Základní terapie

Carboplatina + Etoposid

• www.tecentriq-hcp.com/content/dam/gene/tecentriq-hcp/sclc/pdfs/sclc-real-world-data-brochure.pdf

Durvalumab plus chemotherapy

• no significant differences between patients who survived for at least 18 months or at least 36 months and those with shorter survival with regard to tumour or immune cell PD-L1 expression of 1% or higher
• Tissue tumour mutational burden; and carriage of the HLA-DQB1*03:01 allele, which was linked to OS in an earlier analysis.
• But among patients given durvalumab plus tremelimumab and chemotherapy
• PD-L1 expression was enriched among patients who survived for at least 18 months
• This association continued at 36 months, albeit with small patient numbers, the presenter said.
• HLA-DQB1*03:01 allele carriage
• Was also enriched among patients given the triple regimen at both the 18- and 36-month analyses
• Consistent with earlier OS analysis for this treatment arm, commented Niels Reinmuth.
• oncologypro.esmo.org/oncology-news/daily-news/congress-watch-archives-2022/caspian-long-term-survivor-update-confirms-durvalumab-benefits-for-es-sclc

Imunoterapie

• Lessons from Real-World Cases of Small Cell Lung Cancer, August 15, 2023

• Nichole Tucker, Federico Albrecht, MD

• "Prior to the FDA approvals of atezolizumab and durvalumab, chemotherapy made up the standard of care for patients with SCLC. The backbone of treatment for these patients was platinum-etoposide chemotherapy."
• FDA approved these 2 ICIs in 2019 and 2020 in combination for patients with extensive-stage SCLC
• Based on findings from the IMpower133 trial (NCT02763579) and CASPIAN study (NCT03043872).
• “All the drugs equally have a competitive response rate
• Especially in terms of using them as a maintenance drug
• In small cell lung cancer over the last several decades, the treatment of choice has been the same with the platinum-etoposide backbone
• Over the last few years, the main change we have had, and the exciting thing is
• Adding immune checkpoint inhibitors
• Atezolizumab [Tecentriq] or durvalumab [Imfinzi]
• That has really given more of an improvement in overall survival and decreased the chance of recurrence over time.
• That has changed the landscape of how we treat extensive-stage small cell lung cancer.
• Newer studies that are being explored on anti PD-1 therapy in the first-line setting:
• Several studies going on, but none of them have been FDA-approved yet for early-stage small cell lung cancer

CASPIAN trial with immunotherapy and the addition of pembrolizumab [Keytruda]

• Even now, we can add pembrolizumab as 1 of the other immune checkpoint inhibitors
• We still prefer the atezolizumab and durvalumab at the present time
• All of them are showing improvements in
• Overall survival
• Decrease in disease-free progression has been improved by adding immunotherapy.
• CASPIAN trial is 1 which is promising
• www.targetedonc.com/view/lessons-from-real-world-cases-of-small-cell-lung-cancer

• Small cell lung cancers are very sensitive to chemotherapy and sensitive to radiation
• Initial responses we get quickly
• Couple even in the first 2 rounds of chemotherapy, great response
• Problem here is being able to hold the disease-free progression for a longer period
• Period is very short
• By adding the checkpoint inhibitors
• We have been able to improve not just the overall survival, but the disease-free progression.

- most of the time for small cell, we say that surgery is not an option.

• If it is stage I or small nodule
• Still having the surgeon involved and having it removed
• I think, gives a better prognosis

• If there is disease which is improved after chemotherapy
• Adding radiation because they are radiosensitive is an important part
• Adding prophylactic cranial radiation or radiation to the brain
• To prevent recurrence in the brain is important

• Counseling for smoking, is important
• Helping them with smoking cessation is an important part of it

In IMpower133, the addition of PD-L1 to standard chemotherapy

• Was shown to improve survival in patients with ES-SCLC.
• Atezolizumab (Tecentriq) with carboplatin plus etoposide
• Results showed that the immunotherapy/chemotherapy combination achieved a median overall survival of 12.3 months with the addition of atezolizumab vs 10.3 months with chemotherapy alone
• Median progression-free survival shown was 5.2 months with atezolizumab and chemotherapy compared with 4.3 months with chemotherapy alone.
• www.targetedonc.com/view/lessons-from-real-world-cases-of-small-cell-lung-cancer

CASPIAN study - adding durvalumab (Imfinzi) to platinum-etoposide or of tremelimumab (Imjudo) to platinum-etoposide

• Improved OS in patients with ES-SCLC.
• The median OS of 13.0 months with added durvalumab vs 10.3 months with platinum-etoposide alone.
• www.targetedonc.com/view/lessons-from-real-world-cases-of-small-cell-lung-cancer

• Incorporation of immunotherapy has made a big difference
• Toxicity is important to monitor in these patients.

1. Horn L, Mansfield A, Szczęsna A, et al. First-Line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med. 2018; 379(23):2220-2229. doi: 10.1056/NEJMoa1809064

2. Paz-Ares L, Dvorkin M, Chen Y, 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. doi: 10.1016/S0140-6736(19)32222-6

• www.targetedonc.com/view/lessons-from-real-world-cases-of-small-cell-lung-cancer

ASTRUM-005 trial with programmed cell death protein 1 (PD-1) inhibitors

• Increasing by only 2.0–4.7 months surwieval

CASPIAN trial

• Small population that consistently benefits from immunotherapy, with the three-year OS rate for patients receiving immunotherapy in combination with platinum-based chemotherapy
• Being approximately three times higher than for those treated with chemotherapy alone
• (17.6% or 15.3%, durvalumab plus EP without or with tremelimumab, respectively, vs. 5.8%, EP alone)

KEYNOTE-604 trial

• Similar findings
• 15.5% vs. 5.9%, pembrolizumab plus EP vs. EP alone
• Screening this population by biomarkers is critical for clinical guidance of immunotherapy.
• Neither of the two classic immunotherapy biomarkers, PD-L1 and TMB, seem to stratify SCLC patients.
• www.cancertreatmentreviews.com/article/S0305-7372(23)00099-3/fulltext

6.1.1.1Stage I-IIA (Very Limited Disease, VLD)Approximately 5% of patients with SCLC are diagnosed in stages I and IIA (tumors less than 5 cm in size without lymph node involvement). In most cases, these are patients who undergo surgery for an incidental finding of a peripheral round tumor and histology shows the presence of SCLC. An analysis of the US National Cancer Database evaluated 1574 patients who were followed-up in various ways after such resection [12]. After surgery alone, 5-year survival rates were 40% (n=388), after additional adjuvant chemotherapy it was 52% (n=544), and after additional prophylactic cranial irradiation (PCI) nearly 70% (n=99). Mediastinal radiotherapy did not yield any further survival benefit. Based on the retrospective data, adjuvant chemotherapy with 4 cycles of cisplatin/etoposide can be recommended after surgical resection; the evidence of a PCI benefit is limited due to the small number of cases and possible patient selection.
The database analysis by Raman et al [13] examined the extent of resection required in a total of 1948 stage T1-2N0 SCLC cases undergoing surgical resection. These patients underwent either wedge resection (n=609), segmental resection (n=96), or lobectomy (n=1233). Patients were 75% stage IA, 10% stage IB, and 15% stage II. Adjuvant chemotherapy was given to 35% of patients, and 10% received additional cranial irradiation. Five-year survival rates were 31% and 35% for wedge resection and segmental resection, respectively, and were significantly higher for lobectomy at 45%. Thus, if primary surgery is performed, it should be in the form of lobectomy with systematic lymphadenectomy.
If stage VLD SCLC is detected via classical diagnostics prior to initiation of therapy, combined simultaneous radiochemotherapy is an alternative to primary surgery with adjuvant therapy.
This treatment modality and its results will be discussed in detail in chapter 6.1.1.2.
Unfortunately, there are no stage-specific randomized comparisons between the two treatment modalities of surgery or concurrent radiochemotherapy. Two older clinical trials randomized patients between surgery followed by radiotherapy or radiotherapy alone after neoadjuvant chemotherapy alone. No difference between arms was observed in 146 or 69 randomized patients, respectively. In case series and phase II trials, 5-year survival rates of 50-70% were observed for such a neoadjuvant therapy strategy in patients with stage N0 and between 35-40% for patients with N1.
The value of prophylactic cranial irradiation is not established in stages N0-1. However, registry data suggest an increase in 5-year survival by adjuvant PCI after surgical resection. Its use must be discussed on a case-by-case basis.
6.1.1.2Stage IIB and III (Limited Disease, LD)Approximately one-third of patients with SCLC are first diagnosed in the Limited Disease stage (tumors with T3 or T4 features or N1/N2/N3 involvement). In this case, there is a curative therapeutic claim. The 5-year survival rates are in the range of 30-35%. The standard of care is simultaneous combined radiochemotherapy.Most effective chemotherapy is the combination of cisplatin and etoposide over 4 cycles. Cisplatin/etoposide can be used concurrently with radiotherapy without dose restriction with tolerable side effect profile. Cisplatin has a well-documented radiosensitizing effect; fewer data are available on carboplatin. The standard dose of cisplatin should be 75-90mg/m2 on day 1, but can be divided to 25-30 mg/m2 day 1-3 for better tolerability. In cisplatin-unfit patients, carboplatin is an alternative. Radiotherapy should be started no later than the start of the third cycle.Possible radiotherapy options include hyperfractionated, accelerated radiotherapy with 1.5 Gy twice daily up to a total dose of 45 Gy (up to 60 Gy in phase II trials) or conventionally fractionated, once-daily radiotherapy with 1.8 to 2.0 Gy ED and a total dose of up to 66 Gy. A randomized comparison of these two options yielded no significant difference in the CONVERT trial by Faivre-Finn et al [15], in which the 3-year survival rate was 43% for hyperfractionated RT and 39% for conventional RT. The CALGB study by Bogart et al [16] also showed no significant differences. 638 patients received either concurrent chemoradiation therapy with twice daily RT up to 45 Gy or once daily RT with a GHD of 70 Gy. 60% received radiotherapy using the IMRT technique. Radiotherapy was started with the first cycle of chemotherapy in 45% of patients, and cisplatin was used as the chemotherapy base in 81%. The median survival was just under 2.5 years, and the five-year survival rate was 29% in the twice-daily radiation arm and 34% in the once-daily radiation arm. The rate of adverse events was not different; esophageal complications occurred in 17% of patients.
Dose-escalated hyperfractionated radiotherapy with twice daily hyperfractionated RT up to 60 Gy was used in the randomized phase II trial by Gronberg et al [16]. A total of 176 patients were treated, and two-year survival rates were 74% with 60 Gy compared with 48% with 45 Gy. The most common side effects were hematologic with neutropenia in 80% of cases. Neutropenic infection was seen in 27%. The esophagitis rate was 21 vs. 18%. In both treatment arms, three patients died from treatment-related complications. The concept is currently not a standard approach, and a validation in a randomized phase III trial is pending.
An overview of the results of randomized trials comparing conventional vs. hyperfractionated radiotherapy is shown in Table 7 below.
Table of contentsSummaryBasicsDefinition and basic informationEpidemiologyRisk factorsHistopathology and molecular subgroupsPrevention and early detectionPreventionEarly detectionClinical characteristicsDiagnosisDiagnosticsInitial diagnosisClassificationStagingGeneral performance and comorbiditiesTherapyTreatment structureFirst-line therapyStage I-IIA (Very Limited Disease, VLD)Stage IIB and III (Limited Disease, LD)Prophylactic cranial irradiation (PCI) in stage LDExtensive Disease (ED)Local therapeutic procedures in stage IV (ED) SCLCSecond-line therapyLocal and regional progression - second-line therapySystemic progression - second-line therapySurgeryRadiotherapyThoraxProphylactic cranial irradiationSymptom-oriented radiotherapySystemic drug treatmentSubstances (in alphabetical order)AmrubicinAtezolizumabCarboplatinCisplatinCyclophosphamideDoxorubicin (Adriamycin)DurvalumabEtoposideIpilimumabIrinotecanLurbinectedinPaclitaxelTopotecanVinca alkaloidsPalliative therapy, symptom-orientedBone metastasesBrain metastasesRehabilitationPost-Treatment Control and Follow-upFollow-upReferencesLinksAuthors' AffiliationsDisclosure of Potential Conflicts of InterestSupplementary InformationTranslations(DE) Lungenkarzinom, kleinzellig (SCLC)Small-Cell Lung Cancer (SCLC)

