Small cell lung cancer (SCLC) accounts for about 20-25% of lung cancers, and according to recent epidemiological data, this type has a decreasing trend.SCLC is caused by malignant transformation of lung Kulchitsky cells, which are subdivided into oat cell, intermediate cell and mixed cell types by WHO [2]. The disease is more prevalent in males than females; the site of onset is predominantly the large bronchi (central type). The clinical characteristics are: short multiplication time and rapid progression of tumor cells, often accompanied by endocrine abnormalities or carcinoid syndrome; since patients have early hematogenous metastases and are sensitive to radiotherapy, the treatment of small cell lung cancer should be mainly systemic chemotherapy, combined with radiotherapy and surgery as the main treatment means. Comprehensive treatment is the key to the success of small cell lung cancer treatment. SCLC has high malignancy, rapid development, and extensive distant metastasis in early stage. 70-90% of patients have clinical or subclinical lymphatic or hematologic metastasis when diagnosed, and the natural course of the disease is short. Localized SCLC can be treated with chemoradiotherapy with RR 65-90%, CR 45-75%, MST 10-16 months, and 5-year survival rate 18-51%; extensive SCLC can also achieve RR 70-85%, CR 20-30%, MST 6-12 months, and 5-year survival rate 1-2%.
Chemotherapy US NCCN guidelines, for SCLC.
First-line chemotherapy regimens include ① limited-stage EP regimen (DDP/VP-16), CE regimen (CBP/VP-16), combined with radiotherapy. ② In addition to EP and CE regimens, DDP/CPT-11 regimens can be adopted in the extensive stage.
The second-line chemotherapy regimen should be preferred to clinical new drug trials; if the tumor recurs within 3 months and the patient is in good health, paclitaxel, doxorubicin, Jianzuo (gemcitabine) and isocyclophosphamide can be considered; if the tumor recurs more than 3 months, topotecan, irinotecan, CAV regimen (CTX/ADM/VCR), Jianzuo, paclitaxel, oral VP-16 or norvasc can be considered; if the tumor recurs more than 6 months, topotecan, irinotecan, CAV regimen (CTX/ADM/VCR), Jianzuo, paclitaxel, oral VP-16 or norvasc can be considered. If the tumor has recurred for more than 6 months, the first-line treatment regimen can still be maintained.
First-line chemotherapy regimens: commonly used include caV, VP16+DDP/CBP, IFO+VP16+DDP, CAV has stronger myelotoxicity than the other two regimens! Second-line regimens: Non-cross-resistant regimens can be used.
(1) If the original CAV can be changed to EP/IEP, there is about 15-20% efficiency.
(2) If the original EP can be changed to CAV, but only 7% of the efficiency, so the EP failure is not advocated to use CAV. second-line program new progress: now there is a new drug TOPOTECAN introduced, in the international become the main second-line chemotherapy drugs! But the bone marrow is more toxic, so be careful with it! In addition, there are many studies on non-small cell lung cancer regimens that have achieved certain efficacy. The most notable is CPT-11+DDP, which has achieved very good results in Japan. Additional drugs include: paclitaxel, doxorubicin, etc.
The efficiency of second-line chemotherapy in patients with recurrent SCLC depends mainly on the time from remission after first-line treatment to tumor recurrence. Patients who do not respond to first-line therapy or who are in remission for less than 3 months after first-line therapy are highly resistant to chemotherapy and usually do not respond to any cytotoxic drugs. The aim of first-line therapy is to kill chemotherapy-sensitive cells. The drug efficiency of salvage therapy for refractory tumors is less than 10%, and survival is usually several weeks after second-line therapy. On the other hand, the efficacy of second-line therapy can be increased if the time between remission and progression is longer than 3 months, which is also known as “sensitive” SCLC, and the efficacy is likely to increase as the time between remission and progression increases.
Combination chemotherapy has a higher efficiency than monotherapy: For example, a 4-drug combination of CODE (DDP, VCR, ADM, VP-16) has an 88% efficiency in recurrent SCLC, but this regimen does not show a higher efficiency than standard combination chemotherapy in first-line therapy, and the feasibility of this regimen is unclear because of its toxic side effects. For patients who have received CTX, ADM and VCR/VP-16 combined with DDP as first-line treatment, VP-16, IFO combined with DDP regimen may have 55% efficiency. Whether to apply these combination regimens should be individualized according to the patient’s specific situation, such as the patient’s physical condition, time to recurrence, major organ function, etc.
