Small-Cell Lung Cancer (SCLC)

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.

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 Grønberg 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.

Immunotherapy 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.

Prophylactic 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.

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.

The recommendation for therapy management in patients with brain metastases is based on retrospective data on the efficacy of stereotactic radiotherapy and on subgroup analyses of first-line trials of combined immunotherapy. Therefore, these recommendations are not supported by prospective controlled trials.

The results for systemic therapy in Extensive Disease can be summarized as follows:

• 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.

• In 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.

If patients develop a second intrapulmonary tumor after surgical resection and adjuvant chemotherapy, the possibility of a second primary with a different histology must be considered. In case of a new nodular lesion without lymph node involvement or distant metastasis (by PET-CT and further mediastinal staging if appropriate), another primary resection can be considered. If again histologically SCLC is evident, it is unclear whether repeat adjuvant chemotherapy will be beneficial.
If surgical resection is not performed, histologic confirmation should be sought pre-therapeutically. If SCLC histology is proven pre-therapeutically, simultaneous chemoradiotherapy can be performed as an alternative to surgery. If histology is different, histology- and stage-specific therapy should be initiated.

If patients develop a locoregional recurrence with mediastinal lymph node involvement after surgical resection and adjuvant chemotherapy, simultaneous chemoradiotherapy can be performed after histologic confirmation and exclusion of distant metastasis by PET-CT, analogous to the procedure for LD.

If complete remission of lymph node involvement is achieved in stage LD after simultaneous chemoradiotherapy, but the primary tumor persists or shows local progression again, surgical resection of the primary tumor may be considered in individual cases. Prior to this, PET-CT and, if appropriate, further mediastinal staging should be performed to exclude N2 or N3 involvement, as well as cranial MRI to exclude cerebral metastasis. A pneumectomy should be avoided. Stereotactic radiotherapy may also be considered in individual cases.

If locoregional recurrence with mediastinal lymph node involvement occurs after completion of concurrent chemoradiation therapy, systemic therapy with chemotherapy and immunotherapy analogous to first-line therapy in stage ED is recommended.

If local progression is observed in primary metastatic disease with stable distant metastasis, local irradiation of the progressive tumor can be performed. In this case, chemo-immunotherapy or immunotherapy can be continued initially and a switch to second-line chemotherapy can be made if systemic progression is observed again. It should be noted that primary tumor irradiation during ongoing immunotherapy has not been studied in larger trials and may cause a higher risk of pulmonary toxicity.

If a solitary adrenal or brain metastasis occurs as a recurrence after the initial stage VLD or LD, there is an option of local therapy. In the case of an adrenal metastasis, this can preferably be performed as a resection, and in the case of a brain metastasis, it can preferably be performed as stereotactic radiotherapy. Whether subsequent systemic chemotherapy improves the prognosis is unclear. Given the metastatic disease situation now present and the positive data on chemo-immunotherapy, additional chemo-immunotherapy analogous to primary therapy in stage IV is recommended.
As an alternative to a local approach followed by systemic chemo-immunotherapy, the latter can also be used primarily. Prospective studies on the value of the local approach are not available, the optional recommendation is based on individual case reports and clinical experience.

In case of disseminated progression or relapse, second-line systemic therapy is indicated in patients with ECOG PS 0-2 and those with disease-related ECOG PS 3. It results in symptom relief and prolongation of survival. Depending on the timing of re-progression, a distinction can be made between sensitive progression with freedom from therapy of more than 90 days and refractory progression with freedom from therapy of less than 90 days. This distinction is prognostically relevant and may have an impact on the choice of second-line therapy. The later the progression or relapse occurs, the more effective the second-line therapy and the longer the survival benefit can be expected.

The results for systemic therapy in Extensive Disease can be summarized as follows:

• Second-line chemotherapy in ED-SCLC

  • Drugs with proven efficacy in the second-line setting include topotecan, irinotecan including the nanoliposomal formulation, paclitaxel, ifosfamide, anthracyclines (including amrubicin), and lurbinectedin.

  • A randomized trial compared topotecan vs. best supportive care [38]. Topotecan resulted in a significant prolongation of survival from 14 to 26 weeks. The benefit was seen in both sensitive and refractory relapse. Oral and intravenous administration of topotecan are equivalent.

  • Topotecan is the only therapy currently approved specifically for the second-line treatment of SCLC and has therefore been used in trials as the standard of care in the comparator arm.

  • In a study comparing cisplatin/etoposide/irinotecan vs. topotecan in patients with sensitive recurrence [39], combination therapy prolonged median survival from 12 to 18 months, but without achieving long-term survival beyond 3 years, and with significantly higher toxicity.