DruckfassungKommentierenICD-10C34.-Date of documentJanuary 2023This is the current valid version of the documentCompliance rulesGuidelineConflict of interestsAuthors:Martin Wolf, Annalen Bleckmann, Wilfried Eberhardt, Martin Eichhorn, Martin Früh, Oliver Gautschi, Frank Griesinger, Wolfgang Hilbe, Hans Hoffmann, Klaus Kraywinkel, Sonja Loges, Robert Pirker, Christoph Pöttgen, Martin Reck, Niels Reinmuth, Martin Sebastian, Cornelius Waller, Jürgen WolfPrevious authors:Rudolf Maria Huber, Ron Pritzkuleit, Jan Stöhlmacher, Michael Thomas, Dieter Ukena, Bernhard WörmannSocieties1SummaryLung cancer is the third most common malignant tumor in women and the second most common in men in German-speaking countries. In both men and women, lung carcinomas are the most common cause of cancer-related death. Median age of onset is about 70 years. The main risk factor is smoking.
Small cell lung cancer (SCLC) accounts for about 12-15% of all lung cancers. In Germany, approximately 7,000 - 8,500 people develop SCLC each year. The disease is characterized by a high cell division rate and rapid growth progression. These biological characteristics are the reason for the high sensitivity of the tumor to chemo- and radiotherapy. On the other hand, they also lead to early dissemination and high recurrence rates. In stages I - III (Very Limited Disease, Limited Disease) there is a curative treatment option. Therapy in these stages is multimodal with inclusion of surgery, systemic drug treatment and radiotherapy. In metastatic disease, the additional administration of immunotherapy in addition to chemotherapy has become established. With combined chemo-immunotherapy, 15-20% of patients reach a 3-year survival.
2Basics2.1Definition and basic informationLung carcinomas are malignancies arising from epithelial cells of the respiratory tract. Based on cell line differentiation, a distinction is made between small cell and non-small cell carcinomas, with non-small cell carcinomas being further differentiated according to immunohistological and, more recently, according to molecular parameters.
The lung is a predilection site for metastases of numerous malignancies. These, other rare pulmonary tumors and benign focal lesions must be clarified by history-taking and, if necessary, also histopathologically.
The following statements on epidemiology, risk factors, prevention and early detection refer to all forms of lung cancer. The topic of the following sections of this guideline are primary small-cell lung cancers. The first description of small-cell lung carcinoma is considered to be the observations in workers of the Schneeberg mines in the German Erzgebirge [1].
2.2EpidemiologyThe following results are based on cancer registry data from the regional German federal states, which are regularly compiled at the Center for Cancer Registry Data [2] for nationwide evaluations.
In 2017 - 2019, SCLC accounted for approximately 15% of all lung cancer cases reported to cancer registries via hospitals, practices, or pathologies, with no assignment possible in approximately 5% of cases due to nonspecific histology information.
Approximately 3,500 women and 4,800 men develop SCLC for the first time each year in Germany. Since the approximately 12% of cases known only via death certificates in the registry (DCO) generally do not allow histological differentiation and are therefore included in the incidence of lung cancer but not in that of the two subgroups, the figures given should be understood as minimum figures.
The age-specific incidence increases with age up to the 8th decade of life. In most recent data, the median age at diagnosis was 67 years, and only about 2% of those affected develop the disease before the age of 50 (Figure 1). The age-specific disease rates are declining in men in all age groups and in younger women, and are still increasing in women over 60. These trends reflect the gender-specific trends in smoking behavior with a latency of several decades; therefore, in the medium to long term, a decline is also expected in women. Similar to NSCLC, the absolute number of new cases has been almost constant since about 2015 with a total of about 8,300 cases per year, after having increased continuously in the years before.
In 71% of new cases (women: 68%, men: 73%) with sufficient documentation of tumor stages, distant metastases are already detected at first diagnosis of SCLC; in both sexes, only about 5% of cases are diagnosed in early stages I or II according to UICC (Figure 2).
Relative 5-year survival rate as an estimator of disease-specific survival for the 2017-2019 period for SCLC was 8.2%, only slightly higher than 10 years earlier (7.6%).
Figure 3 illustrates the dependence of survival prognoses on tumor stage. The significantly worse prognosis compared to non-small-cell lung cancers is partly explained by the less favorable tumor stage distribution, but also in the rare cases with early stages the results are worse than in NSCLC.
Figure 1: Annual incidence rates of SCLC per 100,000 persons by age and gender (Germany, 2017-2019)Annual incidence rates of SCLC per 100,000 persons by age and gender (Germany, 2017-2019)Figure 2: Distribution of UICC tumor stages by histology(excluding DCO cases; no tumor stage could be assigned in 27% of cases)Distribution of UICC tumor stages by histology(excluding DCO cases; no tumor stage could be assigned in 27% of cases)Figure 3: Relative survival (compared with age-matched general population) to 10 years after first diagnosis of SCLC, 2017-2019Relative survival (compared with age-matched general population) to 10 years after first diagnosis of SCLC, 2017-20192.4Risk factorsThe main risk factor is smoking. Further statements on risk factors of lung cancer can be found in Lung cancer, non-small cell (NSCLC).
2.5Histopathology and molecular subgroupsImmunohistochemical detection of at least two neuroendocrine markers (TTF-1, CD 56, synaptophysin, chromogranin) is required for the diagnosis of small cell neuroendocrine lung carcinoma from biopsies, endobronchial ultrasound (EBUS), or cytology. The proliferation rate with Ki67 should be above 70% Ki67 positive cells. Differential diagnosis against small-cell basaloid squamous cell carcinoma or non-Hodgkin's lymphoma is particularly important.
Inactivating mutations in the tumor suppressor genes TP53 and RB1 are found in almost all SCLCs and can be understood here as a basic pathogenetic mechanism of malignant transformation. Among further molecular aberrations, mutations in TP73, CREBB genes of the NOTCH family and, less frequently, in additional oncogenes and suppressor genes are found in some cases [3]. The identified molecular aberrations are so far not amenable to targeted therapy.
More recently, a new classification has been proposed based on gene expression analysis in human and murine tumors [4]. This is based on the differential expression of 4 key transcription factors: achaete-scute homologue 1 (ASCL1 = ASH1), neurogenic differentiation factor 1 (NeuroD1), yes-associated protein 1 (YAP1), and POU class 2 homeobox 3 (POU2F3).
Accordingly, the new classification subdivides SCLC types SCLC-A, SCLC-N, SCLC-P, and SCLC-Y. SCLC-I (inflamed gene signature) has been proposed as a further subtype [5]. The delineation of these subtypes and their therapeutic relevance are the subject of current research and debate. Initial data suggest a higher efficacy of immunotherapy in the "inflamed" subgroup.
3Prevention and early detection3.1PreventionGeneral recommendations for prevention relate to previously identified risk factors and private lifestyle, see lung cancer, non-small cell (NSCLC). Avoidance of smoking is the key preventive measure (WHO Framework Convention on Tobacco Control) [6]. Increased consumption of fruits and vegetables reduces the risk of lung cancer, especially in smokers.
3.2Early detectionFor SCLC, there is no recognized early detection in Europe in terms of national screening programs, see Lung carcinoma, non-small cell (NSCLC). In Switzerland, the Swiss Accident Insurance Fund (SUVA) offers a screening program to insured persons with occupational exposure to asbestos according to the NLST criteria.
4Clinical characteristicsThe clinical symptoms of patients with SCLC are not fundamentally different from those of patients with NSCLC, see lung cancer, non-small cell (NSCLC). Typically, SCLC originates in the central airways and often has a short history of tumor-related symptoms such as dyspnea, cough, or signs of superior Vena cava congestion. A distinctive feature of small-cell lung carcinoma is the more frequent occurrence of paraneoplastic syndromes, most commonly with endocrine disease patterns. Table 1 shows the frequency and distribution of paraneoplastic syndromes in patients with lung cancer. The leading symptom of SIADH (syndrome of inadequate anti-diuretic hormone secretion) is hyponatremia; in ACTH syndrome, the characteristic clinical Cushing's picture is often not fully developed because of the clinically short time of development. Lambert-Eaton syndrome is clinically manifested by weakness of the musculature with dysarthria, dysphagia, and proximal limb paresis. Antibody testing (anti-Hu (ANNA-1, Anti-Neuronal Antibody Type 1), anti-Ri (ANNA-2, Anti-Neuronal Antibody Type 2), anti-CRMP5, anti-Ma1, anti-amphiphysin, and others [7]) can confirm the clinical suspicion of a neurologic paraneoplastic syndrome.
Table 1: Paraneoplastic syndromes in patients with lung cancer [6]Syndrome /Symptoms
SCLC
(% of patients)
NSCLC
(% of patients)
SIADH
10
< 0.1
Cushing's (ACTH)
2-4
< 0.1
Lambert-Eaton syndrome
1
< 0.1
Other neuropathies
to 5
< 0.1
Drumstick finger
< 1
5
Osteoarthropathy
< 1
5
Hypercalcemia
< 1
? 10
5Diagnosis5.2Diagnostics5.2.1Initial diagnosisThe first step is to confirm the suspected clinical and/or imaging diagnosis, see Figure 4.
Download ImageFigure 4: Diagnostic algorithm for SCLCSCLCNSCLCOtherYesNothoracic tumorRadiological finding ofthoracic tumorHistologyDistant metastasesintrathoracic extensionSpecial staging forintrathoracic extensionSee guidelines NSCLCSpecific for histological entityM1(Extensive Disease)T3-4 and/or N2-3(Limited Disease)T1-2 N0-1(Very Limited Disease)OrNSCLC = non-small-cell lung cancer; SCLC = small-cell lung cancer;Diagnostic procedures should be performed until metastasis is detected or excluded, and in the absence of metastasis, until TNM criteria are defined, see Table 2.
Table 2: Diagnostics for suspected lung tumorProcedure
Recommendation
Level 1
Imaging evidence of a thoracic mass
Chest radiography in 2 planes
Clinical chemistry
Blood count, electrolytes, uric acid, renal function parameters, liver parameters, LDH, coagulation tests, NSE, and optionally CEA (carcino-embryonic antigen)
CT1 Thorax / Abdomen with contrast6 / FDG-PET-CT7
First choice method
MRI2 thorax / upper abdomen with contrast6
Alternative to CT1
Level 2
Histological or cytological diagnosis
Bronchoscopy with transbronchial biopsy3
At suspect imaging finding
Transthoracic biopsy, mediastinoscopy, thoracoscopy
Optional alternative to obtain tissue samples if bronchoscopy is negative
Level 3
Exclusion of distant metastasis
CT abdomen or MRI abdomen
Alternatively, sonography of the upper abdomen if there is unequivocal evidence of abdominal metastasis.
Alternatively PET-CT, especially in curative approach
Cerebral MRI
Alternatively cerebral CT in case of unequivocal evidence of intracerebral metastasis
Bone scintigram
Alternatively PET-CT, especially in curative approach
Level 4
Detection of intrathoracic tumor spread
PET-CT4
In the case of local option of radiotherapy or surgical resection, to exclude distant metastasis
Only when PET-CT is not available, CT thorax/abdomen and bone scintigram are the alternative); PET-positive findings should be confirmed histo- or cytologically if a change the treatment concept would result
EUS / EBUS5 with biopsy
In potentially resectable tumor with imaging enlargement of N2 lymph nodes (no bulk) to detect / exclude mediastinal lymph node involvement
Mediastinoscopy
In case of potentially resectable tumor with imaging enlargement of N2 lymph nodes (no bulk) to detect / exclude mediastinal lymph node involvement especially in case of negative EUS / EBUS
Pleural puncture
In case of pleural effusion and absence of organ metastasis
Thoracoscopy
in the absence of organ metastasis for the detection of pleuritis carcinomatosa in the case of pleural effusion and negative pleural puncture
1 CT = computed tomography;2 MRI = magnetic resonance imaging;3 Alternative for peripheral space lesions: brush, needle, or other;4 FDG-PET-CT = positron emission tomography with computed tomography;5 EBUS = endobronchial or endoesophageal ultrasound with fine needle biopsy;6 contrast = intravenous contrast agent;7 When there is a high probability of diagnosing NSCLC or SCLC;FDG-PET-CT imaging upgrades patients from stage LD to ED in a significant percentage. In 8 studies with a total of 138 LD SCLC patients, the stage changed to ED in 29 cases, i.e., an average of 20% of patients [8]. This justifies performing PET-CT prior to planned curative therapy using simultaneous chemoradiation or surgery [9].
5.3Classification5.3.2StagingSince January 1, 2017, the new staging according to IASLC/UICC8 is effective [10]. The classification was revised based on data from almost 100,000 patients, including 5,002 patients with SCLC. Results were presented in late 2015/early 2016, see also Lung cancer, non-small cell (NSCLC). Formally, they became effective with the collaboration of IASLC/AJCC and UICC. The description of the TNM stages is summarized in Table 3.
Table 3: Description of TNM stages according to IASLC Lung Cancer Staging Project*T (Primary Tumor)
Label
T0
No primary tumor


Tis
Carcinoma in situ (squamous or Adenocarcinoma)
Tis


T1
Tumor ?3 cm


T1a(mi)
Minimally Invasive Adenocarcinoma
T1a(mi)
T1a
Superficial spreading tumor in central airwaysa
T1aSS
T1a
Tumor ?1 cm
T1a?1
T1b
Tumor >1 but ?2 cm
T1b>1-2
T1c
Tumor >2 but ?3 cm
T1c>2-3


