Management of small cell lung cancer complicated with paraneoplastic Cushing’s syndrome: a systematic literature review

Paraneoplastic Cushing’s syndrome (PCS) is a rare, but clinically important feature of small cell lung cancer (SCLC) that is associated with even worse prognosis. To identify key considerations in comprehensive management of SCLC patients complicated with PCS, we conducted a systematic review of relevant reports on PubMed and Web of Science, focusing on SCLC with PCS cases. The systematic review analyzed 61 reports published between 1985 and 2022 with a total of 157 SCLC patients included. Out of the 157 patients, 132 (84.1%) patients across 58 (95.1%) reports were diagnosed with ectopic Cushing’s syndrome. The immunohistochemical (IHC) staining for adrenocorticotropic hormone (ACTH) was performed on 30 (19.1%) patients across 22 (36.1%) reports and demonstrated encouraging performance. For treatment, chemotherapy and ketoconazole were utilized in 50 (81.97%) and 24 (39.34%) reports, respectively. Regarding cause of death, infection and cancer were equally frequent, each being recorded in 17 (27.87%) reports. To conclude, the majority of PCS cases in SCLC patients were caused by ectopic hormone secretion. In order to make a differential diagnosis, it is recommended to utilize IHC staining for a specific hormone such as ACTH or corticotropin-releasing hormone. In the comprehensive treatment of SCLC with PCS patients, effective management of hypercortisolism and potent safeguarding against infection play two crucial roles. Ultimately, further confirmations are required regarding the specificity and accuracy of IHC staining technique as well as the efficacy and safety of immunotherapy in the treatment of SCLC with PCS patients.

Regarding the management of SCLC with PCS patients, although some effective hypercortisolism controlling methods exist (3,12,13), there was little advancement in treating SCLC for over three decades before the advent of immune checkpoint inhibitors (ICIs) modestly improved its overall survival (14)(15)(16)).However, several reports have emerged on immunotherapyinduced CS, drawing much attention to the adverse effect (17-20).Considering PCS being a poor prognosis marker for SCLC patients, early and further differential diagnosis of CS is relevant for evaluating prognosis of SCLC patients.
Although there have been case reports, case series, and retrospective studies on SCLC complicated with PCS, no systematic review has been carried out on this topic before.Accordingly, we conducted one, incorporating relevant reports of SCLC with PCS available on PubMed and Web of Science.Through this review, we aimed to illustrate the treatment status of this disease previously and to identify key considerations for comprehensive treatment of these patients.

Methods
The systematic review has been conducted and reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement (21).

Literature search and selection
We performed a systematic review of relevant reports of SCLC complicated with PCS on PubMed and Web of Science.The search queries are "(cushing[Title/Abstract]) AND ((sclc[Title/Abstract]) OR (small cell lung cancer[Title/Abstract]) OR (small cell lung carcinoma[Title/Abstract])) NOT ((nsclc[Title/Abstract]) OR (non small cell lung cancer[Title/Abstract]) OR (non small cell lung carcinoma[Title/Abstract]))" on PubMed and "(TS=cushing) AND ((TS=sclc) OR (TS=small cell lung cancer) OR (TS=small cell lung carcinoma)) NOT ((TS=nsclc) OR (TS=non small cell lung cancer) OR (TS=non small cell lung carcinoma))" on Web of Science, respectively.The literature retrieval was performed on 19 November 2022, without restriction on publication date or language.
Selection criteria were as follows: (1) clinical case or case series, prospective or retrospective study, systematic review, or metaanalysis; (2) special reports on this topic or relevant articles involving management of SCLC with PCS patients; (3) critical data available, at least the information on clinical presentation, therapeutic strategy, or causes of death; and (4) no preference for publication date or language.The study was supplemented by screening references of selected articles.
Selection procedures are presented in Figure 1.The evidence quality of included reports has been evaluated using the critical appraisal tools provided by the Joanna Briggs Institute (JBI).

