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• Published: 18 October 2022

A systematic review of interventions to recognise, refer and diagnose patients with lung cancer symptoms

• Mohamad M. Saab   ORCID: orcid.org/0000-0002-7277-6268 1 ,
• Megan McCarthy 1 ,
• Michelle O’Driscoll 1 ,
• Laura J. Sahm 2 ,
• Patricia Leahy-Warren 1 ,
• Brendan Noonan 1 ,
• Serena FitzGerald 1 ,
• Maria O’Malley 1 ,
• Noreen Lyons 3 ,
• Heather E. Burns 4 ,
• Una Kennedy 4 ,
• Áine Lyng 4 &
• Josephine Hegarty 1  

npj Primary Care Respiratory Medicine volume  32 , Article number:  42 ( 2022 ) Cite this article

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• Respiratory signs and symptoms
• Respiratory tract diseases

Patients with lung cancer (LC) often experience delay between symptom onset and treatment. Primary healthcare professionals (HCPs) can help facilitate early diagnosis of LC through recognising early signs and symptoms and making appropriate referrals. This systematic review describes the effect of interventions aimed at helping HCPs recognise and refer individuals with symptoms suggestive of LC. Seven studies were synthesised narratively. Outcomes were categorised into: Diagnostic intervals; referral and diagnosis patterns; stage distribution at diagnosis; and time interval from diagnosis to treatment. Rapid access pathways and continuing medical education for general practitioners can help reduce LC diagnostic and treatment delay. Awareness campaigns and HCP education can help inform primary HCPs about referral pathways. However, campaigns did not significantly impact LC referral rates or reduce diagnostic intervals. Disease outcomes, such as LC stage at diagnosis, recurrence, and survival were seldom measured. Review findings highlight the need for longitudinal, powered, and controlled studies.

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Introduction.

Lung cancer (LC) is the most common cause of cancer incidence and mortality worldwide, with 2.1 million new cases and 1.8 million deaths in 2018 1 . It is estimated that, by 2040, the number of annual LC diagnoses and deaths will increase to 3.63 and 3.01 million respectively 2 . Worldwide, more than half of LCs (53%) are diagnosed in people aged between 55 and 74 years 3 . Data from 185 countries indicate that LC is typically diagnosed at an advanced stage, with a 5-year survival rate of 10–20% 4 .

LC has a relatively broad symptom signature compared to other cancers, such as breast and testicular cancers that typically present with a single identifiable symptom (e.g., painless lump) 5 , 6 , 7 . Early-stage LC can be asymptomatic or can cause a range of symptoms including a persistent cough, changes to an existing cough, shortness of breath, and chest pain 8 , 9 . Systemic symptoms, such as unexplained weight loss and fatigue, are typically associated with advanced disease 10 . Haemoptysis is one of the strongest symptom predictors of LC 8 , 11 . The broad symptom signature of LC, and overlap with common symptoms of benign disease, may contribute to delays in presentation and diagnosis 12 .

Early medical help-seeking for symptoms suggestive of LC is a key enabler of early diagnosis, curative treatment, and improved survival 11 . However, a Swedish study found that patients diagnosed with LC experience, on average, a 6-month delay between symptom onset and initiation of treatment 13 . Reasons for delayed patient help-seeking include patient factors, such as symptom misappraisal, fear of a potential cancer diagnosis, and guilt associated with smoking 14 , 15 , as well as healthcare system factors, such as the high financial cost of healthcare, lack of access to healthcare, and previous bad experiences with the healthcare system 15 , 16 , 17 , 18 .

Primary healthcare professionals (HCPs) play a key role in facilitating early diagnosis through recognising people with signs and symptoms suggestive of LC and referring them appropriately 19 . HCP-related barriers to early diagnosis of LC may include lack of awareness of signs and symptoms of LC, inadequate access to diagnostics and rapid referral pathways, and fear of overburdening the healthcare system 15 , 18 . In this systematic review, we identify and describe the effect of interventions aimed at helping HCPs recognise and refer individuals with signs and symptoms indicative of LC to the appropriate healthcare pathway in a timely manner.

This systematic review was guided by the Cochrane Handbook for Systematic Reviews of Interventions 20 and reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist 21 (Supplementary Table 1 ).

Eligibility criteria

Using a modified version of the population, intervention, comparison, and outcomes (PICO) framework 22 , to include “S” for study design and “T” for timeframe (PICOST), the systematic review inclusion criteria were as follows: population: any HCPs. Studies were included only when patient outcomes were reported as a result of an intervention targeted towards HCPs; Intervention: any intervention, campaign, programme, trial, education, algorithm, decision tree/support, or guide aimed at improving early diagnosis of symptomatic LC; comparison: any pre-post comparison; outcomes: any outcomes (e.g., LC diagnosis among symptomatic patients, stage of LC at diagnosis, LC treatments received, and LC survival); study design: any experimental design; and timeframe: studies published between January 2011 and September 2021 in order to identify the latest evidence.

Studies were excluded if interventions were exclusively targeted at patients, did not incorporate a comparator, and/or used non-experimental designs. Studies focusing on detection of LC in asymptomatic individuals (i.e., through screening or surveillance) were also excluded. Moreover, we excluded conference proceedings, dissertations, and theses.

Search strategy

MEDLINE, CINAHL, ERIC, and Academic Search Complete were searched on September 13, 2021. Truncation “*” was used and keywords were combined using Boolean operators “OR” and “AND” and the proximity indicator “N.” The following keywords were searched based on title or abstract: (Interven* OR program* OR campaign* OR trial* OR experiment* OR educat* OR algorithm* OR “decision* tree*” OR “decision* support*” OR guid*) AND (Refer* OR consult* OR recogni* OR counsel* OR advice OR advis* OR detect* OR find* OR triag* OR direct* OR manag* OR signpost* OR know* OR aware* OR understand*) AND ((Lung* OR pulmo*) N3 (cancer* OR neoplas* OR malignan* OR tumo* OR symptom* OR sign*)) AND (“Health* profession*” OR “health care profession*” OR HCP* OR “health* work*” OR “health care work*” OR HCW* OR clinician* OR nurs* OR “public health nurs*” OR PHN* OR “community nurs*” OR “clinic nurs*” OR “practice nurs*” OR pharmac* OR chemist* OR doctor* OR physician* OR “general practitioner*” OR GP* OR consultant*).