T2
Tumor >3 but ?5 cm or tumor involving:


visceral pleurab,
T2Visc Pl
main bronchus (not carina), atelectasis to hilumb
T2Centr
T2a
Tumor >3 but ?4 cm
T2a>3-4
T2b
Tumor >4 but ?5 cm
T2b>4-5


T3
Tumor >5 but ?7 cm
T3>5-7
or invading chest wall, pericardium, phrenic nerve
T3Inv
or separate tumor nodule(s) in the same lobe
T3Satell


T4
Tumor >7 cm
T4>7
or tumor invading: mediastinum, diaphragm, heart, greast vessel, recurrent laryngeal nerve, carina, trachea, esophagus, spine;
T4Inv
or Tumor nodule(s) in a different ipsilateral lobe
T4Ipsi Nod


N (Regional Lymph Nodes)
N0
No regional node metastasis


N1
Metastasis in ipsilateral pulmonary or hilar nodes


N2
Metastasis in ipsilateral mediastinal/subcarinal nodes


N3
Metastasis in contralateral mediastinal/hilar, or supraclavicular nodes




M (Distant Metastasis)
Label
M0
No distant mestastasis


M1a
Melignant pleural/pericardial effusionc
M1aPl Dissem
or pleural/pericardial nodules


or separate tumor nodule(s) in a contralateral loe;
M1aContr Nod
M1b
Single extrathoracic metastasis
M1bSingle
M1c
Multiple extrathoracic metastases (1 or >1 organ)
M1cMulti
*after [10]TX, NX: T or N status not able to be assesseda Superficial spreading tumor of any size but confined to the tracheal or bronchial wallb such tumors are classified as T2a if>3?4 cm, T2b if>?5 cm.c Pleural effusions are excluded that are cytologically negative, non-bloody, transudative, and clinically judged not to be due to cancer.Categories N1 and N2 are further subdivided into N1a (single-station N1 involvement), N1b (multiple-station N1 involvement), N2a1 (single-station N2 without N1 involvement – “skip”), N2a2 (single-station N2 with N1 involvement) and N2b (multiple-station N2 involvement.
The revised staging is based on the TNM and the UICC 8 criteria [10], see Table 4. Based on the analyses of the IASLC, there is a minimal difference between the staging of SCLC and NSCLC: currently, the old staging from UICC 7 is still maintained for SCLC in M1a and M1b. For a distinction of IVA from IVB, which is to be performed already now, the data were not yet meaningful enough due to too small patient numbers in the subgroups.
Table 4: Classification of SCLC tumor stages according to UICC 8*T/M
Label
N0
N1
N2
N3
T1
T1a?1
IA1
IIB
IIIA
IIIB
T1b>1-2
IA2
IIB
IIIA
IIIB
T1c>2-3
IA3
IIB
IIIA
IIIB
T2
T2aCent, Yisc Pl
IB
IIB
IIIA
IIIB
T2a>3-4
IB
IIB
IIIA
IIIB
T2b>4-5
IIA
IIB
IIIA
IIIB
T3
T3>5-7
IIB
IIIA
IIIB
IIIC
T3Inv
IIB
IIIA
IIIB
IIIC
T3Satell
IIB
IIIA
IIIB
IIIC
T4
T4>7
IIIA
IIIA
IIIB
IIIC
T4Inv
IIIA
IIIA
IIIB
IIIC
T4Ipsi Nod
IIIA
IIIA
IIIB
IIIC
M1
M1aContr Nod
IVA
IVA
IVA
IVA
M1aPl Dissem
IVA
IVA
IVA
IVA
M1bSingle
IVA
IVA
IVA
IVA
M1cMulti
IVB
IVB
IVB
IVB
*after [10]For classification purposes, the division into Limited and Extensive Disease developed by the Veterans Administration Lung Study in 1957 was used for many decades [11], see Table 5.
Table 5: Veterans Administration Lung Study classificationStage
Description
Limited Disease (LD)
Tumor confined to the initial hemithorax with or without ipsi- or contralateral mediastinal or supraclavicular lymph node metastases* and with or without ipsilateral pleural effusion regardless of cytologic result*.
Extensive Disease (ED)
any spread beyond "limited disease”
* supraclavicular lymph nodes and cytologically malignant pleural effusion are also attributed to Extensive Disease stage by some groups.This classification was primarily based on the feasibility of radiotherapy. LD is defined as a tumor extent that can be completely detected and irradiated by means of a tolerable radiotherapeutic target volume. An addition is the subdivision of the "limited disease" stage into a "very limited disease" (VLD) group without evidence of mediastinal lymph node involvement and an LD group with mediastinal lymph node involvement.
Although the VA classification is usually sufficient for clinical purposes, the differentiated classification based on the TNM and UICC criteria [10] is now recommended for standardization of staging and because of its more accurate prognostic value, see above. The assignment of TNM features to the Veterans Administration Lung Study classification is summarized in Table 6.
Table 6: Assignment of TNM features to Veterans Administration Lung Study classification [9]Stages of the Veterans Administration Lung Study
Assignment to TNM classification
Very Limited Disease
T1-2 N0-1
Limited Disease
T3-4 and / or N2-3
Extensive Disease
M1
5.6General performance and comorbiditiesTherapeutic options in patients with lung cancer are often limited by reduced general performance as well as cardiovascular, pulmonary, or other comorbidities, including those related to age. This applies to both curative and palliative therapy. Parameters for assessing operability can be found in Lung cancer, non-small cell (NSCLC).
For objective assessment of general condition, the use of geriatric assessment instruments is recommended for elderly patients, see Geriatric Assessment Knowledge Base. Tests for objectifying mobility and comorbidity are particularly suitable. The indication to perform further tests is based on the clinical impression and the planned treatment.
6Therapy6.1Treatment structure6.1.1First-line therapyThe therapy recommendations are based on the UICC staging. However, the conventional classification into Very Limited, Limited and Extensive Disease will be continued in the description of therapy options, as clinical studies have generally been performed on the basis of this classification and it therefore represents the basis of therapy recommendations.
The most effective form of treatment for small-cell lung cancer is systemic drug therapy (chemotherapy and immunotherapy). In combination with surgery and/or radiation, treatment intent of limited disease is curative; in extensive disease, in addition to palliative symptom improvement, a significant prolongation of survival is now achieved for some patients.
An algorithm for primary therapy is shown in Figure 5. Whenever possible, patients should be treated in the framework of clinical trials.
Download ImageFigure 5: Treatment structure for small-cell lung cancer (SCLC)Optionally followed byOptionally followed byFollowed byorStage I-IIA(? 5 cm and cN0)Stage IIB-III(T3/T4 or N+)Stage IVSurgical resectionhistology -> SCLCPretherapeuticallyproven SCLCAdjuvant chemotherapy4 cycles ofcisplatin + etoposideresectionSurgicalresection+ atezolizumab+ etoposide + durvalumabChemo-immunotherapy4 cycles of carboplatin + etoposide+ atezolizumabor4 (-6) cycles of cis- or carboplatin+ etoposide + durvalumabDurvalumab orAtezolizumab maintenancein case of brain metastasis; if MRT studies are unfeasible: PCI in CR/PRScheduled cranial MRI studies and RTin case of brain metastasis; if MRTstudies are unfeasible: PCI in CR/PRSimultaneouschemoradiotherapy:4 cycles of cisplatin + etoposideplusRT-hyperfract. GHD 45 GyorRT-conventional GHD 60-66 GyAdjuvant chemotherapy4 cycles ofCisplatin + etoposidePCIPCIPCIcurative intention, palliative intention.SCLC = small-cell lung cancer, OP = surgery, PCI = prophylactic cranial irradiation; RT = radiation (radiotherapy); GHD = total therapeutic dose, hyperfraction RT = hyperfractionated radiotherapy 2 x daily, RT-conventional = conventional fractionated radiotherapy 1 x daily, Gy = Gray, CR = complete remission, NC = no change, PR = partial remission, MRI = magnetic resonance imaging.6.1.1.1Stage I-IIA (Very Limited Disease, VLD)Approximately 5% of patients with SCLC are diagnosed in stages I and IIA (tumors less than 5 cm in size without lymph node involvement). In most cases, these are patients who undergo surgery for an incidental finding of a peripheral round tumor and histology shows the presence of SCLC. An analysis of the US National Cancer Database evaluated 1574 patients who were followed-up in various ways after such resection [12]. After surgery alone, 5-year survival rates were 40% (n=388), after additional adjuvant chemotherapy it was 52% (n=544), and after additional prophylactic cranial irradiation (PCI) nearly 70% (n=99). Mediastinal radiotherapy did not yield any further survival benefit. Based on the retrospective data, adjuvant chemotherapy with 4 cycles of cisplatin/etoposide can be recommended after surgical resection; the evidence of a PCI benefit is limited due to the small number of cases and possible patient selection.
The database analysis by Raman et al [13] examined the extent of resection required in a total of 1948 stage T1-2N0 SCLC cases undergoing surgical resection. These patients underwent either wedge resection (n=609), segmental resection (n=96), or lobectomy (n=1233). Patients were 75% stage IA, 10% stage IB, and 15% stage II. Adjuvant chemotherapy was given to 35% of patients, and 10% received additional cranial irradiation. Five-year survival rates were 31% and 35% for wedge resection and segmental resection, respectively, and were significantly higher for lobectomy at 45%. Thus, if primary surgery is performed, it should be in the form of lobectomy with systematic lymphadenectomy.
If stage VLD SCLC is detected via classical diagnostics prior to initiation of therapy, combined simultaneous radiochemotherapy is an alternative to primary surgery with adjuvant therapy.
This treatment modality and its results will be discussed in detail in chapter 6.1.1.2.
Unfortunately, there are no stage-specific randomized comparisons between the two treatment modalities of surgery or concurrent radiochemotherapy. Two older clinical trials randomized patients between surgery followed by radiotherapy or radiotherapy alone after neoadjuvant chemotherapy alone. No difference between arms was observed in 146 or 69 randomized patients, respectively. In case series and phase II trials, 5-year survival rates of 50-70% were observed for such a neoadjuvant therapy strategy in patients with stage N0 and between 35-40% for patients with N1.
The value of prophylactic cranial irradiation is not established in stages N0-1. However, registry data suggest an increase in 5-year survival by adjuvant PCI after surgical resection. Its use must be discussed on a case-by-case basis.
6.1.1.2Stage IIB and III (Limited Disease, LD)Approximately one-third of patients with SCLC are first diagnosed in the Limited Disease stage (tumors with T3 or T4 features or N1/N2/N3 involvement). In this case, there is a curative therapeutic claim. The 5-year survival rates are in the range of 30-35%. The standard of care is simultaneous combined radiochemotherapy.Most effective chemotherapy is the combination of cisplatin and etoposide over 4 cycles. Cisplatin/etoposide can be used concurrently with radiotherapy without dose restriction with tolerable side effect profile. Cisplatin has a well-documented radiosensitizing effect; fewer data are available on carboplatin. The standard dose of cisplatin should be 75-90mg/m2 on day 1, but can be divided to 25-30 mg/m2 day 1-3 for better tolerability. In cisplatin-unfit patients, carboplatin is an alternative. Radiotherapy should be started no later than the start of the third cycle.Possible radiotherapy options include hyperfractionated, accelerated radiotherapy with 1.5 Gy twice daily up to a total dose of 45 Gy (up to 60 Gy in phase II trials) or conventionally fractionated, once-daily radiotherapy with 1.8 to 2.0 Gy ED and a total dose of up to 66 Gy. A randomized comparison of these two options yielded no significant difference in the CONVERT trial by Faivre-Finn et al [15], in which the 3-year survival rate was 43% for hyperfractionated RT and 39% for conventional RT. The CALGB study by Bogart et al [16] also showed no significant differences. 638 patients received either concurrent chemoradiation therapy with twice daily RT up to 45 Gy or once daily RT with a GHD of 70 Gy. 60% received radiotherapy using the IMRT technique. Radiotherapy was started with the first cycle of chemotherapy in 45% of patients, and cisplatin was used as the chemotherapy base in 81%. The median survival was just under 2.5 years, and the five-year survival rate was 29% in the twice-daily radiation arm and 34% in the once-daily radiation arm. The rate of adverse events was not different; esophageal complications occurred in 17% of patients.
Dose-escalated hyperfractionated radiotherapy with twice daily hyperfractionated RT up to 60 Gy was used in the randomized phase II trial by Gronberg et al [16]. A total of 176 patients were treated, and two-year survival rates were 74% with 60 Gy compared with 48% with 45 Gy. The most common side effects were hematologic with neutropenia in 80% of cases. Neutropenic infection was seen in 27%. The esophagitis rate was 21 vs. 18%. In both treatment arms, three patients died from treatment-related complications. The concept is currently not a standard approach, and a validation in a randomized phase III trial is pending.
An overview of the results of randomized trials comparing conventional vs. hyperfractionated radiotherapy is shown in Table 7 below.
Table 7: Controlled trials of simultaneous chemoradiotherapy for locally confined SCLCAuthors
n
Therapy
3-year OS
5-year OS
Turrisi [14]
206
RT 45 Gy, 1.8 Gy x 25
33%
16%
211
RT 45 Gy, 2 x 1.5 Gy x 15
27%
26%
Faivre-Finn CONVERT [15]
270
RT 66 Gy, 1 x 2 Gy x 33
39%
27%
273
RT 45 Gy, 2 x 1.5 Gy x 15
43%
33%
BogartCALGB [16]
325
RT 70 Gy, 1 x 2 Gy x 35
44%
34%
313
RT 45 Gy, 2 x 1.5 Gy x 15
42%
29%
Gronberg [17]
89
RT 60 Gy, 2 x 1.5 Gy x 20
66% (2 years)
42% (4 years)
81
RT 45 Gy, 2 x 1.5 Gy x 15
39% (2 years)
28% (4 years)
RT = radiotherapy, Gy = Gray, OS = overall survivalImmunotherapy in combination with simultaneous chemoradiotherapy
The concept is currently being tested in several studies. So far, there are insufficient data on the side effect profile and also on the efficacy in LD-SCLC, so that the addition of immunotherapy to simultaneous chemoradiotherapy has not yet been established.
Immunotherapy maintenance after simultaneous chemoradiotherapy
The Stimuli trial by Peters et al [18] randomized LD-SCLC patients after concurrent chemoradiation therapy in the absence of progression to maintenance therapy with nivolumab 1 mg/kg and ipilimumab 3 mg/kg every 3 weeks for 4 administrations and then continuation of nivolumab therapy for 1 year vs observation. In a total of 153 patients, the rate of progression-free survival at two years was 40% in the nivolumab-ipilimumab arm and 43% in the placebo arm. Survival at three years was also no different, with 49% in the immunotherapy arm and 51% in the observation arm. Immunotherapy caused an SAE in 96% of patients, and grade 3/4 adverse events were observed in 61% of patients. 5% of patients (4 patients) died from complications. Immunotherapy had to be discontinued in 55% of patients due to toxicities.
Therefore, maintenance therapy with nivolumab and ipilimumab after simultaneous chemoradiotherapy for SCLC is currently not a therapeutic option. The high discontinuation rate limits the conclusion on the efficacy of the therapy to a considerable extent. The results of PD(L)-1 antibody maintenance alone in stage LD have not yet been published.
Details on simultaneous chemoradiotherapy
Simultaneous chemoradiotherapy is superior to the sequential approach and is therefore the preferred treatment option. Therefore, a sequential approach should only be used in individual patients with contraindications to simultaneous chemoradiotherapy.
Carboplatin-based adjuvant chemoradiotherapy protocols have not been adequately tested and should therefore be used here only in patients with clear contraindications to cisplatin. Initial chemotherapy with carboplatin and etoposide followed by consolidative radiotherapy may be a therapeutic option for patients in significantly impaired general condition, if standard therapy with cisplatin and etoposide is not feasible.
Another possible treatment option is simultaneous hyperfractionated chemoradiotherapy with cisplatin/etoposide in the first cycle and parallel RT with 2x1.5 Gy per day starting on the first day of treatment up to a total therapeutic dose (GHD) of 45 Gy and switch to the combination cisplatin/irinotecan for the further three cycles of chemotherapy alone. This approach is equivalent to the standard approach with continuation of cisplatin/etoposide [19].
Administration of anthracycline-containing protocols should be avoided in the setting of concurrent chemoradiation therapy due to poorer efficacy and higher toxicity. Similarly, dose intensification approaches are not recommended outside of trials.
6.1.1.3Prophylactic cranial irradiation (PCI) in stage LDProphylactic cranial irradiation reduces the risk of brain metastases from 40% in non-irradiated patients to less than 10% in cranial irradiated patients and improves 5-year survival by 5% [20].
PCI is therefore an established therapeutic component for patients after simultaneous chemoradiotherapy.
PCI may cause cognitive impairment. Several studies have therefore attempted to reduce this side effect by omitting the hippocampus. A Spanish study by Rodríguez de Dios et al [21] included 150 patients, 75 received classical PCI with 25 Gy in 10 fractions and the other half received the same PCI with hippocampus sparing. Here, better protection of neurocognitive function could be demonstrated by hippocampal sparing. The rates of significant impairment were 8.7% vs 20.6%. A second study from the Netherlands by Belderbos et al [22] included 168 patients. Again, 25 Gy was used in 10 fractions with and without hippocampal sparing. Here, the rates of significant neurocognitive impairment were 29% vs 28% and thus not different. In both studies, the rate of subsequent emergence of brain metastases was not different and survival was also the same.
Thus, hippocampal sparing does not reduce the efficacy of PCI and does not worsen survival. However, the effect on reducing neurocognitive impairment is not clearly established.
6.1.1.4Extensive Disease (ED)60-70% of patients with SCLC are first diagnosed in the Extensive Disease stage. Systemic chemotherapy plus immunotherapy is the standard of care. In addition to improving symptom control and thus quality of life, it leads to a significant prolongation of survival. With chemo-immunotherapy, the median survival of ED patients is approximately 12 months, 2-year survival is 20-25%, and 3-year survival is 15-20%. Thus, the addition of immunotherapy has tripled the 3-year survival rates of patients compared to chemotherapy alone.
Systemic drug treatment in ED
An algorithm for the selection of chemo-immunotherapy in stage IV is shown in Figure 6.Chemotherapy in SCLC
Platinum-containing regimens achieve significantly higher complete remission rates than non-platinum combination therapies. With respect to overall survival, results from meta-analyses are inconsistent. In one meta-analysis of 5,530 patients, no significant difference was found in survival rates at 6, 12, or 24 months [23].
When selecting the platinum agent, the majority of studies show slightly higher efficacy of cisplatin compared with carboplatin. In a meta-analysis based on individual data, cisplatin and carboplatin were equieffective and remission rates were equal. The side effect profile of carboplatin is more favorable. The two platinum derivatives are equivalent in the treatment of stage ED SCLC.
Achievement of the full platinum target dose is an important prognostic factor.
The combination of cisplatin / etoposide achieves remission rates of 60-70% in patients with extensive disease.
In platinum-containing combination therapy, irinotecan and etoposide are equieffective in patients in Central Europe and North America.
In platinum-containing combination therapy, topotecan and etoposide are also equieffective in patients in Central Europe and North America. Topotecan can be administered intravenously or orally.
Anthracycline-containing protocols such as ACO or ACE (doxorubicin or epirubicin plus cyclophosphamide / vincristine or etoposide) are effective but are no longer used in primary therapy because of anthracycline-associated cardiotoxicity, possibly intensified by additional radiotherapy.
Dose escalation increases remission rates but does not prolong overall survival.
Polychemotherapy with addition of ifosfamide and anthracyclines or taxanes to platinum/etoposide increases the remission rate and slightly prolongs survival, but is associated with significantly higher toxicity. These combination therapies are therefore no standard protocols.
Alternating administration of different combination therapies also does not improve survival compared with sequential therapy.
Immunotherapy in SCLC
Results of several randomized phase III trials comparing chemotherapy alone vs. chemotherapy plus immunotherapy are now available.
The addition of ipilimumab (anti-CTLA-4 antibody) alone did not prolong patient survival [24].
The IMpower133 trial [25] randomized 403 patients to either carboplatin/etoposide alone or the same regimen plus the PD-L1 antibody atezolizumab. Remission rates were not different (60% vs. 64%), but the 12-month PFS rate was significantly higher in the atezolizumab arm, 12.6% vs. 5.4%. Median survival was significantly prolonged by 2 months from 10.3 to 12.3 months (hazard ratio 0.76). The 2-year survival rates were 22% vs. 18%. Longer follow-up is not available.
In the CASPIAN trial [26], the anti-PD-L1 antibody durvalumab in combination with platinum/etoposide versus platinum/etoposide also resulted in an increase in overall survival from 10.3 to 13.0 months (hazard ratio 0.73). The 2-year survival rates were 22% vs. 14%. CASPIAN is the only study with available 3-year survival rates. These were 18% vs. 6%.
The addition of tremelimumab as a CTLA-4 antibody did not improve patient survival in the CASPIAN trial.
The Keynote 604 trial [27] studied pembrolizumab added to platinum and etoposide. While the difference was not significant according to the statistical approach of the trial, the 2-year survival rates were 23% vs. 11% (HR 0.80, p=0.016).
The ASTRUM-005 trial [28] tested the PD-1 antibody serplulimab in combination with platinum + etoposide. A total of 585 patients from China were enrolled. Median survival was significantly prolonged at 15.4 vs. 10.9 months. 2-year survival data are not yet available at short follow-up.
The phase III CAPSTONE-1 trial, also only recruiting Chinese patients [29], showed an OS benefit for the anti-PD-L1 antibody adebrelimab in combination with carboplatin/etoposide compared with chemotherapy alone (15.3 months vs. 12.8 months; HR 0.72).
All studies with PD-(L)-1 addition thus show a clear advantage for immunotherapy, so that the combination is now standard in first-line therapy.
Atezolizumab is approved in combination with carboplatin and etoposide, and durvalumab is approved in combination with cisplatin or carboplatin plus etoposide for first-line therapy. In the CASPIAN trial, the addition of durvalumab to cisplatin/etoposide was 10% more effective compared with carboplatin/etoposide. Whether selection effects or interaction contribute to this is not clear from this setting. According to the approval, the duration of treatment is not limited; the combination of chemotherapy and immunotherapy should be administered over 4 to 6 cycles, after which immunotherapy is continued until progression.
The study results for primary combined chemo-immunotherapy are shown in Table 8.

