Safety analysis of immunochemotherapy combined with consolidative thoracic radiotherapy for extensive-stage small cell lung cancer

doi:10.21203/rs.3.rs-1422042/v2

Background: Thoracic radiation therapy (TRT) has been shown to improve local tumour control and provide survival benefits for patients with extensive-stage small cell lung cancer (ES-SCLC) in the era of chemotherapy. However, there are no data to indicate the safety, especially the lung toxicity, of TRT during and following the administration of four cycles of programmed death ligand 1 (PD-L1) inhibitors when used with etoposide and platinum (EP). Hence, this retrospective study aimed to investigate the risk factors for radiation pneumonitis (RP) associated with TRT combined with PD-L1 inhibitors.

Methods: From January 2020, through March 2021, in Shandong Cancer Hospital and Institute, patients with ES-SCLC who received TRT during maintenance with PD-L1 inhibitors combined with EP were enrolled in this retrospective study. RP was investigated and evaluated according to the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) criteria. We used univariate and multivariate logistic regression to analyse the potential risk factors for RP.

Results: From January 2020, to March 2021, 20 patients receiving TRT during maintenance with PD-L1 inhibitors combined with EP were enrolled in this retrospective study. The dose fractions were 1.5 Gy bid or 1.8-3 Gy qd, and the total dose was 30 Gy to 61.4 As a result, 6 patients (30%) experienced grade 2 RP, and no cases of ≥3 grade RP occurred. At the last follow-up, 17 patients suffered from disease progression, 13 suffered from distant progression, three suffered from local failure in the radiation field, and one suffered from distant progression and local failure in the radiation field. The median progression-free time (PFS) was 9 months.

Conclusion: The retrospective analysis showed that the lung toxicity resulting from TRT was tolerable during maintenance with PD-L1 inhibitors combined with EP.

extensive-stage small cell lung cancer (ES-SCLC)

PD-L1 inhibitor

thoracic radiation therapy (TRT)

radiation pneumonitis (RP)

Small-cell lung cancer (SCLC) accounts for approximately 15% of all lung cancers(1). The typical characteristics of SCLC are an exceptionally high proliferation rate, a strong inclination for early metastasis and poor prognosis. Two-thirds of patients with SCLC usually have distant metastasis at the initial diagnosis and are staged as having extensive disease(2).

For over three decades, the standard first-line treatment for newly diagnosed metastatic SCLC has comprised a platinum-containing agent (cisplatin or carboplatin) combined with etoposide. Using this treatment mode, the median survival time (MST) is approximately 10 months(3). In recent years, several clinical trials have evaluated the role of immune checkpoint inhibitors targeting programmed cell death ligand 1 (PD-L1) or programmed cell death 1 (PD-1). It is confirmed that the PD-L1 inhibitors durvalumab and atezolizumab have prolonged overall survival and have become the standard first-line therapy in ES-SCLC according to the CASPIAN and IMpower133 trials. The MST was prolonged beyond 12.0 months(4, 5). Hence, PD-L1 inhibitors combined with EP have become the standard first-line treatment for patients with ES-SCLC.

Thoracic radiotherapy (TRT) has been well established for the treatment of limited-disease (LD) SCLC, and it was demonstrated that ChT/TRT significantly reduced the risk of intrathoracic failure by 30–60%, and the absolute long-term survival rate was increased by 5.4%(6, 7). For patients with ES-SCLC, the role of TRT was also confirmed in the Jeremics trial and CREST trial. Our retrospective study showed that MST was improved from 9.3 months to 17 months when TRT was combined with ChT. Five patients (5/60, 8.4%) suffered from grade 2 pneumonitis, and one patient (1.7%) died of pneumonitis(8).

In the era of immunotherapy, it is not clear whether TRT could play a positive role for patients with ES-SCLC. Therefore, we conducted this retrospective study to explore the efficacy and safety of this approach and especially its associated lung toxicity.