Data extraction and analysis
The following information were collected from eligible articles: age, gender, clinical presentation, the immunohistochemical (IHC) staining for adrenocorticotropic hormone (ACTH), therapeutic strategy, survival time/follow-up time, and cause of death.For retrospective and prospective studies included, the quantitative data on age, survival time, and follow-up time were represented as median (minimum-maximum), while the descriptive information on clinical presentation, therapeutic strategy, and cause of death were recorded as percentages wherever possible.As for clinical presentation, therapeutic strategy, and cause of death, we focused on specific details of critical significance for diagnosis and management of the disease.These specific details were categorized and their frequencies were presented.

Results
Throughout the entire selection process, 61 articles were retrieved, comprising 44 case reports (22-65), 7 case series (66-72), 9 retrospective studies (6)(7)(8)(9)(10)(11)(73)(74)(75), and 1 prospective study (76) published between 1985 and 2022 in English, Japanese, French, German, Spanish, and Korean.A total of 157 SCLC with PCS patients were involved in these 61 articles.Table 1 presents details of included reports and patients while Table 2 displays frequencies of specific details on clinical presentation, therapeutic strategies, and cause of death.The evidence quality of all 61 included reports was evaluated using JBI critical appraisal checklists for case reports, case series, and cohort studies, and results are presented in Supplementary Materials.
All 157 patients were diagnosed with SCLC through histological methods.The one reported by Bodvarsson et al. was a patient with donor-derived SCLC (31).One patient (1/10) reported by Winquist et al. was mixed SCLC with non-small cell lung cancer (NSCLC) (10).The one reported by Qiang et al. was mixed SCLC with large cell neuroendocrine carcinoma (65).The one reported by Vadlamudi et al. had combined SCLC, lung adenocarcinoma, and giant cell carcinoma of the lung (40).
For differential diagnosis of CS, 132 SCLC patients (84.1% of all 157 patients) in 58 reports (95.1% of all 61 reports) were diagnosed with ECS.In 9 (15.5%)reports, 40 (30.3%)patients were diagnosed without strict evidence from combining imaging examinations with laboratory tests or reported with no mention of specific procedures for the diagnosis of ectopic hormone secretion (8,10,22,40,45,49,57,58,72).The patient reported by Cabral et al. (63) and the 23 patients in the report by Nagy-Mignotte et al. (6) were merely diagnosed as PCS without further investigating the hormone origin.The patient reported by Tabata et al. (24) was diagnosed as PCS and his IHC result was negative for ACTH, while some laboratory tests revealed the opposite.In addition, the patient reported by Kosuda et al. was complicated not only by ECS but also by the syndrome of inappropriate antidiuretic hormone secretion (61).Moreover, IHC staining for ACTH was performed in 30 (19.1%) patients, 29 had ECS and 1 had PCS, across 22 (36.1%)reports.Out of these reports, four ECS patients (25,35,39, 57) and one PCS patient (24) showed negative results.It is noteworthy that the case reported by Auchus et al. stained negative for ACTH, but positive for corticotropinreleasing hormone (CRH), which confirmed that the patient's ECS was caused by ectopic CRH secretion rather than ACTH (25).
Regarding clinical presentation, hypokalemia was mentioned in 59 (96.72%) reports as the most frequently recorded clinical feature in PCS patients, followed by hypertension in 42 (68.85%)reports.For treatment, chemotherapy and ketoconazole were the first-line option used for SCLC patients with PCS, in 50 (81.97%)and 24 (39.34%)reports, respectively.As for cause of death, infection was recorded in 17 (27.87%)reports, equally to cancer.The remaining causes included respiratory complications in 16 (26.23%)reports, cardiovascular complications in 8 (13.11%), hormone issues in 7 (11.48%),and other causes (including general condition deterioration) in 15 (24.59%).
General descriptions of specific cases exhibiting long-term survival, mixed pathological types of lung cancer, or negative results in IHC staining for ACTH, as well as a brief introduction to the latest retrospective study, are presented in Supplementary Materials.