Patients with CNS metastases
The efficacy of systemic chemotherapy is lower intracerebrally than outside the central nervous system. In early studies, chemotherapy alone was associated with shorter survival compared with additional radiotherapy.
Thus, as a rule, there is an indication for additional radiotherapy when intracerebral metastasis is detected. The extent and timing of additional local therapy have come under discussion due to recent study results.
The FIRE study [30] is a case collection of 710 patients with brain metastases from SCLC treated by stereotactic radiotherapy. In one third of patients each, 1 or 2-4 or more than 4 brain metastases were present. Median OS times were 11 months, 8.7 months, and 8.0 months in the respective groups. New brain metastases developed in 55% of patients with initially one metastasis and 70% of patients with multiple brain metastases. A matched-pair analysis with patients undergoing whole-brain irradiation (187 vs. 178 patients) showed an overall survival advantage for patients with stereotactic radiotherapy, although the intracerebral recurrence rate of approximately 60% was twice as high as after whole-brain radiotherapy at 30%.
Stereotactic radiotherapy alone was associated with significantly less neurocognitive impairment compared with stereotaxy plus whole-brain radiotherapy in patients with 1-3 brain metastases of different etiologies (60% lung carcinomas) [31].
Whole-brain radiotherapy can also be performed in the form of hippocampus-sparing irradiation in patients without metastases in the hippocampal region. The NRG study [32] showed less neurocognitive impairment with the same efficacy and survival in over 500 patients with brain metastases of different etiologies (60% lung carcinomas).
In the IMpower133 study, patients with brain metastases did not benefit from atezolizumab administration, and in the KEYNOTE-604 study, patients with brain metastases were even more likely to have a disadvantage in the pembrolizumab group. In CASPIAN, progression-free survival was identical in patients with and without brain metastases; median survival was more favorable for the durvalumab group (8.7 vs. 11.8 months), but the curves converge again during progression.
While IMpower133 and KEYNOTE-604 included pretreated (usually irradiated) and stable brain metastases, 90% of patients with brain metastases were not pretreated in CASPIAN.
Both atezolizumab and durvalumab did not reduce the incidence of new brain metastases. Approximately 15% of patients without initial brain metastases developed new brain metastases during the course of therapy.
Among patients with brain metastases in CASPIAN, 3 patients in the durvalumab arm and 4 patients in the durvalumab plus tremelimumab arms achieved 3-year survival, whereas this was not seen in any patient with chemotherapy alone [32].
Therefore, performing combined chemo-immunotherapy and initially foregoing additional radiotherapy is an option in asymptomatic patients, as is stereotactic radiotherapy in patients with a limited number of brain metastases. Symptomatic patients with multiple intracerebral lesions, on the other hand, should receive early whole-brain radiation.
Elderly patients and patients with performance score 2
In older patients in good general condition, the results are comparable to those in younger patients. Thus, age per se does not represent a negative prognostic parameter. Poorer efficacy of immunotherapy in patients of older age has not been proven so far. The higher hematologic toxicity of therapy in older patients, which requires dose adjustments, should be noted.
Only patients with performance score (PS) 0 and 1 were included in the trials of combined chemo-immunotherapy. Whether PS2 patients benefit from the addition of immunotherapy is unclear. Further studies are needed in this patient subgroup. The approval does not exclude PS2 patients. In the case of PS2 due to tumor burden, the administration of additional immunotherapy is warranted despite the lack of study data.
In patients in reduced general condition due to significant comorbidity, purely symptom-oriented therapy or, at most, monotherapy with a chemotherapeutic agent is recommended. Mono-immunotherapy has not been tested and should not be used.
Predictors of immunotherapy efficacy
Predictors for the efficacy of immunotherapy have not yet been adequately defined. Tumor cells in SCLC rarely express PD-L1, more often immune cells in the environment of the tumor are positive.
PD-L1 expression was not predictive of PD-L1 antibody efficacy in either IMpower133 or CASPIAN; in fact, in IMpower133, PD-L1 negative patients tended to benefit more from atezolizumab.
In CASPIAN, PD-L1 positivity and the HLA type DQB1*03:01 were favorable parameters for achieving 3-year survival with durvalumab plus tremelimumab. For durvalumab administration alone, HLA type DQB1*03:01 was not predictive.
Tumor mutational burden was also not a predictive factor for PD-L1 antibody efficacy in either IMpower133 or CASPIAN.
Maintenance therapy
Maintenance therapy with cytostatic drugs or other agents does not prolong survival [33].
After combined chemo-immunotherapy, immunotherapy should be continued as maintenance until progression or intolerance.
Starting immunotherapy only after completion of induction chemotherapy is not very effective. The corresponding maintenance therapy study CheckMate-451 [34] with nivolumab and nivolumab plus ipilimumab vs. placebo in patients without progression after 4 cycles of platinum/etoposide failed to show any benefit. In a total of 854 patients, neither nivolumab alone nor the combination of nivolumab plus ipilimumab significantly prolonged survival.
Implementation of therapy and duration of therapy
Response to chemotherapy and immunotherapy can be assessed after 2 cycles of therapy. In case of response, the combination therapy should be performed for a total of 4 cycles. In case of good tolerability and expected further clinical benefit, an extension up to 6 cycles with subsequent immune maintenance therapy can be considered.
In the absence of response to first-line therapy, the prognosis is very unfavorable. An early switch to second-line therapy can be made. Inclusion in clinical trials of innovative therapeutic concepts is recommended.
An important negative prognostic biomarker is an elevated serum lactate dehydrogenase (LDH).
Tumor lysis syndrome may occur or be exacerbated at the start of chemotherapy.
6.1.1.5Local therapeutic procedures in stage IV (ED) SCLCIn patients without primary chemo-immunotherapy, thoracic radiotherapy consolidation did not significantly improve overall survival (hazard ratio 0.84; p=0.066) in patients without progression after first-line therapy in a randomized EORTC trial [35]. However, it did increase the 2-year survival rate from 3% to 13%. Female patients aged less than 70 years with thoracic residual tumor had particularly benefited from radiotherapy consolidation.
In the case of primary use of combined chemo-immunotherapy, consolidative primary tumor irradiation has not been tested. This was not included in either IMPOWER-133 or CASPIAN. Whether consolidative radiotherapy increases long-term survival in patients with residual thoracic tumor and very good remission of distant metastasis, even with primary use of combined chemo-immunotherapy, is unclear. Given the expected thoracic and pulmonary toxicity with ongoing immune maintenance therapy, this approach is not a standard procedure and should be restricted to clinical trials.
There are different study results on prophylactic cranial irradiation in extensive disease SCLC. In the EORTC study [36] in patients without progression after first-line therapy and without clinical signs of brain metastasis, PCI improved overall survival compared with observation (hazard ratio 0.68; median 1.3 months). However, systematic cranial MRI controls were not performed in this study, and cranial irradiation was initiated in the control arm only when clinical symptoms of CNS involvement were present. Second-line chemotherapy was given to only 45% of patients in the non-PCI arm vs. 68% in the PCI arm; data on the proportion of patients undergoing cranial irradiation in the control arm are lacking.
A randomized Japanese trial [37] included only patients without MRI-based evidence of brain metastases. Here, cranial MRI follow-up was performed every 3 months in the control arm and cranial irradiation was initiated if there was imaging evidence of brain metastases. In this study, 89% of non-PCI patients received second-line chemotherapy, and of 51 patients with new-onset brain metastases, 81% were treated with radiotherapy or surgery. There was a slight, statistically nonsignificant survival disadvantage from PCI in this study, with a median of 11.6 vs. 13.7 months (hazard ratio 1.27; p=0.094).
Therefore, omitting PCI combined with regular cranial MRI follow-up is the usual and most commonly used approach. If regular MRI checks are not feasible, PCI can be discussed with the patient.
6.1.2Second-line therapyThe indication and selection of second-line therapy in SCLC is based on stage, general condition and comorbidity, prior therapy, and the time of re-progression or therapy-free period. The algorithm is shown in Figure 7 and Figure 8, distinguishing between local progression (Figure 7) and systemic progression (Figure 8).
Especially for the setting of local recurrence, only retrospective analyses, case compilations, and clinical experience are available. Therefore, the recommendations are not backed-up by prospective studies, but represent a clinically feasible approach.

