MRI, and bone marrow aspiration biopsy. If a particular test determines extensive lesions, further staging may not be performed. If the patient undergoes radical radiotherapy, head CT/MRI is recommended .The role of combined FDG-PET/CT has been well established and facilitates accurate staging in certain patients.
The staging of SCLC has been based on the two-stage staging method developed by the Veteran’s Administration Lung Cancer Study Group (VALSG), which divides patients into limited stage and extensive stage. Limited stage is defined as a tumor that can be covered by a single irradiation field, and extensive stage is defined as a tumor that extends beyond a single irradiation field.
In 1989, the International Association for the Study of Lung Cancer (IASLC) revised the VALSG staging system, defining limited stage as a tumor that is confined to one side of the chest and can be accompanied by regional lymph node metastases (including ipsilateral and contralateral hilar lymph nodes, supraclavicular and mediastinal lymph nodes) and with ipsilateral pleural effusion. However, in most clinical trials of patients with limited-stage small cell lung cancer, contralateral hilar or supraclavicular lymph node metastases and malignant pleural or pericardial effusions are excluded. The IASLC recommends that small cell lung cancer be staged using the 7th edition of the Lung Cancer Staging Criteria. This recommendation is based on the following reasons: patients with limited N2 and N3 stages have different survival rates than patients with limited N0 and N1 stages; patients with pleural effusion have a prognosis between those with limited and extensive stages; and 3D conformal radiotherapy and intensity-modulated conformal radiotherapy require more precise lymphatic staging.
IV. First-line treatment
1.Limited stage
(1) Etoposide/platinum-based chemotherapy + thoracic radiotherapy is recommended for patients with limited stage, with preference for etoposide/cisplatin. A large meta-analysis and several randomized trials have shown that the 5-year survival rate of patients with limited stage is between 20% and 25% with early use of simultaneous radiotherapy, therefore, this group of patients has the possibility of cure.
(2) Thoracic radiotherapy increases local control and survival in patients with limited disease. A meta-analysis of 13 randomized trials with a total of 2140 cases showed that thoracic radiotherapy increased the 3-year survival rate from 8.9% to 14.3%.
(3) Timing of radiotherapy: The timing of radiotherapy for small cell lung cancer has been discussed in at least 8 trials and multiple meta-analyses, and the definitions of early versus late radiotherapy vary in this literature. The most commonly used time points are 30 days after the start of chemotherapy for early radiotherapy and 9 weeks after the start of chemotherapy for late radiotherapy. fried et al. reported a 2-year survival advantage for early radiotherapy, but this advantage disappeared at the 3-year time point; in one Cochrane meta-analysis, the difference between 2-year survival and 3-year survival was not statistically significant when the full trials were included in the analysis, however, when excluding a trial without platinum-based chemotherapy, the 5-year survival advantage over support for early thoracic radiotherapy (20.2% and 13.8% for early versus late radiotherapy, respectively); one meta-analysis suggested that only early radiotherapy improved survival when chemotherapy had reached a radical dose; another meta-analysis confirmed that if chemotherapy was completed within 30 days of the start of radiotherapy was completed within 30 days after the start of chemotherapy, the 5-year survival rate of patients was higher (RR:0.62,95% CI0.49C0.80,P=0.0003). In conclusion, most evidence suggests that early thoracic radiotherapy with simultaneous etoposide/platinum-based chemotherapy is superior to late thoracic radiotherapy.
(4) Radiotherapy dose splitting: Intergroup trial0096 compared twice daily versus once daily thoracic radiotherapy methods, resulting in a 5-year survival rate of 26% in the experimental group with a radiotherapy dose of 45 Gy, twice daily for 3 weeks, and 16% in the control group with a radiotherapy dose of 45 Gy, once daily for 5 weeks, which is the longest 5-year survival rate reported in a large sample randomized trial to date. the longest 5-year survival rate ever reported in a large sample of randomized trials. However, radiotherapy with 2 daily fractions has not been consistently implemented as the standard standard of care, possibly because of the inconvenience to patients of having 2 radiation treatments in 1 day. The biologic dose of 45 Gy once daily is lower than the same 45 Gy dose twice daily, and the toxicity of the experimental group differs from that of the control group, as shown in the trial, where the incidence of severe esophagitis was 27% and 11% in the 2-times-daily radiotherapy group versus the 1-times-daily radiotherapy group, respectively. The maximum tolerated dose of 2 daily radiotherapy + concurrent chemotherapy is considered to be 45 Gy for 30 sessions for 3 weeks, while the maximum tolerated dose of 1 daily radiotherapy + concurrent chemotherapy is 70 Gy for 35 sessions for 5 weeks. The trial conducted by the North Central Cancer Group did not show any survival advantage for the 48 Gy, 32 daily radiation regimens for 5.6 weeks over the 50.4 Gy, 28 daily radiation regimens for 5.6 weeks. However, the late chest radiotherapy, 2-times-per-day, stopping radiotherapy 2.5 weeks in the middle regimen may affect radiotherapy efficacy. In conclusion, it remains unclear whether a 2-times-daily radiotherapy regimen is superior to a 1-times-daily radiotherapy regimen if the biological effect dose is the same. A number of phase III trials are currently underway comparing the efficacy of a radiotherapy dose of 45 Gy twice daily for 3 weeks versus a once daily regimen with a higher dose of radiotherapy (e.g., 66 Gy/33f/6.6w). intergroup trial0096 concluded that the total duration of thoracic radiotherapy is important for the long-term survival of patients.