Study Population and treatment

We retrospectively reviewed ES-SCLC patients from January 2020, to March 2021 at Shandong Cancer Hospital and Institute. Patients were diagnosed with ES-SCLC according to cytology or histology and the staging system of the Veterans Administration Lung Study Group and were treated with PD-L1 inhibitors and ChT for at least 4 cycles. Then, TRT was added to the therapeutic regimens of patients with partial response (PR) or stable disease (SD) after the administration of PD-L1 inhibitors with EP. We selected 20 patients meeting the above requirements, of whom 17 patients (85%) achieved PR and 3 patients achieved SD before TRT.

Patients received four 21-day cycles of carboplatin (area under the curve of 5 mg per millilitre per minute, administered intravenously on Day 1 of each cycle) or cisplatin (25–30 mg per square metre of body-surface area, administered intravenously on Days 1–3 of each cycle) and etoposide (100 mg administered intravenously on Days 1–5 of each cycle) with either atezolizumab (at a dose of 1200 mg, administered intravenously on the day before chT of each cycle) or durvalumab (at a dose of 1000 mg, administered intravenously on the day before chT of each cycle). Nine patients (45%) were administered atezolizumab, and 11 (55%) were administered durvalumab. Nine patients received TRT after 4–6 cycles of PD-L1 inhibitors combined with EP, and 11 patients received TRT during maintenance with PD-L1 inhibitors combined with EP. Ten patients received PD-L1 inhibitors during TRT.

TRT was administered with an intensity-modulated radiotherapy (IMRT) technique for 20 patients with ES-SCLC. The gross target volume (GTV) comprised the primary tumour and/or the positive lymph nodes with a short-axis dimension of 1 cm on CT scans. We outlined the GTV and the draining area of the positive lymph nodes as the clinical targeted volume (CTV), and the planning target volume (PTV) included the CTV with a 0.5 cm margin. The dose fractions were 1.5 Gy bid or 1.8-3 Gy qd, and the total dose was 30 Gy to 61.4 We extracted dosimetric parameters from the treatment planning system (Eclipse system, Varian Medical Systems, Version 13.5.35), and all dosimetric parameters were lower than the dose constraints of the lung.

Endpoints

1) ≥ grade 2 radiation pneumonitis

Treatment-related pneumonitis was diagnosed according to clinical symptoms, physical examinations, and chest computed tomography (CT). Toxicity was evaluated in accordance with the Common Terminology Criteria for Adverse Events version 5.0. Grade 2 RP was defined as symptomatic; medical intervention indicated limiting instrumental ADL.

2)PFS

Progression-free survival refers to the time between the beginning of enrolment and the observation of disease progression or death from any cause.

Statistical analysis

We used univariate and multivariate logistic regression analyses to identify the risk factors for grade 2 symptomatic pneumonitis. PFS was calculated by using the Kaplan–Meier method.

1.1 Patients and treatment characteristics

Twenty patients were enrolled from January 2020, through March 2021 at Shandong Cancer Hospital and Institute and received immunochemotherapy combined with consolidative TRT for ES-SCLC. Baseline characteristics are summarized in Table 1. Among the 20 patients, 17 were men and 3 were women. The median age was 58.5 years (range, 45-74 years), and all patients had good performance status (KPS scores ≥80). Most patients (70%) had a history of smoking. Ten patients (50%) had 1 metastatic site, and 10 patients (50%) had 2 or more metastatic sites. The most common metastatic sites were the brain and liver (brain metastasis, 9 patients; liver metastasis, 7 patients). All patients received PD-L1 inhibitors; 9 (45%) patients received atezolizumab, and 11 (55%) received durvalumab. All patients received at least 3 cycles of PD-L1 inhibitors and 4-6 cycles of chemotherapy (etoposide combined with platinum) before TRT. The dose fractions were detailed as follows: two patients with 1.5 Gy bid, 7 patients with 3 Gy qd, 7 patients with 1.8-2 Gy qd, and the other 4 patients with 2.5 Gy qd. The total dose was 30 Gy to 61.4 Gy.

