Advances in comprehensive treatment of small cell lung cancer
Small cell lung cancer (SCLC) accounts for about 15%-20% of all lung cancers and is classified as bronchopulmonary neuroendocrine carcinoma, which is the most common and the worst prognosis among them [1]. Patients who do not receive treatment often die within 2-4 months. Although initially treated patients are more sensitive to chemotherapy, they are prone to resistance and recurrence and are relatively insensitive to second-line chemotherapeutic agents, resulting in a poor prognosis. The median survival (MST) of patients with limited-stage SCLC is 16-22 months, and the 5-year disease-free survival (DFS) is about 20%, while the MST of patients with extensive-stage SCLC is only 10 months and the 5-year DFS is only 2% after combined chemotherapy. The 5-year DFS is only 2%. The comprehensive treatment of small cell lung cancer involves chemotherapy, radiotherapy and other means. Over the years, research has established certain comprehensive treatment norms, and in recent years, new anti-tumor drugs and targeted therapy have also been actively explored. Gao Tianhui, Department of Medical Oncology, Henan Provincial People’s Hospital
Chemotherapy for limited-stage small cell lung cancer
Chemotherapy is the main treatment for patients with small cell lung cancer. About 60%-90% of patients with small cell lung cancer in the limited stage are sensitive to chemotherapy, and 45% -75% can reach CR. The EP regimen with cyclophosphamide, adriamycin, and vincristine and the CAV regimen consisting of cyclophosphamide, adriamycin, and vincristine have an overall efficiency of 75%-90% and a complete remission rate of 50% in patients with limited stage, so these two regimens have been used in the treatment of patients with limited stage. This established the EP regimen as the standard first-line treatment option for patients with limited-stage small cells. The substitution of carboplatin for cisplatin has not been adequately evaluated, and a randomized phase III clinical study suggested that carboplatin in combination with pegylated glycosides was as effective as cisplatin in combination with pegylated glycosides, with lower toxicity, including hematologic and non-hematologic toxicity, than the latter [2]. SCLC patients including 241 cases received gemcitabine plus carboplatin (GC) or etoposide plus cisplatin (EP), respectively, resulting in no difference in overall survival, median survival, and median disease-free survival between the two, with a higher incidence of hematologic toxicity in the former and a higher incidence of alopecia and nausea in the latter [3]. It can be used as an alternative treatment for patients who cannot tolerate GI reactions and alopecia.
Chemotherapy for extensive-stage SCLC
Combination chemotherapy remains the mainstay of treatment for extensive-stage SCLC, although initial treatment has a high remission rate and can extend median survival to 8-10 months, and most patients will progress in the short term. 20 years ago, the EP regimen was established as the standard of care for SCLC, with remission rates of 70%-85% and complete remission rates of 20%-30% for extensive-stage SCLC. A multicenter randomized phase III clinical study in Japan compared the efficacy of IP (irinotecan in combination with cisplatin) with EP (etoposide in combination with cisplatin) for the treatment of extensive-stage SCLC, resulting in remission rates of 84.4% (IP) and 64.5% (EP), median survival times of 12.8 months (IP) and 9.4 months (EP), respectively (P=0.002), and 2-year survival rates of The results of a similar randomized phase III clinical trial by Hanna et al. including 331 patients with extensive SCLC showed that the IP regimen did not improve survival compared with the EP regimen, and the efficacy of the two regimens was comparable [5], which maintained the efficacy of the EP regimen for the treatment of extensive SCLC. The results of this study maintain the standard status of the EP regimen for the treatment of extensive SCLC, and the IP regimen has the potential to become an alternative to the standard EP regimen.
Two-drug regimens have been shown to remain more effective than single-drug regimens in older adults with poorer PS status [6-8]. The addition of a third agent improves response rates compared to EP regimens, but produces higher toxicity and does not improve survival [9-12]. Any chemotherapy regimen beyond 4-6 cycles does not benefit, and maintenance therapy or topotecan therapy after 4 cycles of EP regimen does not improve survival [13, 14]. Increasing the dose intensity of chemotherapy also failed to translate into prolonged survival [15]. bcl-2 is thought to have an important role in tumorigenesis and chemoresistance in SCLC, and the application of bcl-2 antisense oligonucleotide oblimersen in combination with EP regimens for extensive stage SCLC did not increase efficacy and increased toxicity compared to controls [16]. The new drug did not show better efficacy than the old one. Where possible, patients are encouraged to participate in clinical trials to further improve efficacy and improve survival.