Study extraction and synthesis

Records were screened in Covidence, an online software used to streamline the production of systematic reviews 23 . First, titles and abstracts were screened, and irrelevant records were excluded. Full texts of potentially eligible records were then sourced and screened. Each record was title, abstract, and full text screened twice by two independent reviewers. Screening conflicts were resolved by a third reviewer.

The following data were extracted for each study using a standardised table 14 , 24 (Supplementary Table 2 ): author(s); year; country; aim; design; theoretical underpinning; sample; setting; relevant outcomes; intervention; procedures; instruments; follow-up time(s); and relevant findings. One reviewer conducted data extraction. Each extracted study was then cross-checked for accuracy by the review team. Meta-analyses were not plausible due to significant heterogeneity in study design, interventions, and outcome measures. Instead, a narrative synthesis was conducted, which involved grouping and synthesising the results according to the outcomes measured within the reviewed studies 25 .

Quality appraisal and level of evidence assessment

The Mixed Methods Appraisal Tool was used to appraise the methodological quality of the included randomised controlled trials (RCTs) and non-RCTs 26 . Quality appraisal was conducted in terms of the appropriateness of recruitment, data collection, and data analysis to the research question. Each item was voted on a “yes,” “no,” and “cannot tell” basis. The Scottish Intercollegiate Guidelines Network 27 grading system was used to assess the level of evidence for each of the included studies. The eight levels of evidence range between 1++, 1+, 1−, 2++, 2+, 2−, 3, and 4. For instance, a score of 1++ corresponds to high quality meta-analyses, systematic reviews of RCTs, or RCTs with a very low risk of bias, whereas a score of 4 is assigned to expert opinions 27 . Quality appraisal and level of evidence assessment were conducted by one reviewer and cross-checked for correctness by the review team.

Study selection

Database searching resulted in 5829 records. Following deletion of duplicates, 3556 records were screened by title and abstract and 3458 irrelevant records were excluded. The full texts of the remaining 98 records were obtained and screened. Of those, seven were included in this systematic review (Fig. 1 ).

Study identification, screening, and selection process.

Study characteristics

Most of the studies were conducted in Denmark ( n  = 2) and England ( n  = 2) and were non-RCTs ( n  = 5). Sample size ranged widely between 72 28 and 56,020 29 participants and follow-up times varied from 3 30 to 37 months 31 . Five different interventions were used across the seven studies, including: (i) Combined public and HCP LC awareness campaigns; 30 , 32 (ii) letters and continuing medical education (CME) meetings to educate general practitioners (GPs) about referral criteria for fast-track evaluation of patients with “reasonable suspicion” of LC (maximum 72 h waiting time for evaluation, which includes low dose computed tomography [LDCT]); 33 , 34 (iii) a cancer fast-track programme (i.e., target of 30 days between well-founded suspicion of cancer by a GP and the start of treatment). Referrals to this programme can also originate from emergency departments or other clinical departments involved in routine monitoring or screening; 29 (iv) the thoracic-trained advanced practice provider-led LC strategist programme to minimise diagnostic redundancy, streamline management decisions for indeterminate nodules, and expedite curative therapy. Once patients were referred from primary care to secondary care, an individual evaluation strategy was developed and followed for them; 31 and (v) multi-disciplinary meetings, screensavers, and posters to reduce delay between initial suspicion of LC and measurement of serum calcium levels 28 . Of note, Hypercalcaemia is a serious complication of LC and is associated with poorer prognosis 28 . The full characteristics of the included studies are presented in Table 1 .

All the included non-RCTs ( n  = 5) used appropriate data collection methods, outcome measures, and intervention administration. Outcome data were complete in all non-RCTs. Four non-RCTs had clear research questions. The study by Philips et al. 31 did not have a clear aim statement, despite clearly stated hypotheses. Only one non-RCT reported that participants were representative of the target population 33 and only one non-RCT reported that confounders were accounted for in the study design 28 . Both RCTs ( n  = 2) had clear research aims, performed randomisation appropriately, collected data in line with the research aims, had groups that were comparable at baseline, and reported on participant adherence to the assigned intervention 30 , 34 . However, the outcome assessor was not blinded in Gudlbrant et al.’s 34 RCT.

Four studies scored 2+ on the Scottish Intercollegiate Guidelines Network 27 level of evidence criteria, indicating well-conducted non-RCTs with a low risk of confounding or bias and a moderate probability that the relationship is causal 29 , 31 , 32 , 33 . Only one study scored 2++, indicating a well-conducted non-RCT with a low risk of confounding or bias and a moderate probability that the relationship is causal 28 . Both RCTs scored 1+ indicating well-conducted RCTs with a low risk of bias 30 , 34 . See Table 2 for quality and level of evidence assessment.

Synthesis of findings

Outcomes reported in the reviewed studies were categorised into four categories as follows: diagnostic intervals; referral and diagnosis patterns; stage distribution at diagnosis; and time interval from diagnosis to treatment.

Diagnostic interval

Four studies aimed to reduce the diagnostic interval (i.e., the time from the first presentation with symptoms of LC until diagnosis 35 ) using the LC strategist programme 31 , a community- and GP-targeted cancer awareness campaign 30 , information on LDCT and CME sessions 34 , and a multimodal quality improvement project 28 .

A retrospective review of the LC strategist programme found that time from suspicious findings on CT chest, chest X-ray, and to a lesser extent abdominal CT, to initiation of diagnostic workup of lung nodules for treatment or surveillance was significantly shorter with the programme in comparison to routine referral (3 vs 28 days respectively, p  < 0.001) 31 . Following referral, the median time to workup was also significantly shorter with the programme in comparison to routine referral (1 vs 7 days respectively, p  < 0.001) 31 .