1.2 The incidence rate of pneumonitis and radiation dosimetric parameters

In the entire cohort of patients, 6 patients (30%) experienced grade 2 RP, 9 patients (45%) experienced grade 1 RP, and the remaining 5 patients did not experience RP. The median time of grade 2 RP onset after completion of TRT was 2.85 months (range, 1.2-6.2 months). The radiation dosimetric parameters for all patients are listed in Table 2. The median radiation dosimetric parameters, such as V5, V20, and MLD, of the 6 patients with grade 2 symptomatic pneumonitis were 42.8%, 23.2% and 113.6 cGy, respectively. Further analysis did not indicate significant risk factors for grade 2 symptomatic pneumonitis.

1.3 The PFS and failure patterns

The last follow-up was January 2022, and the median follow-up time was 16.8 months. At the time of data cut-off, 17 patients had progressive disease, and MST was 9 months for all patients. Among all 20 patients, 17 patients (85%) suffered from disease progression, 10 suffered from brain metastasis, and liver metastasis occurred in five of them, of whom one patient suffered from both brain metastasis and liver metastasis. Four suffered from local failure in the radiation field, and one patient suffered from distant progression and local failure in the radiation field. The local control rate in the chest was 80%, and the intrathoracic PFS was 8.85 months.

To our knowledge, this was the first retrospective study to investigate the safety of consolidative TRT after PD-L1 inhibitors with platinum and etoposide treatment. We concluded that using consolidative TRT to manage the residual lesions in the chest after administrating PD-L1 inhibitors with platinum and etoposide was safe and tolerable, which was supported by the fact that the incidence of grade 2 RP was 30% and no grade 3 RP occurred. We did not identify risk factors for grade 2 RP by using univariate and multivariate logistic regression analyses.

It has been reported that the risk of ≥ grade 2 symptomatic pneumonitis ranges from 5–30% with TRT alone or when combined with platinum-based chemotherapy(9–12). The incidence of checkpoint inhibitor-related pneumonitis is lower than 5% in patients who received PD-(L)1 inhibitors alone, in whom the occurrence rate of any grade pneumonitis resulting from PD-L1 inhibitors is 1.3%(13–17). Theoretically, PD-L1 inhibitors combined with TRT will enhance the probability of pneumonitis because radiation can increase the infiltration of inflammatory cells and inflammatory factors inside the tumour of the targeted area. A retrospective study reported that the incidence rate of pneumonitis at any grade was 33.9% in patients with stage III non-small-cell lung cancer who received PD-L1 inhibitors after administration of concurrent chemoradiotherapy, which was considered tolerable for patients(18). Based on the results of previous studies, the dosimetric parameters of our patients were all within the safe range. We considered that receiving consolidative TRT to manage residual lesions in the chest after administration of PD-L1 inhibitors with platinum and etoposide was tolerable because the incidence of grade 2 RP was 30% and no grade 3 RP occurred in our study.

However, there was another retrospective study showing that the occurrence rate of pneumonitis was 48.96% in patients who received consolidative TRT after PD-(L)1 inhibitors with chemotherapy, which indicated that this treatment mode was harmful to patients(19). Comparing the results of this retrospective study with those of our study, we found that 10 (35.7%) patients in the previous study had pulmonary emphysema, and the majority of patients received PD-1 inhibitors rather than PD-L1 inhibitors as used in this study. Previous studies showed that the occurrence rate of pneumonitis after the administration of PD-1 inhibitors was 3.6%, which was higher than that after the administration of PD-L1 inhibitors(20–22). The potential mechanism of the higher incidence of pneumonitis induced by PD-1 inhibitors is unclear but may be explained as follows. Tumour cells achieve immune escape by expressing PD-L1 and PD-L2 receptors, and immune checkpoint inhibitors can enhance antitumor effects by activating immune cells and preventing immune escape. PD-1 inhibitors not only bind with PD-L1 receptors but also with PD-L2 receptors. PD-L1 inhibitors only bind with PD-L1 receptors; they do not influence the PD-L2 pathway, so PD-L1 inhibitors retain their immunomodulatory function and lower the occurrence of autoimmune diseases. Thus, the occurrence rate of RP is lower in patients who received TRT and PD-L1 inhibitors than in patients who received TRT and PD-1 inhibitors.