In SCLC patients with disease progression after standard first-line chemotherapy and relapse within 3 months after completion of initial chemotherapy, various chemotherapy regimens were disappointing (efficiency <10%). Their best options are supportive care, palliative radiotherapy, and inclusion in clinical trials. For patients with disease progression greater than 3 months after chemotherapy, second-line chemotherapy may be more effective, especially with the recommended regimens of CAE,CAV,CBP/PTX,VP-16/IFO/DDP, but with shorter remission times.
Radiotherapy
Dose and modality of radiotherapy
For small cell lung cancer, conventional radiotherapy of 1,8-2Gy/day is mostly used, with a total of 5 weeks of radiotherapy once a day, and the total dose is about 50 Gy. Chemotherapy is used as induction chemotherapy before radiotherapy or maintenance chemotherapy after radiotherapy. Phase I and II trials of accelerated hyper-segmentation and simultaneous chemotherapy are underway, showing that early side effects are mostly tolerated, but no long-term survival rates have been reported. The foreign ECOG/RTOG study compared the results of chest radiotherapy with a total dose of 45 Gy once a day for 5 weeks and twice a day for 3 weeks. Both groups were treated with concurrent chemotherapy with EP regimen, showing that hyper-segmentation radiotherapy improved survival and survival rates and reduced local recurrence rates. Median survival increased from 19 to 23 months, 1-, 2-, and 5-year survival rates increased from 63%, 44%, and 16% to 67%, 47%, and 26%, and local recurrence rate decreased from 52% to 36%. However, the disadvantage was the increased incidence of radiation esophagitis in the hyper-segmentation radiotherapy group.
In the same retrospective analysis of the SWOG findings, the local recurrence rates were 43% and 69% in the appropriately and inappropriately irradiated field groups, respectively, P=0,04. The above clinical reports tend to support large field irradiation whereas the irradiation field used in the clinical study of Intergroup trial 0096(11) in the United States was 1,5 cm outside the tumor margin, ipsilateral to the hilum. The mediastinum was irradiated from the thoracic inlet to the inferior ramus, without prophylactic irradiation of the contralateral hilum and bilateral supraclavicular region, which is said to have been widely adopted in clinical studies in North America and Europe. Definition of “large field irradiation”: For example, in cases of primary lesions with ipsilateral hilar and mediastinal lymph node metastases, the volume of irradiation should include: 2 cm beyond the tumor margin, the left and right hilar regions, the mediastinum (thoracic inlet to inferior ramus) and the bilateral supraclavicular region.
Timing-order of radiotherapy ,
Radiotherapy to improve the survival rate of LD SCLC is related to the timing of treatment, i.e., the timing in combination with chemotherapy. (1) Evidence from studies in Canada, Japan, and Yugoslavia supports early radiotherapy.(2) The results of the CALGB study showed that late radiotherapy was superior to early radiotherapy, but there was a confounding factor of reduced chemotherapy dose in the early radiotherapy group in this study. (3) There is no evidence to support starting radiotherapy after all chemotherapy has been completed.(4) For some special clinical situations, such as large tumors, combined with impaired lung function and obstructive pulmonary atelectasis, 2 cycles of chemotherapy followed by radiotherapy is reasonable. This is easy to clarify the lesion extent and reduce the irradiation volume, so that patients can tolerate and complete radiotherapy brain irradiation
The brain is the site of distant metastases in SCLC, and the incidence can be as high as 50%. In recent years, with effective systemic chemotherapy and thoracic radiotherapy, the number of patients with long-term survival of limited-stage SCLC has increased significantly, and some data show that the 5-year cumulative CNS metastasis rate of patients with more than 2 years of survival is as high as 80%; some people summarize more than 200 patients, the median time from the diagnosis of SCLC to brain metastasis: 8,01 months, and the median time from the diagnosis of brain metastasis to death: 2,21 months. Therefore, the question of prophylactic brain radiation (PCI) was raised. Studies have shown that PCI is better performed after CR and not in patients with PR, and that PCI is better performed after completion of chemotherapy than before completion of chemotherapy. There are two previous views on whether to do PCI in patients with limited-stage SCLC who have reached CR: the negative view is that the prophylactic use of brain radiotherapy is not recommended and that brain radiation should be administered after the development of brain metastases, based on the following reasons.