In contrast, a concurrent community- and GP-targeted breast, prostate, colorectal, and LC awareness campaign found no statistically significant difference in the total diagnostic interval at community (i.e., public intervention) level (median total diagnostic interval = 114.5 days pre-test vs 114 days post-test, mean difference = 0.06, 95% confidence interval [CI] 0.39–0.5, p  = 0.79) or at GP level (median total diagnostic interval = 115 days pre-test vs 125 days post-test, mean difference = 0.02, 95%CI 0.56–0.60, p  = 0.45) 30 . Likewise, a study measuring the effect of an intervention to inform GPs about direct access to LDCT found no statistically significant difference in primary care interval (i.e., the time from the patient’s first symptomatic presentation in primary care until referral to secondary care 35 ) between patients of GPs who received information about indications for LDCT (intervention group) (media n  = 14 days, inter quartile intervals [IQI] = 4–53) and patients of GPs who did not receive this information (control group) (media n  = 18 days, IQI = 5–69, Prevalence Ratio [PR] = 0.99, 95%CI 0.65–1.54, p  = 0.455) 34 . Moreover, no statistically significant difference was found in the diagnostic interval between patients in the intervention group (media n  = 44 days, IQI = 17–83) and the control group (media n  = 36 days, IQI = 17-112, PR = 0.8, 95%CI 0.5–1.27, p  = 0.299). However, the primary care and diagnostic intervals in the intervention group were significantly shorter if the GP also participated in a 1-h small-group-based CME session (primary care interval median = 9 days [with CME] vs 37 days [without CME], p  = 0.048; diagnostic interval median=23 days [with CME] vs 66 days [without CME], p  = 0.008) 34 .

In their quality improvement project, Apthrop et al. 28 used multidisciplinary meetings, screensavers, and posters encouraging secondary care physicians to order serum calcium levels in patients with a suspected diagnosis of LC. This project aimed to help reduce delay between initial suspicion of LC and ordering serum calcium levels during initial LC diagnostic workup in England. This project led to a statistically significant reduction in overall median time to ordering serum calcium levels in patients with a suspected diagnosis of LC, from 13 days pre-test (i.e., before the quality improvement project) to 7 days post-test ( p  = 0.001) 28 .

Referral and diagnosis patterns

Three studies reported on patterns of LC referral and diagnosis following implementation of a public awareness and GP training campaign 32 , a cancer fast-track programme 29 , and GP information and CME sessions on indications for LDCT 33 . Athey et al. 32 delivered a public and GP LC awareness campaign in six English communities with high LC incidence served by 11 GP surgeries (intervention group). This campaign ran for six weeks and used a “push-pull” approach to “push” the public to seek help for symptoms of concern and encourage GPs to “pull” symptomatic individuals into appropriate services. Five other communities served by nine GP surgeries with similar demographics served as the control group. There was a 27% increase in the number of chest X-rays ordered in the intervention group compared to a 19% increase in the control group during the campaign and six months post-test. In comparison to pre-campaign, there was a sustained increase in chest X-rays requested in the intervention group (20% relative increase) in comparison to a 2% relative reduction in the control group (Incidence Rate Ratio [IRR] = 1.22, 95%CI 1.12–1.33, p  = 0.001) at 12 months post-campaign. Moreover, LC diagnoses increased by 27% (relative increase) in the intervention group and fell by 10% (relative reduction) in the control group. However, this was not statistically significant (IRR = 1.42, 95%CI 0.83–2.44, p  = 0.199) 32 .

In a study of a cancer fast-track programme in Catalonia, Prades et al. 29 noted increased use of the programme over time, with 3336 patients with suspected LC referred via the programme in 2006, compared to 3841 patients in 2009. The proportion of all new LCs that were diagnosed through this programme fell from 60.2% (95%CI 59.8–63.4%) in 2006 to 53.2% (95%CI 51.5–54.9%) in 2009. GPs were the source of 60.6% of referrals to the fast-track programme in 2006 (95%CI 59–62.3%), falling to 41.4% (95%CI 39.7–42.9%) in 2009, demonstrating increased referrals from other sources such as hospital-based clinicians and services. The LC detection rate via the programme fell from 49.9% (95%CI 48.2–51.6%) in 2006 to 39.7% (95%CI 38.1–41.2%) in 2009. Prades et al. 29 reported a statistically significant increase in GP compliance with cancer fast-track referral guidelines from 70.8% in 2006 (95%CI 69.1–72.1%) to 82.3% in 2009 (95%CI 81.1–83.5%).

In a cohort study nested in an RCT, Guldbrandt 33 examined the use of a fast-track referral option for GPs for patients with suspected LC and the effect of GP education and awareness training on direct referral to LDCT. This education comprised a one-hour CME session and information about LDCT, including indications and Positive Predictive Values (PPV) for LC (i.e., the ratio of patients truly diagnosed as positive to all those who had positive test results). Results showed that, out of 648 patients directly referred to LDCT, absolute numbers of referrals were significantly higher (61%, 95%CI 54–66%) among GPs working in a clinic with one or more CME-participating GPs. However, the referral rate to LDCT via fast-track was 0.13 per 1000 adults per month (95%CI 0.09–0.19) for CME-participating GPs compared to 0.14 (95%CI 0.09–0.20) for non-participating GPs. The PPV for LC diagnosis due to referral to a fast-track LC pathway was 13.3% (95%CI 8.7–19.1%) for CME-participating GPs and 6.1% (95%CI 3–11%) for non-participating GPs (2.2 higher PPV). This was found to be statistically significant ( p  = 0.027) 33 .

Stage distribution at diagnosis

Three studies reported on LC stage at diagnosis following an intervention. Athey et al. 32 examined LC stage at diagnosis following a “push-pull” LC awareness campaign, Guldbrandt et al. 34 examined LC stage at diagnosis following an information programme and CME sessions on LDCT for GPs, and Philips et al. 31 examined LC stage at diagnosis following the LC strategist programme. Athey et al. 32 found no significant stage shift three months, six months, or one year following the LC “push-pull” awareness campaign. Similarly, Guldbrandt et al. 34 reported a non-statistically significant difference in stage of LC at diagnosis between the intervention group (i.e., information and CME sessions on LDCT) and control group ( p  = 0.586 for advanced LC and p  = 0.595 for localised LC). Philips et al. 31 also found non-statistically significant difference in stage at diagnosis for the seven patients in the LC strategist programme and 33 routine referral patients who underwent surgery for LC. This was the only study to report on disease free survival and overall survival. It was found that six of the seven patients (85.7%) in the LC strategist programme cohort were found to have early-stage disease with a median time of 37 days from suspicious imaging to treatment 31 . In these six patients, with a median duration of follow up of 33 months, disease free survival and overall survival were 100% (i.e., no LC recurrence and no LC death). As for the routine referral group, 25 of 33 patients (75.7%) were found to have early-stage LC with a median time of 68 days from suspicious imaging to treatment. In these 25 patients, there were six recurrences (76% disease free survival) and no deaths (100% overall survival) over a median time of 35 months. The differences in survival rates between the LC strategist programme group and the routine referral group were not statistically significant 31 .