The mPFS was 9 months for all patients in our study (Fig. 1) and 5.2 months and 5.1 months, respectively, in the Impower133 trial and Caspian trial(4, 5). Among all 20 patients, 17 patients (85%) suffered from disease progression, the brain (50%) and liver (25%) were the most common sites of failure lesions, and only four patients suffered from local failure in the radiation field. The local control rate in the chest was 80%, and the median intrathoracic PFS was 8.85 months. The rate of isolated intrathoracic progression was 15% in our study, compared with 19.8% in the CREST trial. TRT could reduce the occurrence rate of intrathoracic progression. Increasing the dose in the chest may decrease the recurrence rate in the chest. The recurrence rate in the chest was 25.8% in the RTOG0937 trial, which was lower than the 62.5% observed in the CREST trial. The difference between the two trials was the total dose in the chest; the former was 45 Gy/15 f, and the latter was 30 Gy/10 f(23, 24). Moreover, one study showed that a BED (biological effective dose) > 50 Gy was beneficial to overall survival, PFS, and intrathoracic PFS at 1 year(25). We divided the 20 patients into 2 groups according to whether they received BEDs ≥ 50 Gy or BEDs < 50 Gy. However, there was no significant difference between the two groups by statistical analyses perhaps due to the limited number of samples in our study.

In the NRG LU007 (NCT04402788, https://clinicaltrials.gov) trial, patients who were administered 4–6 cycles of platinum and etoposide with or without atezolizumab in first-line treatment were divided into 2 groups according to whether they received radiation therapy (including those with lesions in the chest). The trial was a prospective study and played an important role in confirming the function of TRT after the administration of PD-L1 inhibitors combined with chemotherapy.

This study has some limitations. On the one hand, this was a retrospective study conducted in a single medical centre with a short follow-up time and only 20 patients; thus, we did not identify risk factors for Grade 2 RP after performing statistical analysis. However, only 6 patients (30%) experienced grade 2 RP, and no patients experienced grade 3 or higher pneumonitis. We concluded that it was safe to use consolidative TRT after PD-L1 inhibitors with platinum and etoposide. On the other hand, the follow-up time was short, so most patients did not achieve an overall survival outcome, so we could not analyse the OS of the 20 patients. The mPFS was 9 months for the 20 patients in our study, which was higher than the 5.2 m and 5.1 m observed in the IMpower133 trial and CASPAIN trial, respectively. From these results, we can see that administrating consolidative TRT after PD-L1 inhibitors with platinum and etoposide can improve PFS.

In conclusion, administrating consolidative TRT after PD-L1 inhibitors with platinum and etoposide was safe and tolerable. Thus, we encourage more prospective studies to explore the efficacy and safety of this treatment mode.

ES-SCLC, extensive-stage small cell lung cancer; ICIs, immune checkpoint inhibitors; ICI/ChT, Immune checkpoint inhibitor combined with chemotherapy; ChT, chemotherapy; TRT, thoracic radiation therapy; PD-1, programmed death 1; PD-L1, programmed death ligand 1; EP, etoposide and platinum; KPS, Karnofsky performance status; Gy/f, grays/fraction; PR, partial response; SD, stable disease; RP, radiation pneumonitis; MST, median survival time; MLD, mean lung dose; IMRT, intensity-modulated radiotherapy; CT, computed tomography; GTV, gross target volume; CTV, clinical targeted volume; PTV, planning target volume; PFS, progression free survival; BED, biological effective dose.

Ethics approval and consent to participate

This study was approved by the institutional review board of Shandong Cancer Hospital and Institute and was performed in accordance with the Declaration of Helsinki.

Consent for publication

Agreed.

Competing interests

The authors declare that they have no competing interests.