6.1.3SurgeryIf surgery is performed without previous histological diagnosis to remove a peripheral pulmonary nodular lesion, and histologic workup reveals SCLC, these patients should receive adjuvant chemotherapy postoperatively, and PCI if appropriate, see Figure 5. Postoperative mediastinal radiotherapy should be avoided in patients with stage pN0, since retrospective studies have shown evidence of a negative impact on long-term survival.
In patients with preoperatively proven SCLC and very limited disease, especially in N0 patients, resection with adjuvant chemotherapy is an alternative to radiochemotherapy. Resection should be performed according to the same standard as in patients with non-small cell lung cancer. After lobectomy in stage pT1/2, 5-year survival rates of 53% and a median survival of 65 months can be achieved.
Prior to surgery, the best possible exclusion of distant metastasis and a careful examination of the mediastinal lymph nodes are required. Patients with pre-therapeutically proven N2 or N3 involvement should primarily not undergo surgical resection. In patients with stage N1 disease, the value of surgery is controversial. Exclusion of mediastinal lymph node involvement should be performed by PET-CT, EUS/EBUS, or mediastinoscopy. The goal of surgery is R0 resection. Lobectomy is recommended. Pneumectomy should be avoided in SCLC. Postoperatively, adjuvant chemotherapy and PCI should be performed in case of LD.
A neoadjuvant approach is also feasible in the VLD group. Surgery is particularly important if there is still residual tumor after simultaneous chemoradiotherapy and no mediastinal lymph node involvement is detectable. Here, too, a pneumectomy should be avoided.
Local therapy of a solitary adrenal metastasis is an option especially for those patients who achieve complete remission after combined chemoradiotherapy and who subsequently develop a solitary adrenal metastasis as recurrence site after a prolonged therapy-free period.
6.1.4Radiotherapy6.1.4.1ThoraxRadiation is an effective therapy for SCLC. In stage VLD after primary surgery and adjuvant chemotherapy, registry data from the National Cancer Data Base show no advantage for consolidative mediastinal irradiation. It should not be performed in N0 and N1; in N2, mediastinal reirradiation can be performed. Controlled studies on this are not available.
Radiotherapy is used in combination with chemotherapy in patients with LD and in VLD without surgery.
Chemotherapy should consist of cisplatin and etoposide whenever possible. Carboplatin is less effective or insufficiently tested in the setting of chemoradiation therapy. Simultaneous chemoradiotherapy results in 5-year survival rates of 20-30%, making it a potentially curative therapy. Compared with sequential therapy, 5-year survival is increased by approximately 5-10%. In the case of concurrent administration, an early start of radiotherapy should be aimed for, starting no later than the beginning of the 3rd cycle. This ensures that two complete cycles of cisplatin/etoposide are applied concurrently with radiotherapy. Early initiation of radiotherapy is associated with a higher rate of neutropenia. It is imperative to avoid dose reductions or even treatment discontinuations when simultaneous chemoradiotherapy is used early. Off-protocol therapy implementation worsens the results. Therefore, optimal supportive therapy is of great importance in the context of simultaneous chemoradiation therapy protocols.
When conventional fractionation with daily single doses of 1.8-2.0 Gy is applied, a total dose of radiotherapy of 60-66 Gy is recommended. Hyperfractionation with twice daily application of 1.5 Gy was superior to conventional fractionation with the same total dose of 45 Gy in a randomized study. However, the biologically effective dose is significantly different between the two therapeutic approaches. Comparisons of accelerated-hyperfractionated radiotherapy (AHF) with twice daily 1.5 Gy up to a total dose (GD) of 45 Gy vs. conventional fractionated radiotherapy with daily single doses of 1.8-2.0 Gy up to 70 Gy showed no statistically significant difference. Both treatment regimens are appropriate, although the burden to normal tissue may occasionally suggest an advantage for the AHF regimen.
Patients with ED usually receive primary chemo-immunotherapy with immunotherapy maintenance today. The use of consolidating primary tumor irradiation has not been tested in the context of such a therapeutic strategy and should therefore be reserved for study concepts.
6.1.4.2Prophylactic cranial irradiationProphylactic cranial irradiation leads to a significant reduction in brain metastasis as a recurrence site. In stage LD, this is reduced from approximately 40% to 10%. Here, PCI also leads to a prolongation of overall survival and a 5% increase in 5-year survival. In a meta-analysis of 7 trials involving 987 limited-disease SCLC patients, survival at 3 years was 20.7% compared with 15.3% in the control arm. Possible radiation regimens include.
20 Gy in 5-8 fractions
24 Gy in 12 fractions
25 Gy in 10 fractions
30 Gy in 10-15 fractions
A randomized trial comparing a PCI dose of 25 Gy in 10 fractions with a dose of 36 Gy in 18 fractions showed a reduction in brain recurrence rate from 30% to 24% by the higher dose in 760 patients, but was associated with a less favorable survival curve. Surprisingly, the intrathoracic recurrence rate was increased in the group with the higher PCI dose. Doses above 30 Gy are therefore not a common approach, they are also associated with a higher risk of CNS toxicities including cognitive deficits. These are less pronounced with smaller individual doses and lower total doses.
Divergent study results are available for PCI in patients with extensive disease who had responded to induction chemotherapy. The EORTC trial driven solely by clinical symptoms showed a prolongation of median survival from 5.4 to 6.7 months, while the MRI-driven trial from Japan observed a statistically non-significant survival disadvantage with PCI with a median of 11.6 vs. 13.7 months (hazard ratio 1.27; p=0.094). In the EORTC clinically driven trial, the proportion of patients receiving second-line chemotherapy was significantly lower in the non-PCI arm at 45% compared to 69% in the PCI arm. This may have contributed to the survival benefit for PCI in this study. In the MRI-guided Japanese study, the rate of second-line therapy in both arms ranged from 80% to 90%, and overall survival was also significantly more favorable. PCI in ED may be an option to consider if regular MRI cranial controls are not performed.
6.1.4.3Symptom-oriented radiotherapyLocal radiotherapy is an effective therapy for symptom relief, e.g., in multiple brain metastases or in symptomatic bone metastases.
6.1.5Systemic drug treatmentChemotherapy is the basis of therapy in patients with SCLC. It is used at every stage of the disease, see Figure 5 and Figure 6.
6.1.5.1Substances (in alphabetical order)6.1.5.1.1AmrubicinAmrubicin is a fully synthetic anthracycline with potentially reduced cardiotoxicity. It has efficacy in SCLC, but the randomized second-line trial failed to demonstrate an advantage over topotecan. Therefore, the compound is not approved for the treatment of SCLC.
6.1.5.1.2AtezolizumabAtezolizumab is an anti-PD-L1 monoclonal antibody and belongs to the immune checkpoint inhibitor class. Atezolizumab led to an improvement in overall survival in first-line therapy of patients with stage extensive disease SCLC in combination with carboplatin/etoposide compared to therapy with carboplatin/etoposide alone (improvement OS 2.0 months; HR 0.70; p=0.007). Clinically relevant adverse events included an increase in grade 3/4 diarrhea (2% vs 0.5%) and infusion-related reactions (2% vs 0.5%). Exacerbation of paraneoplastic phenomena may occur with atezolizumab and should be monitored thoroughly.
6.1.5.1.3CarboplatinCarboplatin is a platinum derivative. It has a more favorable side effect spectrum than cisplatin. In stage ED, remission rates are equal to those with cisplatin, and survival rates are probably not different, see Chapter 6.1.5.1.4. Specific severe side effect is hematotoxicity with thrombocytopenia, anemia, and neutropenia. Nausea, vomiting, and neurotoxicity occur but are less severe than with cisplatin. Carboplatin is administered intravenously.
6.1.5.1.4CisplatinPlatinum derivatives are among the most effective single agents. The combination of cisplatin and etoposide is the standard worldwide protocol in stage VLD and LD SCLC and the most commonly used regimen in stage ED patients besides carboplatin / etoposide. Specific serious side effects (grade 3/4) include nausea and vomiting, nephrotoxicity, polyneuropathy, ototoxicity, hematotoxicity, electrolyte shifts, cardiotoxicity, and diarrhea. Cisplatin is administered intravenously.
6.1.5.1.5CyclophosphamideCyclophosphamide is used primarily in combination with anthracyclines; see doxorubicin.
6.1.5.1.6Doxorubicin (Adriamycin)Anthracycline-containing regimens are an alternative first-line treatment in EDs with contraindications to platinum-containing combinations. They are also frequently used as second-line treatment. Doxorubicin and epirubicin have been tested in trials. The anthracyclines are used in combination with cyclophosphamide plus etoposide or vincristine (ACE and ACO, respectively). Remission rates for first-line therapy are 50-60%, and for second-line therapy are 20%. Serious adverse events (grade 3/4) of combination therapy, which occurred in more than 5% of patients in randomized trials, are primarily hematologic: neutropenia (52-87%), febrile neutropenia (5-10%), anemia (5-15%), thrombocytopenia (1-20%). Doxorubicin is administered intravenously.
6.1.5.1.7DurvalumabDurvalumab is an anti-PD-L1 monoclonal antibody and belongs to the immune checkpoint inhibitor class. Durvalumab resulted in an improvement in overall survival compared to chemotherapy alone in first-line treatment of patients with stage extensive disease SCLC in combination with cis- or carboplatin/etoposide. (Improvement OS 2.3 months; HR 0.75; p=0.007). The 3-year OS rates were 18% vs. 6%. Immunotherapy-related side effects should be thoroughly monitored.
6.1.5.1.8EtoposideEtoposide is a topoisomerase II inhibitor. It is a treatment standard in combination with cisplatin for SCLC. In patients with extensive disease, remission rates with combination therapy are 60-70%. Oral monotherapy with etoposide is less effective than intravenous combination therapy and has poorer bioavailability. In first-line palliative therapy, the following serious adverse events (grades 3-4) occurred with cisplatin/etoposide: Neutropenia (68-76%), anemia (11-12%), thrombocytopenia (8-15%), nausea/vomiting (11-12%), %), fatigue (11%), and anorexia (5%). Etoposide can be administered intravenously or orally.
6.1.5.1.9IpilimumabIpilimumab is a CTLA-4 antibody and thus also belongs to the group of checkpoint inhibitors. Ipilimumab alone was not effective as an adjunct to chemotherapy in extensive disease SCLC. Under maintenance therapy with nivolumab and ipilimumab after combined chemoradiotherapy, severe side effects occurred, leading to discontinuation of therapy in approximately 50% of patients. When used as maintenance therapy in combination with nivolumab, no significant survival benefit was detectable. Therefore, the substance has not yet been approved for the treatment of SCLC.
6.1.5.1.10IrinotecanIrinotecan is a topoisomerase I inhibitor. In combination with cisplatin, remission rates of 60-70% are achieved in first-line therapy, and survival rates are comparable to the cisplatin/etoposide combination. Serious adverse events (grade 3/4) occurring in more than 5% of patients on this combination therapy include neutropenia (34%), febrile neutropenia (5%), diarrhea (19%), nausea/vomiting (14%), fatigue (14%), anorexia (13%), dyspnea (8%), and anemia (5%). Irinotecan is administered intravenously.
The nanoliposomal formulation of irinotecan was not superior to topotecan in a randomized phase III study in the second line and therefore will not be available for second-line treatment of SCLC.
6.1.5.1.11LurbinectedinLurbinectedin is structurally similar to trabectedine. The compound inhibits the transcription of tumor cell genes. Phase II studies demonstrated good efficacy of lurbinectedin in second-line SCLC treatment with remission rates of 35% and progression-free survival of 5.3 months. As a result, the compound was approved for SCLC second-line therapy in the United States. However, the subsequent randomized phase III trial failed to show an advantage over topotecan. Lurbinectedin is not approved for the treatment of SCLC in the EU.
6.1.5.1.12PaclitaxelPaclitaxel belongs to the taxanes. Taxanes are effective drugs in the advanced/metastatic stage of SCLC. They are used in combination with platinum derivatives or as monotherapy. Side effects include neutropenia, anemia, thrombocytopenia, nausea/vomiting, diarrhea, nephrotoxicity, neuropathy, and fatigue. Other side effects include edema, alopecia, onychodystrophy, and allergic reactions. Paclitaxel is administered intravenously.
6.1.5.1.13TopotecanTopotecan is a topoisomerase I inhibitor. Topotecan is a standard substance in second-line therapy of SCLC. Remission rates of 20% are achieved here. In combination with cisplatin, topotecan is also effective in first-line therapy and achieves comparable survival rates to cisplatin / etoposide. Serious adverse events (grade 3/4) occurring in more than 5% of patients on this combination therapy include neutropenia (33-88%), anemia (25-31%), thrombocytopenia (7-43%), fatigue (8%), and dyspnea (10%). Topotecan can be administered intravenously or orally.
6.1.5.1.14Vinca alkaloidsVinca alkaloids, most commonly vincristine, are used primarily in combination with anthracyclines; see doxorubicin.
6.1.6Palliative therapy, symptom-orientedPalliative therapy includes the treatment of physical and psychological complaints. It required a multidisciplinary setting. The need for and options of palliative therapy should be discussed early and comprehensively with patients affected. The following specific symptoms occur particularly frequently in patients with SCLC.
6.1.6.1Bone metastasesLocal and systemic measures are available for the therapy of patients with bone metastases. In case of pain or fracture risk, radiotherapy is the treatment of choice. It can be hypofractionated under continuous systemic therapy. An additional option is surgical treatment for pathologic fractures, unstable vertebral body fractures, or as a relief for spinal compression.
Systemic measures include tumor-directed therapy and administration of bone-modifying agents (bisphosphonates, RANKL antibodies). Bone-modifying agents may reduce the risk of skeletal complications in bone metastasis of solid tumors. Results of prospective randomized trials in patients with SCLC are not available.
Bisphosphonates are also indicated for hypercalcemia.
6.1.6.2Brain metastasesThe first measure in symptomatic metastatic disease is the administration of corticosteroids to reduce perifocal edema. In symptomatic patients with multiple cerebral lesions, whole-brain irradiation is the therapy of choice. Depending on the setting, chemotherapy may also be used primarily for SCLC, see Figure 6. Stereotactic radiotherapy may also be considered for single metastases or metastases in small numbers and with good demarcation. In individual cases, local surgical therapy or targeted local irradiation (gamma knife, cyber knife, stereotactic radiotherapy) may be discussed for isolated resectable brain metastases persisting or re-progressing after whole brain irradiation.
7RehabilitationDrug therapy, surgery, radiation therapy, and comorbidity can lead to therapy sequelae of varying severity in patients with small cell lung cancer. They can be alleviated by targeted rehabilitative measures in the somatic and psychosocial areas.
Patients should be informed at an early stage about the possibilities of outpatient and inpatient rehabilitation measures as well as other claims arising from social law. With regard to the rehabilitation clinic, the patients' wishes should be taken into account (§9 SGB IX). Nevertheless, a recommendation for a clinic with an oncological focus should be made in order to ensure optimal rehabilitation success.