Chest radiotherapy
Combination chemotherapy alone was for some time the standard of care for limited-stage small cell lung cancer. Despite the sensitivity to chemotherapy and the high remission rate of limited-stage small cell lung cancer, it is often associated with a high rate of intrathoracic recurrence. A prospective randomized clinical study conducted in the 1980s showed that the combination of chemoradiotherapy had significant advantages over chemotherapy alone in terms of local control rate, failure-free survival, and overall survival for patients with limited stage, and that toxicity, although increased, was tolerable[17] . Meta-analysis of 11 randomized controlled studies showed that patients with limited-stage disease who received chest radiotherapy in combination with chemotherapy had a 5.4% (95% CI, 1.1% -9.7%) increase in 2-year survival, with 9 studies with local control rates showing a 25.3% (95% CI, 16.5% -34.1%) increase in intrathoracic disease control with radiotherapy [18]. A Meta-analysis of 13 randomized clinical trials including 2140 patients with limited-stage small cell lung cancer published in the New England Journal of Medicine in the same year showed that the addition of thoracic radiotherapy reduced mortality by 14% and increased 3-year survival by 5.4%, with a more significant benefit for patients younger than 55 years [19]. For limited-stage SCLC, EP combined with radiotherapy had better efficacy than CAV combined with radiotherapy, with median survival of 14.5 and 9.7 months, respectively (P = 0.001). The 2- and 5-year survival rates were 25% and 10% in the EP group and 8% and 3% in the CAV group (P = 0.0001) [20]. Synchronous chemoradiotherapy reduced distant metastases more than sequential chemoradiotherapy (26% vs. 63%; P = 0.008) [21]. 231 LS-SCLC cases were randomized to synchronous and sequential chemoradiotherapy, both receiving 1.5 Gy of chest radiotherapy twice daily for 3 weeks and 4 cycles of EP regimen chemotherapy, with the synchronous group starting radiotherapy on day 2 of chemotherapy and the sequential group starting radiotherapy after 4 cycles of chemotherapy. The median survival time was 27.2 months in the synchronous group and 19.7 months in the sequential group, strongly suggesting that synchronous radiotherapy is superior to sequential radiotherapy [22]. For the randomized clinical trial containing 417 cases of limited-stage SCLC with EP combined with synchronized radiotherapy showed that twice-daily overdrive chest radiotherapy significantly improved survival compared with once-daily radiotherapy, with median survival of 23 and 19 months, respectively, and 2- and 5-year survival rates of 47% and 26% for the former and 41% and 16% for the latter [23].Meta analysis suggested that early addition of thoracic radiotherapy improved 2-year overall survival more than delayed addition, especially for the combination of hyper-segmented radiotherapy and chemotherapy with platinum-containing regimens, and that early than late radiotherapy improved survival more significantly [24]. A retrospective clinical study from Japan analyzed limited-stage small cell lung cancer with ipsilateral pleural effusion, and in patients who received first-line induction chemotherapy for effusion disappearance, some chose radiotherapy and some did not, resulting in a median survival time of 19.2 months in the chemoradiotherapy group but 10.5 months in the chemotherapy group, with two-year survival rates of 38% and 25%, respectively, suggesting that patients with limited-stage small cell lung cancer patients with pleural effusion, longer survival can be achieved with the addition of radiotherapy after induction chemotherapy to make the effusion disappear [25].
Prophylactic brain irradiation and treatment of brain metastases
The brain is a good site of metastasis in SCLC, and for limited-stage SCLC treated with combined chemotherapy and chest radiotherapy, the median survival is about 18 months, with a 2-year survival rate of about 25%, and after patients achieve complete remission, about 15% develop brain metastases, and the median survival after developing brain metastases in SCLC is only 3-5 months. There has been controversy as to whether PCI should be performed in patients in complete remission. A study from France analyzed the profiles of 987 patients with small cell lung cancer who achieved CR in 7 clinical trials, comparing the survival of those who received prophylactic cranial irradiation (PCI) versus those who did not, resulting in a 5.4% increase in 3-year survival for those who received PCI (15.3 % vs. 20.7%) and increased disease-free survival (rr, 0.75; 95% CI, 0.65 to 0.86; P<0.001) and decreased the incidence of cumulative brain metastases (rr, 0.46; 95% CI, 0.38 to 0.57; P<0.001) [26]. PCI given to patients in complete remission has now become the standard of care for limited-stage SCLC. In a randomized controlled phase III clinical study from Amsterdam, the Netherlands, which analyzed 286 patients with extensive stage small cell lung cancer who responded to chemotherapy, the risk of symptomatic brain metastases was reduced in those who underwent PCI (HR = 0.27 (95% CI: 0.16-0.44; p < 0.001)), and the cumulative incidence of brain metastases within 1 year of PCI was incidence was 15% compared with 40% in the control group, and