Discussion
In this systematic review, we have incorporated relevant reports of SCLC with PCS available on PubMed and Web of Science and presented a comprehensive analysis.Through the review and analysis, we have not only reflected on opportunities to refine the differential diagnostic strategy for PCS, but also discovered key considerations to underpin the comprehensive treatment of SCLC with PCS patients.

Differential diagnosis of ECS from Cushing's disease
Since PCS is a marker of poor prognosis for SCLC patients, it is crucial to perform early differential diagnosis of CS to evaluate the prognosis of SCLC patients.Once the CS has been identified and the ACTH non-dependent type has been ruled out, the most  No individual imaging examination or laboratory test has been explicitly recommended to definitively differentiate between pituitary and ectopic CS (3,66,77).Despite the fact that highdose dexamethasone suppression test and CRH stimulation test may individually yield inaccurate outcomes, their combination has shown a better diagnostic performance (3,12,(77)(78)(79)(80).Following the Pituitary Society's guideline, in the event of negative outcomes for both tests, consideration should be given to diagnosing ECS.Conversely, if both tests yield positive results, CD should be acknowledged.If the results are mismatched, a bilateral inferior petrosal sinus sampling is necessary for a definite diagnosis (77).Furthermore, a conclusion drawn in collaboration with imaging techniques must be more convincing.The guideline recommended magnetic resonance imaging (MRI) as the preferred modality for imaging ACTH-secreting pituitary adenomas (77) despite its high rate of false negative or false positive (12, 66, 81).Moreover, emerging data have suggested that the CRH/desmopressin stimulation test in collaboration with pituitary MRI, subsequently followed by a whole-body computed tomography scan, could be a reliable alternative (77, 82, 83).However, some investigators suggested that a conclusive diagnosis of an ACTH-secreting tumor should only be made post-surgery.After surgical removal of the tumor, the resolution of hypercortisolism symptoms and the positive IHC staining for ACTH or its precursor in excised tissues could indicate an ECS diagnosis (66,81).
IHC staining for ACTH has demonstrated a high degree of reliability for its consistency with outcomes from the combination of laboratory tests and imaging examinations within our reviewed reports.However, none of the three guidelines from the American Endocrine Society, European Society of Endocrinology, or the Pituitary Society contained any histological diagnosis-relevant contents on ECS diagnosis in SCLC patients (13, 77, 78, 84).We The percentage was calculated as the proportion of the articles with records of corresponding details out of the all 61 articles.look forward to this technique being evaluated by a proficient multidisciplinary team in the future and the latest guidelines shedding some light on this diagnostic method.The IHC staining of a distinctive hormone (either ACTH or CRH) allows us to make an early diagnosis of ECS in conjunction with the pathological diagnosis of SCLC and to take prophylactic measures against hypercortisolism, which can exacerbate cancer-induced immunosuppression and cause severe infectious complications afterwards (6,8,9,11,64,85).
Based on the literatures reviewed and the charts appreciated (3, 11-13, 66, 78, 82, 86, 87), we improved and perfected the specific flowchart for the multistep diagnostic procedures of ECS from Deldycke et al. (66).The flowchart is displayed in Figure 2. Frontiers in Endocrinology frontiersin.org