  • Similarly, in the French study by Baize et al [40], an advantage for repeat therapy with carboplatin/etoposide over topotecan was observed in patients with sensitive recurrence and more than 90 days off therapy before relapse.

  • Orther studies showed no superiority for the ACO protocol and for single agents such as amrubicin, lurbinectedin, and nanoliposomal irinotecan compared with topotecan therapy.

  • The Atlantis study [41] comparing adriamycin plus lurbinectedin vs. topotecan or ACO in the control arm in 600 patients also showed no advantage for the combination. The preceding therapy-free interval had to be at least 30 days. Median survival was 8.6 months in the lurbinectedin arm and 7.6 months in the control. The survival curves were almost identical.

  • The RESILIENT trial comparing nanoliposomal irinotecan vs. topotecan in 450 patients also showed no advantage for the nanoliposomal encapsulated agent [42].

• Second-line immunotherapy in ED-SCLC

  • The administration of immunotherapy in the second-line setting has achieved remission rates of approximately 12% in phase II trials (CheckMate-032) [43], but has not been successful in randomized trials. In the CheckMate-331 trial, there was no difference between nivolumab vs. topotecan in progression-free and overall survival in the overall population [44].

  • Due to the use of first-line immunotherapy, second-line immunotherapy is no longer important today.

• Targeted substances

  • Antiangiogenic agents are not indicated in either first- or second-line settings after negative studies of aflibercept, bevacizumab, thalidomide, vandetanib, and others.

  • Furthermore, negative randomized phase II studies are available on mTOR inhibitors, HDAC inhibitors, BCL-2 antisense agents and PARP inhibitors.

  • The maintenance therapy trial with the PARP inhibitor niraparib showed no difference in either progression-free survival or overall survival between the two treatment arms.

  • Studies with rovalpituzumab tesirine (Rova-T), a drug conjugate directed against DLL-3, were also negative. TAHOE [45] included 442 patients and compared topotecan with Rova-T in DLL3 high-positive metastatic SCLC. Median survival was 6.3 months in the Rova-T arm and 8.6 months in the topotecan arm. The HR was 1.46. As a result, the study was terminated early. MERU [46] randomized 748 patients to Rova-T maintenance therapy or placebo after completion of chemotherapy and lack of progression. Again, the Rova-T arm tended to be less favorable than the placebo arm with a median of 8.5 vs 9.8 months. The drug was also associated with a higher rate of treatment-related adverse events, including pleural effusions in nearly 30% of patients, peripheral edema, and photosensitivity reactions.

  • Combinations of Rova-T with nivolumab with/without ipilimumab achieved remission rates of 30%, but were associated with high toxicities, leading to discontinuation of the studies.

  • A newer compound under investigation is AMG-757 (Tarlatamab), a bispecific antibody (BiTE molecule) that binds to DLL-3 on the surface of small-cell tumor cells on the one hand and to CD 3 on cytotoxic T cells on the other. The compound was used in 66 patients [47] and achieved a response rate of 20% in a heavily pretreated patient population. Main side effects were the occurrence of CRS (cytokine release syndrome) in 44% of patients. Further studies are currently ongoing in this regard.

• Indication for therapy and differential therapy

  • In PS 0-1 patients, the use of repeat combination treatment in the second-line setting is warranted after outweighing the treatment goals against therapy-associated toxicity.

  • If progression occurs after a therapy-free period of more than (6-) 12 months, the first-line regimen can be used again.

  • With a therapy-free interval of 4-12 months, combination of cisplatin/irinotecan and etoposide can be used (see study results). Alternative combinations include cis- or carboplatin with irinotecan or topotecan, but also carboplatin with paclitaxel. Repeat therapy with carboplatin/etoposide is also an option. Platinum-free combinations include ACO or AIO (adriamycin, ifosfamide, vincristine) or ACE (adriamycin, cyclophosphamide, etoposide).

  • In cases of treatment refractoriness with progression during therapy or within 3 months after the end of therapy, topotecan is the only substance tested with an advantage over best supportive care. In this case, the value of repeated combination therapy is not certain.

  • In case of limited general performance or deliberate avoidance of renewed combination therapy, topotecan as monotherapy is the approved standard (cave myelosuppression). An alternative is weekly paclitaxel treatment.

  • If available, lurbinectedin and liposomal irinotecan are also alternatives.

  • If the general performance is severely reduced, a best-supportive-care approach is usually indicated. A possible option here is, at best, oral etoposide or trofosfamide administration with the aim of symptom relief.

Radiation 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.

Prophylactic 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.

Local radiotherapy is an effective therapy for symptom relief, e.g., in multiple brain metastases or in symptomatic bone metastases.

Local 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.

The 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.