PCI prolonged disease-free survival (HR = 0.76; 95% CI: 0.59-0.96, p = 0.02) and overall survival (HR = 0.68; 95% CI; 0.52-0.88, p = 0.003). The 1-year survival rate reached 27% in the PCI group compared to 13% in the control group [27], suggesting that for patients with extensive-stage small cell lung cancer, they would also benefit from receiving prophylactic brain irradiation after the effectiveness of primary chemotherapy. The main reason that hinders the implementation of PCI is the fear of decline in central biblical function due to PCI, and neurocognitive function tests performed before and after PCI in patients with small cell lung cancer who responded to chemotherapy suggest that there is a significant and transient decline in executive and language function early after PCI, and that this deficit will no longer be evident if the progression of non-CNS disease is controlled, and that this difference no longer continue, with significant improvements in language and motor coordination later in life. Multifactorial analysis did not reveal a significant difference before and after PCI [28]. Abbreviated PCI treatment due to concerns about neurotoxicity is not advocated. In patients who have developed brain metastases, there is no disagreement about the role of radiotherapy in reducing symptoms and improving survival, so what about the role of chemotherapy in brain metastases? A phase II clinical study of an efficacious sample in the United States showed that irinotecan combined with carboplatin for the treatment of brain metastases from small cell lung cancer had an efficiency of 65% [29], which initially showed the place of chemotherapy in the treatment of brain metastases, and further studies are needed.
Treatment of recurrent refractory cases
Although small cell lung cancer has a high remission rate, most face recent recurrence, and the prognosis for patients with recurrence is poor, but there is evidence of a survival benefit from salvage therapy for appropriate patients. Topotecan is the only drug approved by the US FDA for second-line treatment, with an RR of 10%C40% and a median survival time of 6 months, but heavy myelosuppression [30, 31]. Several new drugs are being evaluated and present positive results. One of the most promising drugs is amilorubicin, a third-generation synthetic anthracycline analogue and a potent topoisomerase II inhibitor, which was combined with irinotecan to treat 13 cases of primary ED-SCLC even achieving an ORR of 100%, MST of 17.4 months and 1-year survival rate of 76.9%, showing a good application of this drug in anti-SCLC prospect [32]. A recent retrospective small sample clinical study showed that amrubicin alone had RRs of 59%, 50%, 100%, and 46% for overall, primary, primary-sensitive and recurrent, and refractory recurrent extensive-stage small cell lung cancer, respectively, and RRs of 50%, 33%, and 69% for doses of 30 mg/m(2), 35 mg/m(2), 40 mg/m(2), and 45 mg/m(2), respectively. were 50%, 33%, 69%, and 100%, respectively, with no difference in toxicities between doses and a median survival time of 230 days for recurrent cases, suggesting that amrubicin alone is an effective agent not only for first-line treatment of extensive-stage small cell lung cancer, but also for second-line treatment of recurrent cases [33]. A Japanese multi-center, phase II clinical study evaluated second-line treatment with amrubicin in 60 patients with refractory recurrence (16) and sensitive recurrence (44) of SCLC, resulting in overall response rates of 50% and 52% and disease-free survival, overall survival, and 1-year survival rates of 2.6 and 4.2 months; 10.3 and 11.6 months; and 40% and 46%, respectively. Phase II clinical studies have shown that high-dose pemetrexed has limited efficacy in the second-line treatment of SCLC [35].
Summary
Since the establishment of the EP regimen as the standard chemotherapy regimen for small cell lung cancer more than 20 years ago, the efficacy of small cell lung cancer has improved significantly and remains the cornerstone of comprehensive SCLC treatment today. After more than 20 years of efforts, a series of advances have been made in the comprehensive treatment of small cell lung cancer, including the addition of chest radiotherapy to chemotherapy for limited-stage SCLC, the superiority of twice-daily radiotherapy over single radiotherapy, PCI after complete remission for limited-stage SCLC, and a 5%-10% increase in overall survival with each new progression. Additional local radiotherapy may prolong survival in patients with stage II SCLC who achieve CR after chemotherapy, and additional PCI may reduce the incidence of brain metastases and improve survival in patients with extensive stage II SCLC who achieve CR after chemotherapy. To further improve the efficacy, new drugs and new combination therapy regimens have been actively explored. The combination of irinotecan and cisplatin has achieved efficacy at least not inferior to that of EP regimens, and may be used as an alternative regimen for extensive SCLC. Clinical studies have also identified a promising anti-SCLC drug, amiloride. However, the efficacy of pemetrexed is limited, and the combination regimen of increasing dose intensity and adding a third drug has failed to improve survival, and the long-term survival rate of SCLC remains low.