I. Treatment of limited-stage small cell lung cancer
Chemotherapy is an important treatment for patients with small cell lung cancer. About 60-90% of patients with limited-stage small cell lung cancer are sensitive to chemotherapy, and the overall efficiency of EP and CAV regimens in patients with limited-stage lung cancer is 75%-90%, with a complete remission rate of 50%. The advantage is clear. The substitution of carboplatin for cisplatin has not been fully evaluated, and it is generally believed that carboplatin should be used only when the toxicity of cisplatin is intolerable. Although chemotherapy has achieved high remission rates in limited-stage small cell lung cancer, it is often associated with considerable intrathoracic recurrence. and a 25.3% increase in intrathoracic disease control [5]. Another meta-analysis showed a 14% reduction in mortality and a 4% increase in 3-year overall survival for limited-stage small cell lung cancer in patients younger than 55 years of age with combination chemoradiotherapy [6]. A recent study found that EP regimens resulted in better survival improvement and lower esophagitis compared with previous regimens of cyclophosphamide and adriamycin combined with radiotherapy [7, 8], and the addition of a third chemotherapeutic agent such as paclitaxel did not improve survival [9]. The 2-year survival rate was 5% higher in the early participation group (within 9 weeks of chemotherapy initiation) compared to the late participation group (after 9 weeks), and subgroup analysis showed a greater advantage of twice-daily radiotherapy in combination with platinum-based chemotherapy [10].
If the lesion is confined to one side of the chest without mediastinal lymph node metastasis ((T1-2N0) surgical treatment is preferable to thoracic radiotherapy [11], but postoperative combination with adjuvant chemotherapy is required, and phase II clinical studies have shown that both preoperative and postoperative chemotherapy are feasible with 5-year survival rates of 10-50% [12]. Because 10-15% of small cell lung cancers have a mixed non-small cell lung cancer component, limited-stage small cell lung cancers that do not go into complete remission or recur after conventional chemoradiotherapy may be considered for surgical resection.
From the available evidence-based medical evidence, it can be concluded that the combination of radiotherapy and EP regimens is currently the best treatment option for patients with limited-stage small-cell lung cancer, and that early involvement of radiotherapy is preferable to late involvement (1-2 weeks after the start of chemotherapy), and that the toxicity of combination therapy, such as esophagitis, can be tolerated in patients with good PS scores. EP regimen has a response rate of 80-100% and a complete remission rate of 50-70%, and cisplatin and pegylated glycosides have synergistic effects.
First-line treatment of extensive-stage small cell lung cancer
Approximately 60-70% of SCLC patients are in extensive stage at the time of initial diagnosis, and combination chemotherapy remains the main treatment for extensive stage SCLC, which can extend the MST to 8-10 months. Despite the high remission rate with induction chemotherapy, most CR patients progress within 90 days. Moreover, the length of remission with first-line therapy is an important predictor of the efficacy of second-line therapy. Several new drugs and new combination chemotherapy regimens have been used in recent years for the treatment of extensive-stage SCLC, including isocyclophosphamide (IFO), topotecan (TPT), irinotecan (CPT-11), paclitaxel (PAX), gemcitabine (GEM), amiloride, pemetrexed, and other single-agent or combination regimens, but have not shown more evidence of significant advantages compared with EP regimens and often have increased toxicity due to multi-drug combinations. Conventional chest radiotherapy for extensive stage SCLC does not improve survival, and radiotherapy should only be used for prevention and treatment of brain metastases, spinal cord compression, palliative treatment after recurrence, and poor response to chemotherapy, superior vena cava syndrome, etc. However, if distant metastases are in complete remission in extensive stage small cell lung cancer, concurrent chemoradiotherapy of chest lesions may have survival benefit.