Time interval from diagnosis to treatment

The time from LC diagnosis to treatment was measured in two studies following two specialist programmes, namely the cancer fast-track programme 29 and the LC strategist programme 31 . The latter study found that the time from suspicious imaging to definitive management plan was 14.5 days in the LC strategist programme and 46.5 days in routine referral ( p  < 0.001) 31 . It was also found that referral to the programme moved patients into low-risk nodule surveillance approximately one month earlier relative to routine referral (12.5 vs 39 days respectively, p  < 0.001). Compared to routine referral, management through the programme also significantly reduced the median number of hospital trips (4 vs 6 respectively, p  < 0.001), median number of clinicians seen (1.5 vs 2 respectively, p  = 0.08), median number of diagnostic studies obtained (4 vs 5 respectively, p  = 0.01), median time from suspicious radiological findings to diagnosis (30.5 vs 48 days respectively, p  = 0.02), and median time from suspicious radiological findings to treatment (40.5 vs 68.5 days respectively, p  = 0.02) 31 . Moreover, time from suspicious radiological findings to surgical resection was significantly shorter in patients managed through the programme in comparison to routine referral (38 vs 69 days respectively, p  = 0.05). Among patients with early-stage non-small cell LC treated with radiation therapy, the LC strategist programme led to a substantial reduction in the time from suspicious radiological findings to initiation of treatment in comparison to routine referral (62.5 vs 122.5 days respectively, p  = 0.08) 31 . Conversely, in the cancer fast-track programme, Prades et al. 29 noted a variable trend in mean time from detection of suspected LC in primary care to start of initial treatment. The 30-day target was not achieved, with mean times of 30.8 days, 38.9 days, 32.25 days, and 36.7 days in 2006, 2007, 2008, and 2009 respectively. There was also an increase in the proportion of patients waiting between 30 and 45 days (23.7% in 2006 vs 26.1% in 2009) and over 45 days (13.6% in 2006 vs 22.6% in 2009) from the time of LC detection to initiation of treatment.

Achieving early diagnosis is an essential step in improving LC outcomes 28 , 29 , 30 , 31 , 34 . While more than 85% of patients subsequently diagnosed with cancer initiate their diagnostic pathway in primary care 35 , timely recognition and referral of people with suspected LC is complicated by various primary HCP and system-related factors. For example, a scoping review of 33 studies identified low index of suspicion, delays in obtaining access to diagnostic tests, multiple specialist consultations and lack of rapid assessment services as barriers to early diagnosis of LC 36 . Additionally, a qualitative study of 16 GPs from five practices in the United Kingdom found that GPs often required high levels of suspicion to refer patients to secondary care and were concerned about overloading the healthcare system by over-referring patients 37 . More recently, Saab et al. 38 interviewed 36 primary HCPs (GPs, community pharmacists, GP practice nurses, and public health nurses) about their experience of referring individuals with suspected LC in Ireland. It was found that “typical” LC lung signs and symptoms such as cough and haemoptysis triggered referrals, whereas “atypical” signs and symptoms like back pain and pallor, were perceived as difficult to interpret. Participants suggested educating primary HCPs about early LC referral using “communications from professional organisations, webinars, interdisciplinary meetings, education by lung specialists, and patient testimonials” (p.1) 38 . The use of simple, clear, and visually appealing LC referral checklists and algorithms in primary care was also recommended 38 .

Several studies included in the present review reported on efforts to raise awareness of LC signs and symptoms among HCPs, and prompt timely referral for further diagnostic or specialist evaluation. These included: a combined public and HCP LC awareness campaign which used GP education resource cards with symptom risk assessment charts to increase symptom awareness and early specialist referral among GPs; 30 a push-pull campaign that involved educating GPs and community pharmacists about chest X-ray referral criteria for symptomatic patients; 32 and CME sessions for GPs addressing the indications for LDCT for signs and symptoms that raised GPs’ suspicion of LC, but fell short of satisfying the fast-track referral criteria 33 , 34 . Indeed, the effect of CME meetings on raising GPs’ awareness of cancer signs and symptoms and prompting early referral is well documented in the wider literature. Toftegaard et al. 39 studied the impact of CME meetings in Denmark to support GPs in recognising and referring patients with cancer warning signs and symptoms. An evaluation of this initiative found that CME meetings significantly improved knowledge of cancer among GPs and increased the number of urgent referrals 39 , which is associated with better cancer survival 40 , 41 .

Interventions that were successful in reducing the diagnostic interval included a multi-modal quality improvement project in primary care 28 and the LC strategist programme in secondary care 31 . In contrast, statistically significant reductions in diagnostic intervals were not achieved following a community- and GP-targeted awareness campaign 30 as well as information for GPs on LDCT for symptomatic patients 34 . GP participation in a 1-h CME session on LDCT, however, was associated with shorter primary care and diagnostic intervals 34 , higher absolute number of referrals to LC fast-track, and higher PPV for LC diagnosis 33 .

Postal questionnaires offer a pro-active, if somewhat resource intensive, option for primary HCPs to prompt help-seeking among high-risk symptomatic patients. For example, Wagland et al. 42 studied the impact of sending a postal symptom questionnaire, incorporating nine symptoms of LC, to patients identified as high risk for LC in eight GP practices in England. Through this intervention, a small, clinically relevant group (6.7%, n  = 61/908) of primary care patients was identified who, despite reporting potential symptoms of LC, had not consulted a GP in ≥12 months. Primary care consultations significantly increased in the 3-month period following receipt of the symptom elicitation questionnaire compared to the 3-month period pre-questionnaire ( p  = 0.002) 42 . Participants who decided not to consult their GP cited concerns over wasting their own and the GP time and reported a high symptom tolerance threshold and a greater tendency to self-manage their symptoms 42 . These barriers are well documented in the wider literature 15 , 16 , 18 .