Bifunctional immune checkpoint-targeted antibody–ligand traps

• Can sequester cytokines suppressing immune responses
• pure.rug.nl/ws/portalfiles/portal/74019809/Lung_cancer_stem_cells_origin_features_maintenance_mechanisms_and_therapeutic_targeting.pdf

Carboplatina over cisplatina

• Karboplatina a cisplatina jsou oba platinové cytostatika, která se používají k léčbě SCLC.
• Studie však ukázaly, že karboplatina je obecně účinnější než cisplatina u SCLC.
• Jedna studie zjistila, že pacienti s SCLC, kteří dostávali karboplatinu, měli vyšší míru přežití než pacienti, kteří dostávali cisplatinu.
• Karboplatina je méně toxická než cisplatina
• Lze podávat ve vyšších dávkách. Vyšší dávky mohou vést k většímu poškození rakovinných buněk.
• Karboplatina je účinnější při ničení rakovinných buněk, které jsou rezistentní na cisplatinu
• Buněk, které měly mutaci v genu MDM2
• Karboplatina je obecně účinnější než cisplatina u SCLC

Bard, Gemini Google

Interakce s karboplatinou zde

• Acetylsalicylic acid - risk or severity of nephrotoxicity can be increased when Acetylsalicylic acid is combined with Carboplatin.
• Acetaminophen - Carboplatin may decrease the excretion rate of Acetaminophen which could result in a higher serum level. (otrava paracetamolem)
• Avoid echinacea. Co-administration may decrease effectiveness of immunosuppressants.
• Ambroxol - The risk or severity of methemoglobinemia can be increased when Carboplatin is combined with Ambroxol.
• Budesonide The risk or severity of adverse effects can be increased when Carboplatin is combined with Budesonide.
• Capsaicin The risk or severity of methemoglobinemia can be increased when Carboplatin is combined with Capsaicin.
• Celecoxib The risk or severity of nephrotoxicity can be increased when Celecoxib is combined with Carboplatin
• Chondroitin sulfate Carboplatin may decrease the excretion rate of Chondroitin sulfate which could result in a higher serum level.
• Chromium Carboplatin may decrease the excretion rate of Chromium which could result in a higher serum level.
• Ciprofloxacin Carboplatin may decrease the excretion rate of Ciprofloxacin which could result in a higher serum level.
• Cortisone acetate The risk or severity of adverse effects can be increased when Carboplatin is combined with Cortisone acetate.
• Dalteparin The risk or severity of bleeding can be increased when Dalteparin is combined with Carboplatin.
• Dexamethasone The risk or severity of adverse effects can be increased when Carboplatin is combined with Dexamethasone
• Dexpanthenol Carboplatin may decrease the excretion rate of Dexpanthenol which could result in a higher serum level.
• Diclofenac The risk or severity of nephrotoxicity can be increased when Diclofenac is combined with Carboplatin.
• Etoposide The risk or severity of adverse effects can be increased when Etoposide is combined with Carboplatin.
• Eucalyptus oil Carboplatin may decrease the excretion rate of Eucalyptus oil which could result in a higher serum level.
• Folic acid Carboplatin may decrease the excretion rate of Folic acid which could result in a higher serum level.
• Heparin The risk or severity of bleeding can be increased when Heparin is combined with Carboplatin.
• Ibandronate The risk or severity of nephrotoxicity and hypocalcemia can be increased when Carboplatin is combined with Ibandronate.
• Ibuprofen The risk or severity of nephrotoxicity can be increased when Carboplatin is combined with Ibuprofen.
• Indapamide Indapamide may increase the excretion rate of Carboplatin which could result in a lower serum level and potentially a reduction in efficacy.
• Indomethacin The risk or severity of adverse effects can be increased when Indomethacin is combined with Carboplatin.
• Inositol Carboplatin may decrease the excretion rate of Inositol which could result in a higher serum level.
• Isosorbide Isosorbide may increase the excretion rate of Carboplatin which could result in a lower serum level and potentially a reduction in efficacy.
• Isotretinoin Carboplatin may decrease the excretion rate of Isotretinoin which could result in a higher serum level.
• Magnesium The serum concentration of Magnesium can be decreased when it is combined with Carboplatin.
• Metformin Carboplatin may decrease the excretion rate of Metformin which could result in a higher serum level.
• Naloxone Carboplatin may decrease the excretion rate of Naloxone which could result in a higher serum level.
• Naproxen The risk or severity of nephrotoxicity can be increased when Naproxen is combined with Carboplatin.
• Nitric Oxide Carboplatin may decrease the excretion rate of Nitric Oxide which could result in a higher serum level.
• Potassium Potassium may increase the excretion rate of Carboplatin which could result in a lower serum level and potentially a reduction in efficacy.
• Pyridoxine Carboplatin may decrease the excretion rate of Pyridoxine which could result in a higher serum level.
• Rosiglitazone Carboplatin may decrease the excretion rate of Rosiglitazone which could result in a higher serum level.
• Salbutamol Carboplatin may decrease the excretion rate of Salbutamol which could result in a higher serum level.
• Salicylic acid The risk or severity of nephrotoxicity can be increased when Salicylic acid is combined with Carboplatin.
• Selenium Carboplatin may decrease the excretion rate of Selenium which could result in a higher serum level.
• Sodium citrate The risk or severity of bleeding can be increased when Sodium citrate is combined with Carboplatin.
• Sorbitol Carboplatin may decrease the excretion rate of Sorbitol which could result in a higher serum level.
• Testosterone Carboplatin may decrease the excretion rate of Testosterone which could result in a higher serum level.
• Tocopherol Carboplatin may decrease the excretion rate of Tocopherol which could result in a higher serum level.
• Verapamil Carboplatin may decrease the excretion rate of Verapamil which could result in a higher serum level.
• Warfarin Carboplatin may decrease the excretion rate of Warfarin which could result in a higher serum level.