In 2002, Kazumasa Noda, a Japanese scholar, published in the New England Journal of Medicine the results of a randomized clinical study of extensive-stage small cell lung cancer [13], in which 230 patients with extensive-stage small cell lung cancer were randomly assigned to receive either the cisplatin + irinotecan regimen (IP) or the standard cisplatin + VP16 (EP) regimen of chemotherapy. the remission rate, median survival, and The remission rate, median survival and 2-year survival rates were 84%, 12.8 months and 19.5% for the IP regimen and 68%, 9.4 months and 5.2% for the EP regimen, respectively. However, a similar randomized phase III clinical trial by Nasser Hanna with 221 patients in the IP arm and 110 patients in the EP arm showed no survival improvement with the IP regimen versus the EP regimen, and the EP regimen showed more hematologic toxicity versus 3/4 diarrhea and vomiting with the IP regimen. The remission rates of 48% vs 43.6%, median TTP of 4.1 months vs 4.6 months, and median survival of 9.3 months vs 10.2 months for both did not reach the same conclusions as in Japan [14], maintaining the EP regimen as the standard of care for extensive-stage small cell lung cancer. However, the results of the IRIS study, a randomized phase III clinical study applying irinotecan + carboplatin versus oral VP-16 + carboplatin in the treatment of extensive-stage small cell lung, were presented at the 2007 ASCO annual meeting, with 220 patients enrolled and 210 patients evaluated, with an OS of 255 days vs 214 days in the IC and EC groups (p=0.04) and an overall survival HR of The HR for overall survival was 1.34, (95% CI: 1.01-1.79), 1-year survival rate was 35% vs 28%, with 18 CR cases in the IC group and 7 in the EC group (P=0.02). There was no statistically significant difference in the incidence of hematologic toxicity and diarrhea between the two [15].
Second-line treatment of recurrent or metastatic small-cell lung cancer
To date, evidence-based medical evidence for second-line chemotherapy for recurrent small cell lung cancer is limited, and it is generally accepted that selection of patients for second-line therapy should be based on the duration of the untreated interval, the response of first-line treated patients, the toxicity of first-line therapy, and the status of the patient’s PS score. The recently published randomized phase III clinical trial of topotecan and best supportive care group versus best supportive care group alone was the first clinical study in favor of the trial group and showed that the topotecan and best supportive care group was significantly better than the control group both in terms of overall survival, median survival, quality of life and improvement in symptoms [16].
Several randomized clinical trials have also studied different chemotherapy regimens in comparison, but in these studies the median survival of patients did not differ significantly. In a phase III clinical trial study by O’Bryan D in which patients enrolled in previous first-line treatment received CAV regimens or VP-16 [17], the median survival time was only 6 weeks and the general status of the patients was poor, and no benefit was found for patients in this trial. In contrast, in the study by VonPawel et al [18] most patients received previous first-line platinum-based combination chemotherapy and were treated effectively and had a time to relapse of more than 2 months after initial treatment, and patients enrolled were in good general condition, and this study showed an improvement in cancer-related symptoms in patients in the topotecan group compared to the CAV group, although there was no statistical difference, and the US FDA has approved single-agent The difference between these two phase III clinical trials may be attributable to differences in the general condition of the selected patients, as topotecan was used intravenously as second-line treatment for recurrent small cell lung cancer. Two studies compared the efficacy of oral versus intravenous administration of topotecan [19, 20], with remission rates of 18.3% and 23.1% in the oral group and 21.9% and 14.8% in the intravenous group, respectively, and both studies showed a higher incidence of diarrhea in the oral topotecan group, however, bone marrow suppression was more pronounced in the intravenous administration group, and both clinical studies showed that oral topotecan is a viable treatment for patients who are not Both clinical studies showed that oral topotecan is a viable option for patients who are not suitable for intravenous therapy. According to the NCCN 2007 clinical guidelines for small cell lung cancer, second-line chemotherapy for SCLC is preferred to clinical trials, and isocyclophosphamide, paclitaxel, doxorubicin, and gemcitabine are recommended for patients who relapse within 2-3 months after first-line therapy and have PS0-2; topotecan, irinotecan, the CAV regimen, and gemcitabine are recommended for those who relapse 2-3 to 6 months after first-line therapy. For patients who relapse 2-3 months to 6 months after first-line therapy, topotecan, irinotecan, CAV regimen, gemcitabine, paclitaxel, oral VP-16, and vincristine are recommended; for those who relapse 6 months after first-line therapy, the initial regimen is still recommended.
There is limited evidence that those patients with recurrent small cell lung cancer can benefit from second-line therapy. Poor PS scores and recurrence within 6 weeks of first-line therapy are currently considered poor prognostic factors for patients with small cell lung cancer, often suggesting low response rates to chemotherapy and short survival. An analysis of a subgroup of five clinical studies of monotherapy for recurrent small cell lung cancer showed that the evaluation of PS was particularly critical in the selection of treatment for recurrent small cell lung cancer and that patients with poor PS scores did not benefit from second-line therapy [21].