The benefits of cancer fast-track pathways/programmes are well documented in the international literature 43 , 44 , 45 , 46 . Fast-track referral criteria are typically based on the presence of combinations of, or individual, ‘alarm’ cancer signs and symptoms and/or relevant radiological findings, usually with a PPV for cancer of 3% or above 47 . Two of the reviewed studies evaluated the impact of specialist-led and fast-track programmes on time from suspicious radiologic findings 31 and LC detection 29 to the planning and initiation of treatment. In comparison to routine referral, the specialist-led LC strategist programme significantly reduced the intervals between suspicious radiologic findings and definitive management plan, diagnosis, and treatment 31 . In contrast, in their evaluation of a cancer fast-track programme from its inception in 2006 until 2009, Prades et al. 29 reported a significant increase in waiting times from LC detection to initiation of treatment. This may be explained by factors including the complexity of LC treatment, including thoracic surgery at tertiary hospitals 29 .

Interventions aimed at prompting early referral and diagnostic work-up do not always lead to significant improvements in stage of LC at diagnosis and overall survival. Our systematic review demonstrated that CME sessions on the indications for LDCT 34 , the specialist-led LC strategist programme 31 , and a combined public and HCP cancer awareness campaign 32 , were not associated with significant differences in stage of LC at diagnosis. In addition, Philips et al. 31 found non-statistically significant differences in LC recurrence and mortality in patients referred through the LC strategist programme in comparison to those referred through routine referral. Larger scale studies with more statistical power and prospective RCTs with longer follow-up are recommended 31 , 32 , 34 .

This review offers valuable insights into interventions aimed at improving the early diagnosis of symptomatic LC. However, a few limitations are worthy of note. While there is some evidence for the effectiveness of CME meetings and fast-track programmes, recommendations for clinical practice should be made with caution, particularly due to the small number of studies included in this review and the fact that meta-analyses were not possible due to significant heterogeneity in study design, interventions, and outcome measures. Study selection bias could have occurred, as only studies relevant to the review aims were included, the search did not include records from the grey literature or clinical trial registries, and the review was limited to studies published within a 10-year timeframe.

In conclusion, findings from this review indicate that CME meetings for primary HCPs may facilitate early LC referral, diagnosis, and survival. We also found evidence that fast-track programmes, such as the LC strategist programme 31 , may improve time from initial presentation with symptoms in primary care to LC diagnosis, and time from diagnosis to treatment, in addition to reducing hospital visits and the number of clinicians seen between initial presentation and initiation of treatment. However other interventions, such as awareness campaigns, were not associated with significant improvements in outcomes 30 , 32 . Outcomes such as LC stage shift and mortality rates were seldom measured in the reviewed studies. When measured, statistical significance was not reached, hence the importance of conducting future studies that are appropriately powered, controlled, and have longer follow-up.

Review findings may inform cancer control policy, including the design and implementation of interventions aimed at overcoming barriers to early LC diagnosis. These interventions may include awareness and education campaigns targeting the public and HCPs, and implementation of specialist-led fast-track referral programmes to facilitate timely diagnosis.

Data availability

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

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Acknowledgements

The authors would like to thank the National Cancer Control Programme, Health Services Executive, Ireland for funding this research.

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M.M.S., H.E.B., U.K., Á.L. and J.H. contributed to study conception. M.M.S., M.Mc.C., M.O’.D., L.J.S., P.L.-W., B.N., S.F., M.O’.M. and N.L. performed screening, data extraction, and quality appraisal. M.M.S. and M.Mc.C. drafted the manuscript and all authors provided critical revisions and editing of the manuscript.

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Saab, M.M., McCarthy, M., O’Driscoll, M. et al. A systematic review of interventions to recognise, refer and diagnose patients with lung cancer symptoms. npj Prim. Care Respir. Med. 32 , 42 (2022). https://doi.org/10.1038/s41533-022-00312-9

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A systematic literature review of real-world treatment outcomes of small cell lung cancer

Stokes, Michael MPH a ; Berfeld, Noami MSc b ; Gayle, Alicia MSc c,* ; Descoteaux, Andrew MS a ; Rohrmoser, Oscar MD d ; Franks, April PhD d

a Evidera, Waltham, Massachusetts, United States

b Evidera, London, United Kingdom

c AstraZeneca, Cambridge, United Kingdom

d AstraZeneca, Gaithersburg, Maryland, United States.

Received: 9 June 2021 / Received in final form: 24 November 2021 / Accepted: 25 May 2022

Supplemental Digital Content is available for this article.

This study was funded by AstraZeneca.

Michael Stokes is a full-time employee of Evidera, holds PPD stock options, and received funding from AstraZeneca. Noami Berfeld and Andrew Descoteaux are full-time employees of Evidera and received funding from AstraZeneca. Alicia Gayle, Oscar Rohrmoser, and April Franks are full-time employees of AstraZeneca and hold AstraZeneca stocks options.

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.

How to cite this article: Stokes M, Berfeld N, Gayle A, Descoteaux A, Rohrmoser O, Franks A. A systematic literature review of real-world treatment outcomes of small cell lung cancer. Medicine 2022;101:26(e29783).

*Correspondence: Alicia Gayle, Epidemiology, AstraZeneca, OBU, Global Medical Affairs, Global Real World Evidence Generation, City House, 126–130 Hills Road, Cambridge CB2 1RY, United Kingdom (e-mail: [email protected] ).

This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background: 

Robust evidence from real-world studies is needed to aid decision-makers and other stakeholders in choosing the best treatment options for patients. The objective of this work was to assess real-world outcomes of treatment strategies for limited- and extensive-stage small cell lung cancer (SCLC) prior to the global introduction of immunotherapies for this disease.

Methods: 

Searches were conducted in MEDLINE and Embase to identify articles published in English from October 1, 2015, through May 20, 2020. Searches were designed using a combination of Medical Subject Heading (Medline), Emtree (Embase subject headings), and free-text terms such as SCLC. Observational studies reporting data on outcomes of initial treatment strategies in patients with limited- and extensive-stage SCLC were included. Studies with limited sample sizes (<100 patients), enrolled all patients prior to 2010, or did not report outcomes for limited- and extensive-stage SCLC separately were excluded. Data were extracted into a predesigned template by a single researcher. All extractions were validated by a second researcher, with disagreements resolved via consensus.