(1) More than 90% of brain metastases are accompanied by metastases from other organs
(2) Radiotherapy after the appearance of brain metastases can still achieve a good palliative effect
(3) PCI is associated with radiation brain damage
(4) A small percentage of patients still have brain metastases again after PCI, when the brain damage from re-radiation increases, and the effect of chemotherapy is not good. However, many studies in recent years have shown that: and most of the previously classified radiation brain damage existed before radiotherapy, PCI should be performed after CR for limited-stage SCLC, and PCI improved disease-free survival and overall survival of SCLC patients, improved 2- and 3-year survival rates of SCLC patients (3YS15,3% to 20.7%), and reduced the incidence of 2-year cumulative brain metastases (which could from 67% to 40%), and PCI is recommended at the end of chemotherapy for patients with limited stage SCLC in CR.
Analysis of cerebral prophylactic irradiation (PCI) irradiation doses (8Gy, 24-25Gy, 30Gy, 36-40Gy) in cases in complete remission from radiotherapy showed (1) a trend of decreasing brain metastasis rate with increasing dose (2) timing of irradiation: a trend of low brain metastasis rate with early PCI administration (3) analysis did not show a significant effect of PCI on intelligence
Surgical treatment
A number of foreign lung cancer collaborative groups have conducted numerous clinical trials. All patients with small cell lung cancer were given preoperative induction chemotherapy first, and those with effective induction chemotherapy were then treated surgically, followed by postoperative supplemental chemotherapy and chest radiotherapy. The preoperative induction chemotherapy ranged from 2 to 4 weeks, and the total chemotherapy efficiency was above 88%. Surgical treatment is feasible for 60-70% of patients with effective preoperative induction chemotherapy. Radical resection is possible in more than 80% of them.
The ability of preoperative induction chemotherapy to improve the cure and survival rates of small cell lung cancer has been confirmed by numerous clinical trials. The postoperative survival rate is closely related to its TNM stage, with a better 5-year survival rate of 70% for stage 1 and a median survival time of 20-33 months and a 5-year survival rate of 20%-30% for stage 2 and 3 patients after comprehensive treatment. Long-term survival after induction chemotherapy is mostly possible in patients with radical lobectomy, while patients who still need total pneumonectomy after induction chemotherapy have a low 5-year survival rate of less than 10%.
There is no uniform standard on how to continue multidisciplinary comprehensive treatment after surgery. The generally accepted principle is that except for surgical resection specimens with no residual tumor cells and no distant metastases, all other cases should be treated with chemotherapy-based comprehensive therapy according to the postoperative pathological stage.
For those who cannot be operated, multidisciplinary comprehensive treatment should be used.
Specific markers
Small cell lung cancer markers should have diagnostic sensitivity and specificity. Currently, neuron-specific enolase (NSE for short) is a good tumor marker for small cell carcinoma, but there are some shortcomings. Such deficiencies include low positive rate in early stage patients, positive results in non-small cell lung cancer, false positives in hemolyzed specimens, and less significant differences between normal healthy individuals and small cell lung cancer. If the treatment is effective, the NSE level in the patient’s body can be reduced to within the normal range after one or two courses of chemotherapy. Exponentially increasing NSE levels are a reliable precursor to recurrence, and NSE levels are most valuable in assessing the prognosis of SCLC patients on treatment, but cannot predict when recurrence will occur. In recent years, Pro-Gastrin-ReleasingPeptide31-98 (ProGRP) has become another good marker for small cell lung cancer. As a new marker for small cell lung cancer, ProGRP has high sensitivity and specificity with positive predictive value and negative predictive value above 90%, and the positive rate for limited stage lesions is also higher than that of NSE, which improves the possibility of early diagnosis to some extent, and provides valuable information for post-chemotherapy response, evaluation of efficacy, disease monitoring during the course of the disease and prognosis determination.