Etoposide

Meta-analysis of 7,173 patients from 36 trials

• Survival benefit for treatment combinations with etoposide
• Compared to a treatment without etoposide.
• Treatment regimens with cisplatin
• But without etoposide
• Are probably not significantly better than regimens using neither drug
• Only one trial in the meta-analysis formally compared these two treatments
• Clinical relevance of this finding is unclear

Recent meta-analysis in 5,530 patients from 29 trials by the Cochrane Collaboration

• Suggested no significant benefit of platinum-based chemotherapy regimens
• Compared with nonplatinum-based regimens
• no significant difference between the two treatment groups in terms of survival at 6, 12 and 24 months.
• no significant difference in terms of overall tumour response
• Platinum-based treatment regimens
• Did have a significantly higher rate of complete response
• Platinum-based chemotherapy regimens
• Had significantly higher rates of nausea and vomiting, anaemia and thrombocytopenia

ELCWP meta-analysis 11

• Showed a survival benefit with EP
• The Cochrane meta-analysis did not formally compare EP with other platinum-based regimens

• Neither of these meta-analyses used individual patient data from the original trials

Etoposide jako malá výhoda, když je součástí chemoterapie

Randomised phase III trial published in 2002 Sundstrom et al.

• Not included in the meta-analyses of Pujol et al. 10 and Mascaux et al.
• Compared treatment with EP to that with cyclophosphamide, epirubicin and vincristine
• Documented significantly higher 2- and 5-yr survival rates in the EP arm in LS-SCLC
• A trend in survival benefit was seen in the patients with ES-SCLC
• With a median survival of 6.5 months in the cyclophosphamide, epirubicin and vincristine group
• Compared to 8.4 months in the EP group
• erj.ersjournals.com/content/35/1/202

Kombinace Etoposid + cisplatina méně toxické než jenom etoposid

Side-effect of cisplatin nephrotoxicity

• Prevention hyperhydration is required
• Can be problematic in the more fragile and elderly patient
• Or in patients with cardiac or renal comorbidity

One randomised phase III trial by Hellenic Cooperative Oncology Group compared the efficacy and toxicity of EP versus etoposide/carboplatin

• In previously untreated patients with SCLC (both LS- and ES-SCLC)
• Authors demonstrated that carboplatin in combination with etoposide
• Was as effective as, but less toxic than, EP
• Results provide a rationale for the use of the etoposide/carboplatin combination over EP
• Because of similar efficacy and decreased toxicity.

Etoposide intravenous lepší než perorálně

• Whether etoposide should preferably be administered intravenously or as on oral formulation
• Oral formulation of etoposide exists and seems an attractive

Several studies have demonstrated that

• Oral etoposide was less effective and sometimes more toxic than using intravenous administration

2 randomised trials

• Prematurely stopped because of inferior survival with oral etoposide at the interim analysis
• Unpredictable events may be linked to variable bioavailability of the oral formulation.
• erj.ersjournals.com/content/35/1/202

• Etoposide inhibits DNA topoisomerase II
• Inhibiting DNA re-ligation
• Causes critical errors in DNA synthesis at the premitotic stage of cell division
• Can lead to apoptosis of the cancer cell
• Etoposide is cell cycle dependent and phase specific
• Affecting mainly the S and G2 phases of cell division
• Inhibition of the topoisomerase II alpha isoform
• Results in the anti-tumour activity of etoposide
• Also capable of inhibiting the beta isoform
• Not associated with the anti-tumour activity but carcinogenic effect
• Side effects include
• Alopecia,
• Constipation,
• Diarrhea,
• Nausea and vomiting
• Secondary malignancies (leukemia)

Interakce Etoposidu zde

• go.drugbank.com/drugs/DB00773

Etoposide capsules as maintenance therapy

• For patients with extensive-stage small cell lung cancer: a prospective two-stage, two-center study

The study was divided into two stages:

• Stage I, a single-center
• One-arm prospective study
• Stage II,
• A multicenter, controlled non-randomized prospective study
• NCT02179528
• All patients received six cycles of etoposide plus platinum.
• Patients who were evaluated as complete remission (CR) or partial remission (PR) entered the maintenance treatment (MT)
• etoposide capsule, once a day for 20 days,
• Every 28 days as a cycle, until disease progression
• In stage I, the dose of etoposide was 25 mg
• In stage II, patients were non-randomized into etoposide capsule (25 mg/50 mg) and observation groups

Results:

• Ninety-two patients were enrolled.
• Stage I, the median PFS was 6.700 months (95% CI: 6.408–6.992).
• Stage II, the median PFS of the MT group was better than that in the NMT group
• 8.930 vs. 5.900 months, P=0.002
• In the pooled analysis, the overall median PFS of the MT group was better than that of the NMT group (7.870 vs. 5.900 months, P=0.003).
• There was no significant difference in OS between the groups (15.030 vs. 14.330 months, P=0.813)
• Multivariate Cox regression analysis showed that maintenance therapy was an independent protective factor for PFS in patients with ES-SCLC.

Conclusions

• Etoposide capsules as maintenance therapy significantly prolonged the PFS of patients with ES-SCLC who responded to etoposide plus platinum, with acceptable tolerability.
• jtd.amegroups.org/article/view/48563/html

Interakce Etoposidu

Acetaminophen - metabolism of Etoposide can be increased when combined with Acetaminophen.Acetazolamide - serum concentration of Etoposide can be increased when it is combined with Acetazolamide.Acetylsalicylic acid - risk or severity of bleeding can be increased when Acetylsalicylic acid is combined with Etoposide.Adenine - metabolism of Etoposide can be decreased when combined with Adenine.Alfuzosin - metabolism of Alfuzosin can be decreased when combined with Etoposide.Allopurinol - risk or severity of adverse effects can be increased when Allopurinol is combined with Etoposide.Ambroxol - risk or severity of me-moglobinemia can be increased when Etoposide is combined with Ambroxol.Aminophylline - metabolism of Aminophylline can be decreased when combined with Etoposide.Atorvastatin - metabolism of Atorvastatin can be decreased when combined with Etoposide.Azithromycin - metabolism of Etoposide can be decreased when combined with Azithromycin.Caffeine - metabolism of Etoposide can be decreased when combined with Caffeine.Calcitriol - metabolism of Etoposide can be increased when combined with Calcitriol.Cannabidiol - serum concentration of Etoposide can be increased when it is combined with Cannabidiol.Capsaicin - risk or severity of me-moglobinemia can be increased when Etoposide is combined with Capsaicin.Carvedilol - serum concentration of Etoposide can be increased when it is combined with Carvedilol.Chloroquine - metabolism of Etoposide can be decreased when combined with Chloroquine.Cholesterol Cholesterol may increase - excretion rate of Etoposide which could result in a lower serum level and potentially a reduction in efficacy.Citalopram - metabolism of Etoposide can be decreased when combined with Citalopram.Clarithromycin - metabolism of Etoposide can be decreased when combined with Clarithromycin.Clindamycin - metabolism of Clindamycin can be increased when combined with Etoposide.Clopidogrel - metabolism of Etoposide can be decreased when combined with Clopidogrel.Cortisone acetate - metabolism of Etoposide can be increased when combined with Cortisone acetate.Curcumin - metabolism of Etoposide can be decreased when combined with Curcumin.Cyanocobalamin - -rapeutic efficacy of Cyanocobalamin can be decreased when used in combination with Etoposide.Dalteparin - risk or severity of bleeding can be increased when Dalteparin is combined with Etoposide.Danaparoid - risk or severity of bleeding can be increased when Danaparoid is combined with Etoposide.Dapagliflozin - metabolism of Etoposide can be decreased when combined with Dapagliflozin.Desogestrel - metabolism of Etoposide can be increased when combined with Desogestrel.Dexamethasone - metabolism of Etoposide can be increased when combined with Dexamethasone.Dextran - risk or severity of bleeding can be increased when Dextran is combined with Etoposide.Diazepam - metabolism of Etoposide can be decreased when combined with Diazepam.Diclofenac - metabolism of Etoposide can be decreased when combined with Diclofenac.Diltiazem - metabolism of Etoposide can be decreased when combined with Diltiazem.Diosmin - serum concentration of Etoposide can be increased when it is combined with Diosmin.Dipyridamole - risk or severity of bleeding can be increased when Dipyridamole is combined with Etoposide.Disulfiram - metabolism of Etoposide can be decreased when combined with Disulfiram.Echinacea - metabolism of Etoposide can be increased when combined with Echinacea.Enoxaparin - risk or severity of bleeding can be increased when Enoxaparin is combined with Etoposide.Epinephrine - serum concentration of Etoposide can be increased when it is combined with Epinephrine.Epirubicin - risk or severity of adverse effects can be increased when Epirubicin is combined with Etoposide.Erythromycin - serum concentration of Etoposide can be increased when it is combined with Erythromycin.Erythropoietin - risk or severity of Thrombosis can be increased when Erythropoietin is combined with Etoposide.Estradiol - metabolism of Etoposide can be decreased when combined with Estradiol.Ethanol - metabolism of Etoposide can be increased when combined with Ethanol.Fluoxetine - metabolism of Etoposide can be decreased when combined with Fluoxetine.Fluticasone - metabolism of Etoposide can be increased when combined with Fluticasone.Fluvastatin - metabolism of Etoposide can be decreased when combined with Fluvastatin.Fondaparinux - risk or severity of bleeding can be increased when Fondaparinux is combined with Etoposide.Fusidic acid - metabolism of Etoposide can be decreased when combined with Fusidic acid.Ginkgo biloba - metabolism of Etoposide can be decreased when combined with Ginkgo biloba.Glycerol phenylbutyrate - metabolism of Etoposide can be increased when combined with Glycerol phenylbutyrate.Grapefruit - serum concentration of Etoposide can be increased when it is combined with Grapefruit.Heparin - risk or severity of bleeding can be increased when Heparin is combined with Etoposide.Hydrocortisone acetate - metabolism of Etoposide can be increased when combined with Hydrocortisone acetate.Hydroxychloroquine - risk or severity of adverse effects can be increased when Etoposide is combined with Hydroxychloroquine.Indomethacin - metabolism of Etoposide can be decreased when combined with Indomethacin.Insulin beef - metabolism of Etoposide can be increased when combined with Insulin beef.Irbesartan - serum concentration of Etoposide can be increased when it is combined with Irbesartan.Irinotecan - metabolism of Etoposide can be decreased when combined with Irinotecan.Avoid grapefruit products. Grapefruit inhibits CYP3A4 metabolism, which may increase - serum concentration of etoposide.Exercise caution with St. John's Wort. This herb induces CYP3A4 metabolism, which may reduce serum levels of etoposide.Levothyroxine - serum concentration of Etoposide can be decreased when it is combined with Levothyroxine.Lidocaine - risk or severity of me-moglobinemia can be increased when Etoposide is combined with Lidocaine.Losartan - serum concentration of Etoposide can be increased when it is combined with Losartan.Lovastatin - metabolism of Lovastatin can be decreased when combined with Etoposide.Magnesium - serum concentration of Magnesium can be decreased when it is combined with Etoposide.Mannitol - serum concentration of Etoposide can be increased when it is combined with Mannitol.Methotrexate - risk or severity of adverse effects can be increased when Methotrexate is combined with Etoposide.Metronidazole - serum concentration of Etoposide can be increased when it is combined with Metronidazole.Nadroparin - risk or severity of bleeding can be increased when Nadroparin is combined with Etoposide.Naproxen - metabolism of Naproxen can be decreased when combined with Etoposide.Niacin - serum concentration of Etoposide can be increased when it is combined with Niacin.Nicardipine - metabolism of Etoposide can be decreased when combined with Nicardipine.Niclosamide - metabolism of Etoposide can be decreased when combined with Niclosamide.Nifedipine - metabolism of Etoposide can be decreased when combined with Nifedipine.Obeticholic acid - risk or severity of adverse effects can be increased when Obeticholic acid is combined with Etoposide.Pentoxifylline - metabolism of Pentoxifylline can be decreased when combined with Etoposide.Phenylalanine - risk or severity of adverse effects can be increased when Phenylalanine is combined with Etoposide.Pravastatin Pravastatin may decrease - excretion rate of Etoposide which could result in a higher serum level.Praziquantel - metabolism of Etoposide can be decreased when combined with Praziquantel.Prednisolone - metabolism of Etoposide can be increased when combined with Prednisolone.Probenecid - metabolism of Etoposide can be increased when combined with Probenecid.Procaine - risk or severity of me-moglobinemia can be increased when Etoposide is combined with Procaine.Progesterone - metabolism of Etoposide can be decreased when combined with Progesterone.Quinine - serum concentration of Etoposide can be increased when it is combined with Quinine.Reserpine - serum concentration of Etoposide can be increased when it is combined with Reserpine.Simvastatin - serum concentration of Etoposide can be increased when it is combined with Simvastatin.Sodium citrate - risk or severity of bleeding can be increased when Sodium citrate is combined with Etoposide.St. John's Wort - serum concentration of Etoposide can be decreased when it is combined with St. John's Wort.Taurocholic acid Taurocholic acid may decrease - excretion rate of Etoposide which could result in a higher serum level.Telmisartan Telmisartan may decrease - excretion rate of Etoposide which could result in a higher serum level.Testosterone - metabolism of Etoposide can be increased when combined with Testosterone.Testosterone cypionate - metabolism of Etoposide can be decreased when combined with Testosterone cypionate.Tetracycline - serum concentration of Etoposide can be increased when it is combined with Tetracycline.Thalidomide - metabolism of Etoposide can be increased when combined with Thalidomide.Tretinoin - metabolism of Etoposide can be decreased when combined with Tretinoin.Triamcinolone - metabolism of Etoposide can be increased when combined with Triamcinolone.Valproic acid - serum concentration of Etoposide can be increased when it is combined with Valproic acid.Verapamil - serum concentration of Etoposide can be increased when it is combined with Verapamil.Vitamin E - metabolism of Etoposide can be increased when combined with Vitamin E.Warfarin - -rapeutic efficacy of Warfarin can be increased when used in combination with Etoposide.