Results: 

Forty articles were included in this review. Most enrolled patients from the United States (n = 18 articles) or China (n = 12 articles). Most examined limited-stage (n = 27 articles) SCLC. All studies examined overall survival as the primary outcome. Articles investigating limited-stage SCLC reported outcomes for surgery, chemotherapy and/or radiotherapy, and adjuvant prophylactic cranial irradiation. In studies examining multiple treatment strategies, chemoradiotherapy was the most commonly utilized therapy (56%–82%), with chemotherapy used in 18% to 44% of patients. Across studies, median overall survival was generally higher for chemoradiotherapy (15–45 months) compared with chemotherapy alone (6.0–15.6 months). Studies of extensive-stage SCLC primarily reported on chemotherapy alone, consolidative thoracic radiotherapy, and radiotherapy for patients presenting with brain metastases. Overall survival was generally lower for patients receiving chemotherapy alone (median: 6.4–16.5 months; 3 years, 5%–14.9%) compared with chemotherapy in combination with consolidative thoracic radiotherapy (median: 12.1–18.0 months; 3 years, 15.0%–18.1%). Studies examining whole-brain radiotherapy for brain metastases reported lower median overall survival (5.6–8.7 months) compared with stereotactic radiosurgery (10.0–14.5 months).

Conclusions: 

Under current standard of care, which has remained relatively unchanged over the past few decades, prognosis remains poor for patients with SCLC.

1. Introduction

Worldwide, there are >1800,000 new cases of lung cancer each year. [ 1 ] Approximately 15% of new lung cancer cases are small cell lung cancer (SCLC), [ 2 ] which is characterized by late diagnosis, poor prognosis, and high frequency of recurrence with existing treatments. [ 2–4 ] Lung cancer primarily affects older adults, with a median age at diagnosis of 71 years. [ 5 ] Men and women are affected, though incidence rates are higher for men. [ 6 ] Based on the National Cancer Institute Surveillance, Epidemiology, and End Results Program data for SCLC in 2017, men and women had age-adjusted incidences of 5.87 and 5.30 cases per 100,000 individuals, respectively. [ 7 , 8 ]

There are many prognostic factors to consider for SCLC, including age, presence of metastasis, and performance status. [ 9 ] Lung cancer is mainly caused by smoking. For SCLC, the risk is highly elevated for current smokers (odds ratio >100). [ 10 ]

The Veterans Administration Lung Study Group 2-stage system is typically used to classify SCLC into limited- and extensive-stage diseases. Limited stage refers to cancer that is confined to only 1 lung that can be treated within a single radiation field; extensive stage describes cancer that has spread throughout the lungs or to other organs. [ 11 ] The American Joint Committee on Cancer tumor, lymph nodes, metastases (TNM) system, which categorizes disease into stages I to IV, [ 11 , 12 ] is also used. Typically, TNM stage I to III and stage IV map to limited and extensive stages, respectively. Most patients (two-thirds) present with extensive-stage disease, where treatment options are poor and vary depending on disease stage at presentation.

Patients with limited-stage disease are often treated with chemoradiotherapy (CRT) and surgery or radiation for stages I to IIA; chemotherapy (CT) alone has been the standard of care (SOC) in the treatment of extensive-stage disease for the last several decades. [ 4 ] According to National Comprehensive Cancer Network (NCCN) guidelines, the preferred primary systemic therapy regimen for limited-stage SCLC includes a platinum agent (such as cisplatin) in combination with etoposide [ 9 ] ; this has been the SOC for >30 years.

For extensive stage, randomized clinical trials (RCTs) recently demonstrated survival benefits with the addition of immunotherapy to CT. In the phase III CASPIAN trial, durvalumab plus platinum–etoposide was associated with a significant improvement in median overall survival (OS; 13.0 vs 10.3 months) over platinum-etoposide alone (hazard ratio [HR] = 0.73; P = .0047). [ 13 ] Additionally, in the phase III IMpower133 trial, atezolizumab with carboplatin–etoposide showed significant improvement in median OS (12.3 vs 10.3 months; HR = 0.70; P = .007) and progression-free survival (5.2 vs 4.3 months; HR = 0.77; P = .02) compared with placebo with carboplatin–etoposide. [ 14 ] The NCCN guidelines now recommend combining durvalumab or atezolizumab with platinum-based CT as first-line treatment for extensive-stage SCLC. [ 9 ]

While the efficacy of immunotherapy has been studied in RCTs, data on their real-world (RW) effectiveness in SCLC is limited. To aid decision-makers and other stakeholders in choosing the best treatment options for patients, robust evidence from RW studies is needed. The aim of our review was to provide an overview of RW outcomes, particularly OS, of initial treatment strategies for limited- and extensive-stage SCLC reported in studies published between October 1, 2015, to May 20, 2020.

We considered recommendations from the Cochrane Collaboration [ 15 ] and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines [ 16 ] in the design, conduct, and reporting of the systematic review. Given the nature of this work, specific ethics/institutional review board approval was not applicable.

2.1. Search strategies

Searches were conducted to identify RW observational studies examining: (1) the prevalence and incidence of SCLC or (2) treatment patterns and associated outcomes in patients with limited-stage and extensive-stage SCLC. Searches were conducted in MEDLINE (via PubMed.com) and Embase (via Embase.com) to identify original articles published in English from October 1, 2015, to May 20, 2020. This period was chosen to focus on recently published data, consistent with the study’s aim to collect outcomes data from contemporary samples of patients to increase the usability of the data. The studies published prior to October 1, 2015, would have likely included the majority of patients using an enrollment end date that was several years prior to 2015. The searches were conducted on May 20, 2020, and were designed using a combination of Medical Subject Heading (Medline), Emtree (Embase subject headings), and free-text terms included in the abstract or title of a publication. The detailed search strings and corresponding numbers of identified publications are provided in Supplementary Tables 1 and 2, https://links.lww.com/MD/G814 .

2.2. Study selection

The publications identified by the database searches were deduplicated and screened against predefined inclusion and exclusion criteria (Supplementary Table 3, https://links.lww.com/MD/G814 ). Studies were included if they reported data on patients with SCLC and assessed disease incidence or prevalence or examined outcomes (including mortality, OS, disease progression, or progression-free survival). Studies were excluded if they had limited sample sizes (<100 patients), enrolled all patients prior to 2010, or did not report OS or progression outcomes, separately, for limited and/or extensive stages. Only full-text papers published in English were included.