There is insufficient evidence to recommend a specific chemotherapy regimen for second-line chemotherapy, and it is generally accepted that those who relapse more than 3 months after the end of first-line treatment may benefit from the same initial regimen, with the majority of first-line regimens currently being EP regimens, with CAV and EC regimens also available. Topotecan may be a possible alternative for patients who have been in remission for 45 days or longer on first-line therapy. It is unclear whether topotecan should be administered orally or intravenously, with oral administration showing a higher 3/4 diarrhea and intravenous administration resulting in a higher 3/4 neutrophil decline. There is currently no standard second-line chemotherapy regimen for those who do not respond to first-line therapy or who relapse soon after first-line therapy. More clinical studies are needed to define the best treatment regimen for second-line therapy.
Prophylactic cranial irradiation (PCI) for small cell lung cancer
Brain is a common site of metastasis in small cell lung cancer, and due to improved long-term survival after treatment, brain metastasis has become a major site of metastasis. 20% of patients develop brain metastasis at initial diagnosis, and the rate of brain metastasis in SCLC patients with CR after treatment is as high as 50-67%.
A meta-analysis compiling 7 clinical trials of a total of 987 patients with limited-stage small cell lung cancer in complete remission after chemotherapy who underwent prophylactic brain irradiation showed a 5.4% increase in 3-year survival and a decrease in the incidence of brain metastases from 59% to 33%, and this study also found that a radiation dose of 30-36 GY and initiation of PCI 6 weeks after completion of chemotherapy had a tendency to further reduce recurrence of brain metastases [ 22]. Prophylactic brain irradiation for patients in complete remission is currently the standard of care for limited-stage small cell lung cancer.
At the 2007 ASCO Annual Meeting B. Slotman et al. reported at the Congress on behalf of the EORTC Radiation Oncology and Lung Cancer Group a randomized clinical trial [23] of a randomized controlled study of prophylactic brain irradiation in previously treated ED-SCLC patients in remission (EORTC 08993-22993), in which 286 patients who had previously had 4-6 weeks of chemotherapy and were effective Acute toxicity was mainly nausea and vomiting in 30% of patients in the PCI group and delayed mild headache in 30%, and PCI significantly reduced the incidence of brain metastases (P<0.0001< span="">, HR=0.27, CI: 0.16-0.44), with a cumulative incidence of brain metastases at 1 year of 14.6 The 1-year cumulative incidence of brain metastases was 14.6 % in the PCI group and 40.4 % in the control group, and significantly prolonged PFS (P=0.0218, HR=0.76, CI: 0.59-0.96) and OS (P=0.0033, HR=0.68, CI: 0.52-0.88). With 1-year survival rates of 27.1% and 13.3%, respectively, this study demonstrated the survival advantage of PCI in patients with extensive-stage small cell lung cancer in remission after chemotherapy.
V. Other treatments
(i) Maintenance and intensive therapy studies
A phase II clinical trial evaluated the efficacy of maintenance therapy with thalidomide in patients with extensive-stage small cell lung cancer who were treated with chemotherapy, with a median survival of 12.8 months (95% CI: 10.1- 15.8 months) in a total of 30 patients treated with thalidomide 200 mg orally daily for 3-6 weeks after the end of chemotherapy. M. Arnold et al. conducted a randomized phase II clinical trial of maintenance therapy with Vandetanib (ZD6474) in SCLC patients with effective induction chemotherapy (NCIC CTG BR.20.). The results of the study showed that maintenance therapy did not improve the survival of SCLC patients [25].
The current evidence suggests that maintenance consolidation therapy by dose-density chemotherapy, maintenance consolidation therapy and alternate application of non-cross-resistant chemotherapy regimens do not bring significant survival benefit to patients with small cell lung cancer compared with standard therapy.
(ii) Targeted therapy for small cell lung cancer
Most SCLCs express C-KIT protein, a member of the type III receptor tyrosine kinase family [26], and a study conducted in the Netherlands showed a lack of mutations in c-kit exon 11 in c-kit/Cd117-positive specimens, which may be a major reason for the insensitivity of SCLC to imatinib [27]. In another study, imatinib was not effective in 12 SCLC patients expressing c-kit.28 A phase II clinical study conducted by ECOG using the mTOR inhibitor Temsirolimus (CCI-779) in the treatment of extensive small cell lung cancer showed a median PFS of 2.2 months, which also did not yield good results.