• go.drugbank.com/drugs/DB00773

PD-1 inhibitors Pembrolizumab and Nivolumab

• PD-L1 inhibitors mainly include Atezolizumab and Durvalumab.
• Other PD-1/PD-L1 inhibitors, such as Avelumab
• Currently being tried for SCLC and the results have not yet been published.

A literature search of the PubMed, Embase, and Cochrane Library databases

• Extracted the data, and evaluated the risk of bias of the included studies. RevMan 5.3 software was used for meta-analysis.
• Results
• 4 studies involving 1,981 patients with ED SCLC were included.
• Overall survival (OS) [hazard ratio (HR) =0.80, 95% confidence interval (CI) (0.68, 0.95), P=0.009]
• Progression-free survival (PFS) [HR =0.82, 95% CI (0.75, 0.90), P <0.00001]
• Were longer in the immunotherapy group than in the chemotherapy group.
• Incidence of total treatment-related adverse events in the immunotherapy group
• Were lower than those in the chemotherapy group [relative risk (RR) =1.050, 95% CI (1.010, 1.080), P=0.007]
• Differences were statistically significant.
• apm.amegroups.org/article/view/56721/html

Atezolizumab

• SCLC spreads very rapidly,
• Often doubling the amount of tumor in the patient’s body in a matter of weeks

Frances Shepherd, M.D., a lung cancer researcher at Princess Margaret Cancer Centre in Toronto

• At the time of their diagnosis, most patients have what is called extensive-stage disease

Dr. Shepherd said, and surgery is not a treatment option.

400 patients in the trial—called IMpower

• Had extensive-stage disease
• Atezolizumab, an immune checkpoint inhibitor + standard chemotherapy ( carboplatin + etoposide) or chemotherapy + placebo.
• Standard treatment actually shrinks tumors in most patients
• But the response is transient
• Atezolizumab + chemotherapy for four treatment cycles, called induction therapy
• Then continued to receive atezolizumab or placebo alone after that, known as maintenance therapy.
• Patients in the atezolizumab group
• Lived longer overall - median of 12.3 months
• Versus 10.3 months
• Time it took for patients’ disease to begin progressing
• Improved by approximately one month
• A median of 5.2 months, versus 4.3 months.
• Side effects related to treatment were seen in both patient groups
• More immune-related side effects in patients treated with the checkpoint inhibitor
• The most common serious side effects in patients treated with atezolizumab included
• Anemia
• Neutropenia
• Increases the risk of infection.

Dr. Liu

• www.cancer.gov/news-events/cancer-currents-blog/2018/small-cell-lung-cancer-atezolizumab-survival

Nejdelší přežívání

• Podle nejnovějších studií vede k co nejdelšímu přežívání u lidí s malobuněčným karcinomem plic kombinace chemoterapie a imunoterapie.
• Studie z roku 2022, která byla publikována v časopise New England Journal of Medicine, zjistila, že kombinace chemoterapie a imunoterapie (atezolizumab a karboplatina a etopozid) vedla k delšímu přežívání než chemoterapie samotná (karboplatina a etopozid). Studie zjistila, že medián celkového přežití u pacientů, kteří dostávali kombinaci chemoterapie a imunoterapie, byl 13,3 měsíců, zatímco medián celkového přežití u pacientů, kteří dostávali pouze chemoterapii, byl 9,3 měsíců.
• Další studie z roku 2022, která byla publikována v časopise The Lancet Oncology, zjistila, že kombinace chemoterapie a imunoterapie (pembrolizumab a karboplatina a etopozid) vedla k delšímu přežívání než chemoterapie samotná (karboplatina a etopozid). Studie zjistila, že medián celkového přežití u pacientů, kteří dostávali kombinaci chemoterapie a imunoterapie, byl 13,6 měsíců, zatímco medián celkového přežití u pacientů, kteří dostávali pouze chemoterapii, byl 8,7 měsíců.
• Tyto studie naznačují, že kombinace chemoterapie a imunoterapie je nejúčinnější léčbou malobuněčného karcinomu plic.

Bardt Gemini Google

• V České republice jsou schválené následující indikace podání imunoterapie při malobuněčném karcinomu plic:

První linie léčby:

• Kombinace atezolizumabu a karboplatiny a etopozidu
• U pacientů s malobuněčným karcinomem plic s pozitivní expresí PD-L1 (tumorové buňky i nádorové mikroprostředí)
• Kombinace pembrolizumabu a karboplatiny a etopozidu
• U pacientů s malobuněčným karcinomem plic s pozitivní expresí PD-L1 (tumorové buňky i nádorové mikroprostředí)

Druhá linie léčby:

• Atezolizumab
• U pacientů s malobuněčným karcinomem plic, kteří prodělali první linii léčby chemoterapií a imunoterapií
• Pembrolizumab
• U pacientů s malobuněčným karcinomem plic, kteří prodělali první linii léčby chemoterapií a imunoterapií
• Podrobné informace o těchto indikacích jsou uvedeny v příbalových informacích k jednotlivým léčivým přípravkům.

Bardt Gemini Google

Keytruda® (pembrolizumab)

• The US Food and Drug Administration initially granted Keytruda
• An accelerated approval for the treatment of third line SCLC in 2019.

%

Based on results from the KEYNOTE-158 and KEYNOTE-028 trials

• Keytruda monotherapy led to a 19% objective response rate in SCLC patients whose cancer had progressed despite prior therapies.
• Continued approval was dependent on a post-marketing study demonstrating superiority of Keytruda
• By overall survival
• Keytruda failed to meet this requirement in the KEYNOTE-604 trial

Long-term follow-up results at the IASLC World Conference on Lung Cancer 2022 in Vienna

• Keytruda + etoposide + platinum chemotherapy (EP) combination
• Improved overall survival when used as initial therapy in previously untreated extensive stage small cell lung cancer
• The three-year overall survival was 15.5% for Keytruda treated patients
• Compared to 5.9% for those treated with EP alone

Additional studies pembrolizumab + anti-TIGIT therapy vibostolimab (MK-7684)

• Currently recruiting patients
• news.cancerconnect.com/lung-cancer/checkpoint-inhibitor-chemotherapy-for-treatment-of-small-cell-lung-cancer

• Platinum compound (either cisplatin or carboplatin)
• Combined with a topoisomerase inhibitor (etoposide or irinotecan;)
• Additionally, epirubicin is of therapeutic interest and has been investigated in several clinical trials in SCLC
• aacrjournals.org/clincancerres/article/29/22/4644/729958/Entinostat-Enhances-the-Efficacy-of-Chemotherapy

PD-1 and PD-L1 inhibitor therapy

PD-1 is a protein on the surface of T cells

• Helps keep the body’s immune responses in check
• PD-L1 is a protein found on some types of cancer cells
• PD-1 attaches to PD-L1, it stops the T cell from killing the cancer cell.
• PD-1 and PD-L1 inhibitors keep PD-1 and PD-L1 proteins from attaching to each other.
• This allows the T cells to kill cancer cells. Atezolizumab and durvalumab are types of PD-L1 inhibitors.
• www.cancer.northwestern.edu/types-of-cancer/lung/small-cell-lung-cancer.html

Platinum-based chemotherapy

• Small-cell lung cancer (SCLC) is highly sensitive
• Indication in patients with a poor performance status
• Patients with poor PS, Eastern Cooperative Oncology Group PS 3 and 4

18 patients

• 12 chemotherapy
• Improved in 7 (58.3%, including the PS 4 cases)
• 5 patients showed partial responses to chemotherapy (41.7%)
• Remained stable in 2 (16.7%)
• Deteriorated in 3 (25%)
• 6 with supportive care alone

• Neutropenia
• Grade 3–4 developed in 10 (83.3%) patients
• Grade 3 febrile neutropenia occurred in 5 (41.7%) patients
• no grade 4 non-hematological toxicity was noted
• Mortality associated with lung toxicity (grade 5) due to treatment occurred in a 77-year-old-male patient with PS 3

• No substantial difference in survival
• Between patients with PS 3 and 4
• Even when including those treated with supportive care alone

• Treatment had a positive effect on survival:
• After chemotherapy, the 6-month survival rate of PS 3 and 4 patients was 66.7%.

• In contrast, all patients treated with supportive care alone
• Died within 5 months.

• These findings suggest that chemotherapy is indicated in selected SCLC patients not only with PS 3, but also with PS 4.
• karger.com/cro/article/12/2/613/91268/Small-Cell-Lung-Cancer-Treatment-of-Newly

Prophylactic radiotherapy to the central nervous system (CNS)

• [prophylactic cerebral irradiation (PCI)]
• Diminished the incidence of brain metastasis as the site for relapse in LD and ED patients
• Therefore it should be offered to patients with complete response to induction first-line treatment.
• Regarding second-line treatment,
• Results are more modest
• Topotecan is accepted as treatment for this scenario offering a modest benefit.
• tlcr.amegroups.org/article/view/6537/6254

Radioterapie

• 1-yr survival rate was
• 27% in the irradiation group
• 13% in the control group

Study of Slotman et al.

• Global health status score was 8 points higher in the radiation group
• Cut-off of a 10-point difference for clinical significance
• Most important side-effects of PCI were fatigue and hair loss
• Impact on other health-related quality-of-life aspects
• (cognitive and emotional functioning), was limited
• It seems reasonable to offer PCI to all patients with ES-SCLC who respond to induction first-line chemotherapy.
• erj.ersjournals.com/content/35/1/202

• Radiation therapy can similarly induce ImmuneCellDeath (ICD)
• By accumulating DNA damage in cells.

In a mouse model of SCLC

• Radiation + targeting DNA damage repair pathways induced ICD
• By activating the stimulator of interferon gene (STING) pathway
• Upregulating PD-L1 expression on tumor cells
• Remodeling the inflammatory TIME
• Notably increasing the infiltration of CTLs when combined with PD-1 inhibitors
• www.cancertreatmentreviews.com/article/S0305-7372(23)00099-3/fulltext

• Regulatory cell death such as ferroptosis, necroptosis, and pyroptosis
• Also types of ICD that can induce local inflammation and improve immunogenicity in SCLC
• Increase immune cell interactions in the TIME
• Trigger a mighty anti-tumor immune response
• Thus promote the conversion of immune cold, to hot tumors
• www.cancertreatmentreviews.com/article/S0305-7372(23)00099-3/fulltext

Surgery

• Current clinical guidelines recommend surgery only for cT1-2N0M0 small cell lung cancer (SCLC) patients
• Recent studies, the role of surgery in the treatment of SCLC needs to be reconsidered.

Reviewed all SCLC patients who underwent surgery from November 2006 to April 2021

• Clinicopathological characteristics were retrospectively collected from medical records
• 196 SCLC patients undergoing surgical resection were enrolled
• 5-year overall survival for the entire cohort was 49.0% (95% CI: 40.1–58.5%).
• PN0 patients had significantly superior survival to pN1–2 patients (p < 0.001)
• The 5-year survival rate of pN0 and pN1–2 patients were 65.5% (95% CI: 54.0–80.8%) and 35.1% (95% CI: 23.3–46.6%)
• Smoking, older age, and advanced pathological T and N stages
• Were independently associated with poor prognosis
• Age, smoking history, type of surgery, and range of resection, were not independently prognostic factors for the pN0 SCLC patients.
• Pathological N0 stage SCLC patients
• Have significantly superior survival to pN1–2 patients, regardless of features, including T stage
• Studies with larger cohort might help verify the benefit of surgery, especially for T3/4 patients.
• Two-thirds of the patients had extensive metastatic diseases when first diagnosed
• 5-year survival rate of less than 7%
• eurjmedres.biomedcentral.com/articles/10.1186/s40001-023-01044-3

PORT - post operative radioterapy

• Study demonstrated that additional PORT was suggested for patients with T1-2N0M0 SCLC
• Prolonged the overall survival.
• A nomogram that incorporated age, gender, T stage, surgical type, and PORT
• Achieve satisfactory prediction of 3/5/10-year OS probability
• www.hindawi.com/journals/jo/2022/6280538/

Thoracic radiation

• May also improve long-term outcomes for these patients
• www.cancer.gov/types/lung/hp/small-cell-lung-treatment-pdq