Level I abstract screening was conducted by 1 researcher with an initial 15% random sample screened by a second researcher. Upon validation of this initial sample, the accuracy of the included abstracts was deemed acceptable, and no further validation was conducted. Insufficient information in the abstract was not a criterion for exclusion. The full-text articles were retrieved for all abstracts passing the first round of review. Full-text (level II) screening was conducted independently by 2 reviewers. Any discrepancies in decisions to include/exclude studies were resolved by consensus, with input from a third researcher when necessary. For this review, only a subset of studies comparing outcomes of initial treatment strategies was included. Additionally, limited SCLC studies reporting results for TNM stage subgroups only (e.g., stage I or stage III only) were excluded.

2.3. Data extraction and synthesis

Data on median OS (months), OS rates at 1, 3, and 5 years, initial treatment strategy, SCLC stage, and data source type were extracted for this study into a predesigned template by a single researcher. All extractions were validated by a second researcher, with disagreements resolved via consensus. Extracted data were grouped according to SCLC stage (limited vs extensive) and synthesized qualitatively. Median estimates (and ranges) for OS statistics were summarized across all included studies by SCLC stage and treatment strategy. Study characteristics, including whether the sample size was ≥500, use of statistical analyses to adjust for confounding effects, and if the study included data on baseline performance status, were also extracted for a simple assessment of study quality. Studies without these characteristics were deemed to be of lower quality compared to studies with some or all of these traits. Note: all included studies used clinical data such as physician diagnoses recorded on medical charts to identify patients with SCLC and classify them by limited and extensive stages.

3.1. Search results

Database searches identified 1298 unique publications, of which 40 fulfilled the study selection criteria ( Fig. 1 ). Twenty-five publications reported outcomes data for limited stage, [ 17–41 ] 13 for extensive stage, [ 42–54 ] and 2 for both. [ 55 , 56 ] All studies examined OS as the primary outcome. Studies from China (limited n = 10 extensive n = 6) and the United States (US) (limited n = 12 extensive n = 6) comprised the majority of studies included in the review. Collectively, the studies examining limited- and extensive-stage SCLC enrolled 109,841 and 37,094 patients, respectively.

3.2. Study characteristics and quality assessment

3.2.1. limited stage..

Among the studies examining outcomes of limited-stage SCLC, approximately one-third enrolled patients from large, population-based data sources with a sample size of n ≥ 500. [ 17 , 18 , 25 , 27 , 28 , 33–36 , 38 , 39 ] Of these, nearly all examined patients residing in the US using the secondary National Cancer Database (NCDB) or Surveillance, Epidemiology, and End Results, with 1 examining patients identified from a cancer registry in the Netherlands. [ 18 ] The NCDB captures data for 70% of new cancer diagnoses from >1500 Commission on Cancer-accredited program registries in the US. Most studies identified enrolled patients with limited-stage SCLC from single centers with n < 500 patients. [ 21 , 22 , 26 , 29–32 , 37 , 40 , 41 , 55 , 56 ] Of these, nearly all examined patients in Asia, including 6 in China, [ 21 , 26 , 30 , 32 , 37 , 40 ] 1 in Japan, [ 29 ] and 2 from South Korea. [ 22 , 41 ]

Ten studies were identified that compared initial treatment with surgery (± other treatment strategies) to nonsurgical modalities. [ 29 , 32–36 , 38–40 , 56 ] Prophylactic cranial irradiation (PCI; yes vs no) was examined in 10 studies; of which 3 looked at PCI following surgery [ 27 , 30 , 31 ] and 7 examined PCI following CT or CRT. [ 19 , 20 , 22 , 26 , 37 , 41 , 55 ] Four studies compared various nonsurgical treatment strategies, including CRT versus CT alone, [ 17 , 24 , 25 ] CRT vs radiotherapy (RT) alone, [ 25 ] and CRT vs palliative CT or RT. [ 56 ] Five studies examined various aspects of treatment with CRT, including CRT with radiation delivered twice daily (BID) vs radiation delivered once daily (QD), [ 18 , 21 , 28 ] and concurrent vs sequential CRT. [ 18 , 23 , 24 ]

Nearly all studies examining limited-stage SCLC employed statistical methods to adjust for differences in baseline characteristics (e.g., age, sex, and stage) between study groups when examining OS. The most commonly used statistical methods included Cox proportional hazard models. [ 17–19 , 23 , 25–28 , 30 , 31 , 33–36 , 38 , 39 , 41 , 55 , 56 ] Matching with propensity scores [ 17 , 29 , 31 , 35 , 57 ] or alternate methods [ 32 ] were used in 6 publications. Five studies did not use any statistical adjustment of outcomes, [ 20–22 , 24 , 40 ] of which only 2 reported that groups were balanced with respect to baseline characteristics. [ 21 , 40 ] Although all studies included cancer stage as a baseline variable, approximately one-half reported data on performance status, [ 19–22 , 24 , 26 , 29 , 31 , 32 , 37 , 41 , 55 , 56 ] an important covariate that can influence prognosis. Therefore, residual confounding was likely an issue in many studies.

3.2.2. Extensive stage.

Most publications examining patients with extensive-stage SCLC had <500 patients, [ 42–44 , 46–48 , 51 , 53–56 ] with enrollment at single study sites. Of these, most examined patients in China, [ 44 , 46–48 , 53 , 54 ] with 2 studies enrolling patients in the US [ 42 , 51 ] and another in Germany. [ 43 ] Only one-quarter of studies included data from population-based sources and had a sample n ≥ 500. [ 45 , 49 , 50 , 52 ] Among these, all used data from the US NCDB.

Consolidative thoracic radiotherapy (TRT) following CT was compared with CT alone in 7 studies. [ 42 , 46 , 47 , 52–54 , 56 ] PCI was examined in 3 studies, [ 44 , 51 , 55 ] with 2 comparing PCI versus no PCI [ 44 , 51 ] following CT. Three studies compared whole-brain radiotherapy (WBRT) with stereotactic radiosurgery (SRS) in patients with brain metastases (BM). [ 45 , 48 , 50 ] One study compared WBRT versus CT alone [ 49 ] and another compared outcomes after WBRT in groups with synchronous versus metachronous BM. [ 43 ]

Statistical analyses adjusting for patient characteristics were used in every study comparing treatment strategies, with most using propensity score matching (PSM) and Cox proportional hazards models [ 45–52 ] ; 5 employed Cox proportional hazard models only [ 42–44 , 54 , 56 ] and 1 used PSM only. [ 53 ] One study was noncomparative and followed patients after PCI only. [ 55 ] Most (two-thirds) studies reported data on performance status [ 42–44 , 46–48 , 53–56 ] and, of these, nearly all enrolled patients outside the US. No publications using the US NCDB included performance status, raising questions as to how well these studies could adequately control for confounding.