(5) Chest irradiation dose:The optimal radiotherapy dose is still undetermined because there are no randomized trials directly comparing chest irradiation doses. However, retrospective studies have shown that the local control rate increases with increasing irradiation dose. Several recent studies have concluded that a dose regimen of 60C70Gy/6C7W is feasible. Studies of total irradiation dose and total treatment time for SCLC are ongoing in Europe and the United States, but there is currently no information to support high irradiation dose thoracic radiotherapy except for clinical trials.
(6) Chest irradiation target volume: The optimal irradiation target volume remains unclear because the irradiation target volumes obtained from retrospective studies are not appropriate. Selective irradiation of mediastinal lymph nodes based on positive versus negative lymph nodes on CT images should be performed with caution, as one study showed that such selective irradiation of mediastinal lymph nodes resulted in isolated lymph node failure in 3 of 27 patients. The failure rate was low, i.e., only 2 out of 60 patients had isolated lymph node failure.
(7) Surgical treatment: For very early stage limited (i.e. T1-2,N0) patients, surgical treatment with postoperative adjuvant chemotherapy and prophylactic brain irradiation can be considered. Preoperative staging should include mediastinoscopy. There are no randomized trials comparing the efficacy of surgical treatment regimens with concurrent radiotherapy regimens.
2.Extensive stage
(1) Chemotherapeutic agents: Cisplatin or carboplatin + etoposide chemotherapy is recommended for patients in the extensive stage. The prognosis for patients in the extensive phase is extremely poor, with a median survival of only 10 months, a 2-year survival rate of 10%, and rare long-term survival. One of the largest, most recent randomized trials, which included both limited and extensive stage patients, concluded that cisplatin + etoposide chemotherapy improved survival in patients with small cell lung cancer. However, several meta-analyses of platinum-based chemotherapy over the past 30 years, including patients with limited and extensive disease, have yielded conflicting results. A meta-analysis of 19 randomized trials with a total of 4054 cases showed that patients treated with platinum-based chemotherapy had higher remission rates and longer survival; a recent Cochrane systematic review study, which included 29 randomized trials, showed that platinum-based chemotherapy compared with platinum-free chemotherapy, although the hazard ratio supported platinum-based chemotherapy, the two groups A meta-analysis of 36 randomized trials comparing etoposide +-cisplatin or carboplatin with chemotherapy without etoposide +-cisplatin or carboplatin showed a survival benefit that supported the use of etoposide alone or combination chemotherapy with cisplatin. Although there is some disagreement, most evidence supports that cisplatin or carboplatin + etoposide chemotherapy should be the standard of care. Carboplatin can be chosen for palliative chemotherapy in patients with extensive disease, while cisplatin is recommended for radical chemotherapy in patients with limited disease.
The results of trials comparing etoposide + cisplatin or carboplatin with topotecan or irinotecan + cisplatin or carboplatin in patients with extensive disease are conflicting. Topotecan or irinotecan is not recommended as first-line therapy. Two randomized trials comparing the efficacy of etoposide monotherapy orally with standard multidrug intravenous administration had similar results, namely that etoposide monotherapy orally was inferior to standard multidrug intravenous regimens in terms of survival, symptom control, and quality of life. Etoposide monotherapy orally is not recommended as a first-line treatment option. The addition of a third drug regimen to standard two-drug chemotherapy in patients with limited or extensive disease has not been uniformly shown to be beneficial.
(2) Duration of chemotherapy: Two trials have shown that 6 cycles of induction chemotherapy followed by maintenance chemotherapy does not improve survival in patients who are effective on induction chemotherapy. Four to six cycles of chemotherapy are recommended for both limited- and extensive-stage patients, and maintenance chemotherapy is not recommended in the absence of relevant clinical benefit.
(3) Dose intensity: The role of increasing the dose intensity of chemotherapy remains unclear; therefore, dose-intensity therapy is not recommended for patients with either limited or extensive disease, except in clinical trials.
(4) Prophylactic brain irradiation: Patients with either limited or extensive disease should be given prophylactic brain irradiation after completion of first-line therapy as long as it is effective for first-line therapy. In a recent trial comparing the efficacy of two different doses of prophylactic brain irradiation, 720 patients with limited stage in complete remission were randomized to either the 25 Gy/10f group or the 36 Gy/18f (or 36 Gy/24f) group, and as a result, mortality increased in the high-dose group and brain metastases did not decrease if the dose.