Funding

This study was sponsored by the National Natural Science Foundation of China (Grant numbers. 82103632 and 81972862), the National Natural Science Foundation of Shandong Province (Grant number. ZR2021QH245).

Authors’ contributions

YL and HZ conceived and drafted the manuscript. YL, JC, XJ, and JL acquired the patient data. XJ, YZ and XT analyzed these patient data. HZ edited and corrected the manuscript. All authors read and approved the final manuscript.

Acknowledgements

Not applicable.

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Table1: Patients and treatment characteristics

Characteristic

No. of Patients (%)

Sex

Men

Women

17（85）

3（15）

Age, y

Range

Median

<70

≥70

45-74

58.5

17（85）

3（15）

KPS score

80

90

15（75）

5（ 25）

Smoking status

Yes

No

14（70）

6（30）

No. of metastatic organs

1

≥2

10（50）

Brain metastasis

Yes

No

9（45）

11（55）

Liver metastasis

Yes

No

7（35）

13（65）

PD-L1 ICIs

Atezolizumab

Durvalumab

9(45)

11(55)

Abbreviations: KPS, Karnofsky performance status; ICIs, immune checkpoint inhibitors.

Table 2: Radiation parameters

Patients		Response to ICI/ChT before TRT	No. of ICI cycles before TRT	Dose (Gy/f)	Grade of RP	V5 (%)	V20 (%)	MLD (cGy)	GTV (ml)	PTV (ml)	The time of RP after TRT (month)
	1	PR	10	45/15	2	27.53	14.49	725.8	38.59	140.24	3.9
	2	PR	6	30/10	2	21.14	6.07	408	11.7	123.54	1.2
	3	PR	6	54/27	2	22.43	9.11	513.9	30.95	138.57	3.6
	4	PR	6	45/15	2	40.95	11.56	717.5	95.52	308.61	1.9
	5	PR	9	50/20	2	22.39	11.07	576.5	22.33	114.82	6.2
	6	PR	7	50/25	2	42.84	23.18	1113.6	188.42	457.31	2.1
	7	PR	5	45/15	1	35.86	19.98	926.5	44.05	267.87	4.33
	8	PR	4	54/30	1	39.85	19.77	1067.8	50.27	382.48	4.03
	9	PR	4	50/20	1	9.15	4.36	263	5.29	31.84	4.83
	10	PR	5	50/20	1	10.87	1.96	213.1	4.25	36.56	7.93
	11	PR	6	46/23	1	26.92	6.56	508.9	14.8	68.53	3.27
	12	SD	6	45/15	1	50.56	14.51	979.0	69.3	294.92	2.00
	13	PR	5	56/28	1	30.48	16.42	890.5	163.34	347.98	2.63
	14	SD	6	50/25	1	24.83	12.17	712.9	106.99	252.19	4.13
	15	PR	4	45/15	1	46.74	21.24	1141.1	42.62	370.28	4.33
	16	PR	7	39/26	0	28.88	12.81	630.8	47.49	298.09
	17	PR	6	30/10	0	28.35	4.74	473.6	18.61	116.28
	18	SD	3	45/30	0	37.60	10.71	659.1	100.08	377.28
	19	PR	5	1.823+2.010	0	46.3	16.96	1025.2	24.63	240.25
	20	PR	7	46.8/26	0	46.54	18.78	1003.9	339.57	576.29

Abbreviations: TRT, thoracic radiation therapy; ChT, chemotherapy; ICI, Immune checkpoint inhibitor; ICI/ChT, Immune checkpoint inhibitor combined with chemotherapy; KPS, Karnofsky performance status; Gy/f, grays/fraction; PR, partial response; SD, stable disease; RP, radiation pneumonitis; MLD, mean lung dose

No competing interests reported.

Safety analysis of immunochemotherapy combined with consolidative thoracic radiotherapy for extensive-stage small cell lung cancer

Status:

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Abstract

Figures

Introduction

Patients And Methods

Study Population and treatment

Statistical analysis

Results

Discussion

Abbreviations

Declarations

References

Tables

Additional Declarations

Status:

Version 2