Therapeutic strategy for SCLC with PCS
The treatment of SCLC with PCS patients demands two primary factors.On one hand, it is vital to manage hypercortisolism and take prophylactic measures against infections.On the other hand, some therapeutic strategies have advanced in the treatment of SCLC.
On one hand, both infection and cancer ranked highest among all causes of death, with each being mentioned in 17 (27.87%)reports.Furthermore, a significant number of patients had infections recorded before respiratory complications (indicated in 16 reports).Infection facilitated by glucocorticoid-induced immunosuppression and chemotherapy-induced agranulocytosis is a significant poor prognostic factor for SCLC with PCS patients (6,8,9,11,64,85).Therefore, management of hypercortisolism and prophylaxis against infection is particularly important throughout the entire treatment process.Many authors emphasized the importance of controlling hypercortisolism by a specific treatment before or concurrently with chemotherapy to prevent infectious complications (6,43,52,64,75,76).Apart from radiotherapy and surgical removal, the main pharmacological treatments for PCS include steroidogenesis inhibitors (e.g., ketoconazole, metyrapone, mitotane, etomidate, and osilodrostat), glucocorticoid receptor antagonists (e.g., mifepristone), somatostatin analogs (e.g., octreotide, lanreotide, and pasireotide), and dopamine agonists (e.g., cabergoline) (3,4,12,13).According to guidelines and high-quality reviews, steroidogenesis inhibitors have been the principal treatment to control hypercortisolism while somatostatin analogs and dopamine agonists are recommended to inhibit ectopic ACTH production with limited intensity (3,4,12,13).Within our included reports, steroidogenesis inhibitors were used most frequent as in 39 (63.93%) reports, especially ketoconazole recorded in 24 (39.34%)reports, while somatostatin analogs and mifepristone were used little and no dopamine agonists were recorded.
On the other hand, the ultimate cause of hypercortisolism is ectopic hormone secretion by tumor tissues, meaning that the treatment for cancer is fundamental to the management of hypercortisolism and effective anti-cancer treatment could alleviate PCS symptoms.All 61 reports we examined recorded chemotherapy and radiotherapy as anti-tumor therapeutic strategies apart from surgery.In fact, there had been no substantial progress in treatment of SCLC for over 30 years until ICIs updated the treatment pattern and modestly improved its overall survival (1,2,14,15).Formerly, platinum plus etoposide combination chemotherapy was the preferred regimen for both limited and extensive SCLC.Nowadays, the new standard of care in first-line setting for SCLC is immuno-chemotherapy that combines atezolizumab or durvalumab with platinum-etoposide (14,15,88,89).Considering significant improvement in medical care over recent years and the introduction of immunotherapy into therapeutic strategy for SCLC, we look forward to seeing some reports, especially high-quality large-sample studies conducted by proficient teams, evaluating the efficacy and safety of some novel medical approaches, particularly the immunotherapy, for the treatment of SCLC with PCS in the future.
We retrieved all drug approval notifications for SCLC in the Oncology (Cancer)/Hematologic Malignancies Approval Notifications) section on the official website of USA Food and Drug Administration, which revealed a slow progression in treatment of SCLC compared to NSCLC, as summarized in Supplementary Materials.

Limitations
This systematic review has some limitations that need to be acknowledged in order to contextualize the conclusions that have been drawn or will be drawn from it.Firstly, the literature available on the subject is relatively limited, and there exists a significant degree of heterogeneity among the reports included in this review.This review includes several types of studies, and there are significant differences in outlines, focuses, and details of reported management of the disease, even within the same study type.Secondly, the evidence grade of case reports or case series is low.Among the 61 included reports, a significant proportion is composed of 44 case reports and 7 case series.As a result, the complete data in Table 2 were derived from the number of reports that had records of corresponding details, rather than from the number of patients, which makes the statistical analysis sketchy and generalized.Thirdly, the included reports stretch over a period from 1985 to 2022, during which medical care rapidly evolved, which could be the inherent limitation for systematic reviews with too wide a temporal scope.Ultimately, it is essential to acknowledge that this systematic review serves only as a preliminary exploration for the management of SCLC with PCS patients, and further validation is eagerly awaited from future high-quality studies covering significant sample sizes.

Conclusions
This systematic review indicated that the majority of PCS complications in SCLC patients were caused by ectopic hormone secretion.Furthermore, it is recommended to enhance the employment of IHC staining for distinctive hormones (ACTH or CRH) in clinical practice for early differential diagnosis of PCS.Moreover, effective management of hypercortisolism and potent safeguarding against infections could form the foundation of comprehensive treatment of SCLC with PCS patients.

Data availability statement
The original contributions presented in the study are included in the article/Supplementary Material.Further inquiries can be directed to the corresponding author.

FIGURE 1 Flow
FIGURE 1Flow diagram for publication selection procedures performed according to the PRISMA 2020 Statement.

TABLE 1
The 61 reports of SCLC complicated with PCS from PubMed and Web of Science.

TABLE 2
The frequency of specific details recorded in all 61 reports.