*For medical professionals only
How can patients with ES-SCLC benefit more? The CSCO guidelines recommend this.
Lung cancer ranks first in the incidence and mortality of malignant tumors in mainland China[1], seriously endangering the health of mainland residents. According to the differences in histopathological types, lung cancer is divided into two categories: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). SCLC accounts for approximately 15% of lung cancers[2], while two-thirds of SCLC is diagnosed with broad-stage SCLC (ES-SCLC)[3]. Although SCLC responds well to chemotherapy initially, it is highly prone to recurrence and is susceptible to drug resistance. Over the past few decades, chemotherapy has limited overall survival for SCLC patients. Until the advent of immunotherapy, a new chapter in SCLC treatment was opened, bringing new therapeutic hope.
In the 2021 edition of the Chinese Society of Clinical Oncology (CSCO) Guidelines for the Diagnosis and Treatment of Small Cell Lung Cancer[4], how is ES-SCLC first-line treatment recommended? The Medical Oncology Channel specially invited Professor Lu Dehong of Changtu County Central Hospital in Liaoning Province and Professor Zhang Zheng of Luotian County People's Hospital in Hubei Province to share.
2021 CSCO Guidelines ES-SCLC First-Line Treatment Recommendations
Chemotherapy is the foundation
Etoposide plus cisplatin and carboplatin (EP/EC regimen) is the standard regimen for first-line therapy with ES-SCLC, and irinotecan plus platinum regimen is also an option for first-line therapy. In patients without local symptoms and without brain metastases, if the PS score is 0 to 2, or the PS score is 3 to 4 (due to SCLC), chemotherapy plus immunotherapy or chemotherapy alone may be chosen. For patients with complete remission (CR) or partial remission (PR), chest radiotherapy or prophylactic brain radiotherapy is recommended. For patients with a PS score of 3 to 4 who are not SCLC-induced, optimal supportive care is recommended.
For patients with local symptoms, if there is superior vena cava syndrome, radiation therapy + chemotherapy is recommended; if there is spinal cord compression, local radiotherapy is recommended to control compression symptoms + chemotherapy; if there is bone metastases, radiation therapy + local palliative external beam radiation therapy is recommended, and patients with high risk of fractures can be treated with orthopedic fixation. For patients with CR or PR, prophylactic brain radiotherapy is recommended.
Table 1 ES-SCLC first-line treatment recommendations
Immunotherapy breaks through the bottleneck of ES-SCLC treatment
In recent years, immune checkpoint inhibitors (ICIs) have become the standard first-line treatment choice for many tumor types, and with the increasing application value of immunotherapy in the field of lung cancer treatment, it provides a new direction and idea for the treatment exploration of ES-SCLC. PD-L1 combination chemotherapy has become the new standard for first-line treatment of broad-stage small cell lung cancer recommended by guidelines.
At present, there are two PD-L1 inhibitors approved in the field of SCLC in China, namely dovalibularizumab and atenibizumab, the main clinical studies of the two, the CASPIAN study of duvallizumab and the IMpower133 study of atenizumab have reached the main endpoints, which have brought benefits to patients with ES-SCLC.
ES-SCLC immunotherapy shines
The 2019 World Conference on Lung Cancer (WCLC) published a CASPIAN study in which the median overall survival (OS) of ES-SCLC in the first-line treatment of duvalliumab combined with chemotherapy was 13 months, setting a new survival record [5]. At median follow-up of 25.1 months, the OS in the duvalizumab plus chemotherapy group continued to benefit (12.9 months vs 10.5 months, HR 0.75, P=0.0032) compared with the chemotherapy group, with a two-year survival rate of 22.2%, that is, duvalliumab combined with chemotherapy enabled nearly one-fourth of patients to achieve survival for more than two years [6].
Figure 1 CASPIAN study design
In the latest results of the CASPIAN study[7] presented at the 2021 European Society of Oncology (ESMO) conference, the benefits of 3-year follow-up OS data and the significant benefits of progression-free survival (PFS) and duration of remission (DOR) at 1-year and 2-year also confirmed the long-term efficacy advantage of duvalliumabab in combination therapy. Studies showed that the median OS of the duvalliumab combination group was 10.5 vs 12.9 months compared with the chemotherapy group, the 2-year OS rate was 22.9% vs 13.9%, and the 3-year OS rate was 17.6% vs 5.8%, showing the "long tail effect" of immunotherapy, and the long-term OS benefit advantage was obvious.
In addition, analysis of patient-reported outcomes (PROs) at the secondary endpoint of the CASPIAN study showed a tendency to delay the deterioration of all symptoms, function, and overall health/quality of life reported by patients compared with chemotherapy [8].
At the same time, the 2021 IMpower133 study also released the latest data [9]. In the updated analysis, the median OS was 12.3 and 10.3 months in the immune and placebo+chemotherapy groups (HR 0.76; 95% CI 0.60-0.95; P=0.0154), respectively, in the updated analysis. At 18 months, 34.0% of patients in the immune group and the placebo+chemotherapy group survived, respectively. Patients may benefit from immunotherapy regardless of PD-L1 immunohistochemical or hematologic tumor mutation load (bTMB) status.
Expert reviews
Professor Zhang Zheng: Immunotherapy has become a new standard for first-line treatment of ES-SCLC
Professor Zhang Zheng pointed out that the previous standard treatment mode of ES-SCLC was 4 to 6 cycles of EP/EC chemotherapy, but the therapeutic effect was limited. Fortunately, the results of the CASPIAN and IMpower133 study showed that immunotherapy can significantly prolong OS compared with chemotherapy, bringing about the first breakthrough in ES-SCLC treatment in 30 years. Accordingly, the 2021 CSCO guidelines introduce immunotherapy to the front line, immunotherapy establishes a new standard for ES-SCLC first-line treatment, and China's ES-SCLC first-line treatment has achieved international standards.
Although immunotherapy has brought about a major breakthrough in ES-SCLC treatment, there are still many problems in SCLC treatment that need to be further explored. First, SCLC lacks a clear driver gene for targeted therapy; second, although topotecan has been recommended for second-line therapy, due to its high price, its current clinical accessibility is still poor, and it is hoped that new drugs such as lurbinectin will bring more second-line treatment options to patients in the future; third, anlotinib is the new standard for SCLC third-line and above treatment recommended by the current CSCO guidelines, but more alllotinib combination treatment options are worth further exploration; fourth, Concurrent chemoradiotherapy is the standard treatment model for localized SCLC, but the choice of hyperdivision and conventional segmentation needs to be further demonstrated.
Professor Lu Dehong: Prospects for the future exploration of SCLC immunotherapy
Professor Lu Dehong pointed out that in the past few decades, people have been looking for breakthroughs in SCLC treatment, including driving gene testing, but they have not achieved good results. Immune checkpoint inhibitors have brought new options for ES-SCLC treatment, especially with the publication of the 3-year follow-up results of the CASPIAN study, which confirmed the long-term survival benefit of duvallizumab combined with chemotherapy first-line treatment, and brought long-term survival hopes to domestic ES-SCLC patients.
In view of the future exploration direction of SCLC immunotherapy, Professor Lu Dehong said that with the continuous accumulation of clinical experience, it is hoped to further explore the biomarkers of SCLC immunotherapy efficacy prediction in the future, including PD-L1, tumor mutation burden (TMB), mismatch repair defect (dMMR)/high microsatellite instability (MSI-H), etc., so as to screen out the people who can really benefit from immunotherapy. In addition, in the future, more modes of immunotherapy should be explored, such as immune combination anti-angiogenesis therapy, which may have the effect of 1+1>2.
brief summary
In summary, although chemotherapy is the cornerstone of SCLC treatment, the intervention of immunotherapy allows SCLC to survive longer. In March 2021, China's State Drug Administration (NMPA) approved the PD-L1 inhibitor altenizumab combined chemotherapy for the first-line treatment of ES-SCLC; in July 2021, nmPA approved the PD-L1 inhibitor valliyumab with etoposide + carboplatin or cisplatin in combination with a new indication for the first-line treatment of ES-SCLC patients, believing that the future two PD-L1 inhibitors will bring hope and benefits to more patients.
*Experts are ranked in no particular order
Expert Profiles
Professor Zhang Zheng
Director of the Department of Oncology, Luotian County People's Hospital, Deputy Chief Physician
ESCO Director, Deputy Chief Physician of Radiation Oncology
Member of radiation therapy committee of Hubei Anti-Cancer Association
Member of the Molecular Targeted Therapy Committee of Hubei Anti-Cancer Association
Standing Committee Member of Southeast Hubei Anti-Cancer Alliance
Vice Chairman of the Oncology Committee of Huanggang Medical Association
Standing Committee Member of Radiation Oncology Committee of Huanggang Medical Association
Professor Lu Dehong
Director of the First Department of Oncology, Changtu County Central Hospital, Chief Physician
Member of the Tumor Prevention and Control Committee of Liaoning Preventive Medicine Association
Member of the Lung Cancer Committee of Liaoning Life Sciences Society
Member of gastrointestinal branch of Liaoning Life Science Society
Member of Liaoning Life Science Cancer Support and Palliative Care Society
Member of Liaoning Society of Life Science Cancer Psychology and Treatment
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[3] Oronsky B, Reid TR, Oronsky A, Carter CA. What’s new in SCLC? A review. Neoplasia 2017; 19: 842–47.
2021 Edition of The Chinese Society of Clinical Oncology (CSCO) Guidelines for the Diagnosis and Treatment of Small Cell Lung Cancer.
[5] Paz-Ares L, et al. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet. 2019;394(10212):1929-1939.
[6] Paz-Ares L, et al. 2020 ASCO. Abstract 9002.
[7] Paz-Ares L, et al. ESMO 2021. LBA61
[8] Goldman JW, Garassino MC, Chen Y, et al. Patient-reported outcomes with first-line durvalumab plus platinum-etoposide versus platinum-etoposide in extensive-stage small-cell lung cancer (CASPIAN): a randomized, controlled, open-label, phase III study. Lung Cancer. 2020 Nov;149:46-52.
[9] Liu SV, et al. Updated Overall Survival and PD-L1 Subgroup Analysis of Patients With Extensive-Stage Small-Cell Lung Cancer Treated With Atezolizumab, Carboplatin, and Etoposide (IMpower133). J Clin Oncol. 2021;39(6):619-630.
Approval number: CN-90293 Expiration Date: 2023-2-16
The interviews/authors/publications of this article are supported by AstraZeneca and are intended for healthcare professionals only
Disclaimer: The interviews/authors/publications of this article are supported by AstraZeneca and are intended for healthcare professionals only
*This article is only used to provide scientific information to medical personnel and does not represent the views of this platform