3.3. Outcomes of limited-stage SCLC

OS according to treatment strategy for limited-stage SCLC is shown in Table 1 and Supplementary Table 4, https://links.lww.com/MD/G814 . The median OS exceeded 20 months (range: 18–79 months) in nearly every study examining treatment strategies that included surgery. The highest OS was found in a study of patients (n = 92) undergoing surgery and adjuvant CT with/without RT at West China Hospital. [ 40 ] This study enrolled relatively young patients (72% <60 years old), and nearly two-thirds were nonsmokers.

There was general agreement across studies that surgery resulted in a significant OS benefit compared with receipt of nonsurgical modalities only. Only a small fraction of patients was eligible for surgery. Among the studies enrolling patients with stage I to III disease, the proportion undergoing surgery was 4.2% to 10.8%. [ 24 , 38 , 39 , 56 ] An OS benefit favoring surgery compared with treatment with CT and/or RT was observed in patients in stage I to II (median: 31–34 vs 23–24 months, P < .001), [ 34 , 35 ] stage I to III (26-not reached vs 6 months, P < .001), [ 33 ] and stage IIB–IIIC SCLC (20 vs 14 months, P < .001), [ 36 ] as well as in patients (stage I–III) with no evidence of receipt of CT ( P < .001, all). [ 38 ] Surgery with CT/CRT conferred a significant survival advantage compared with CT/CRT alone (median OS: 18–79 vs 12–23 months, P < .05, all), [ 29 , 39 , 40 , 56 ] and relative to palliative CT or RT (40.2 vs 10.7 months, P < .001) [ 56 ] in stage I to III SCLC. Surgery did not result in a significant survival advantage in patients with stage II to III SCLC [ 32 ] or in subgroups with stage IIIB or IIIC. [ 36 ]

The studies examining patients who did not undergo surgery tended to report higher OS among patients treated with CRT (range: 15–45 months) compared with groups receiving CT and/or RT (11–24 months) and CT alone (6–15.6 months) ( Table 1 ). In studies enrolling patients across multiple treatment strategies, CRT was the most commonly utilized therapy (56%–82%); CT was used in 18% to 44% of patients and RT only in 2% to 4% ( Fig. 2A ). Four studies compared outcomes of CRT directly with treatment strategies other than surgery [ 17 , 24 , 25 , 56 ] ( Fig. 3 ). Significant OS benefits were achieved for patients receiving CRT relative to CT alone (median: 15–32.0 vs 7.5–10.5 months, P < .001, all), [ 17 , 24 , 25 ] RT alone (8.3 months, P < .001), [ 25 ] and CRT compared with palliative CT or RT (32 vs 10.7 months, P < .001). [ 56 ] There was significant variability in OS estimates across the studies examining CRT. OS was lowest in groups receiving sequential CRT [ 18 , 23 ] and in a study enrolling only elderly patients (≥70 years old) [ 17 ] ( Table 1 ). The highest OS was found in a study enrolling younger patients (64% <60 years old) with high-performance status (93% Karnofsky Performance Status ≥90). [ 32 ]

Several studies examined whether BID RT with CT had a survival benefit over QD administration [ 18 , 21 , 28 ] ( Fig. 3 ). Only Schreiber et al [ 28 ] reported a statistically significant OS benefit favoring BID administration (median: 22.1 vs 18 months, P < .001). However, results should be viewed with caution as the authors did not have access to key variables such as performance status. It is possible that those with worse status were more likely to undergo QD radiation due to better tolerability compared with BID regimens.

Three studies examined the timing of radiation therapy [ 18 , 23 , 24 ] relative to CT ( Fig. 3 ). Damhuis et al [ 18 ] reported a statistically significant OS benefit favoring concurrent CRT versus sequential CRT (median: 26–27 vs 17 months, P < .001, all) and Ohara et al [ 24 ] did not. Ohara et al did not perform any statistical adjustment to account for differences in baseline characteristics. Additionally, there were notable differences in the age of the cohorts in Ohara et al. For example, patients in the sequential group were much younger compared with the concurrent group. Manapov et al [ 23 ] examined CRT and the impact of interval of simultaneous treatment (IST) durations, where IST was defined as the interval in days where CT and RT were applied simultaneously. Although, the sequential (IST = 0) treatment group (median OS: 17.5 months) had significantly lower survival compared with IST >0 to <35 (38.4 months) ( P < .05), when the IST exceeded 35 days (16 months), no benefit over sequential CRT was realized.

Ten studies examined the benefits of PCI following initial treatment. Median OS ranged from 24 months to not reached (59% survival at 5-year follow-up) in patients receiving PCI. OS was heavily influenced by initial treatment type. In groups receiving surgery, [ 27 , 30 , 31 , 53 , 58 ] 5-year OS rates ranged from 40% to 59% compared with 15% to 38% in patients initially treated with CT or CRT [ 19 , 20 , 22 , 26 , 37 , 41 , 55 ] ( Table 1 ). Among the studies of PCI following surgery, a statistically significant OS benefit favoring PCI was observed in stage II (median: 36.4 vs 24.1 months, P = .047), stage III (median: 29.3 vs 21.2 months, P = .009), [ 30 ] stage IIIA (5-year rate: 35.9% vs 18.8%, P = .047), [ 31 ] and node positive (35% vs 20%, P = .008) [ 27 ] SCLC, but not in node negative [ 27 ] or stage I 30 SCLC. In the studies comparing PCI with no PCI in patients treated with CRT or CT, there was broad agreement that PCI results in a significant OS benefit [ 19 , 20 , 22 , 26 ] ( Fig. 3 ). One exception was in Choi et al, [ 41 ] which examined the effect of more accurate staging with positron emission tomography (PET) on the role of PCI. The authors noted that patients who had initial staging with PET achieved long-term survival even without PCI.

3.4. Outcomes of extensive-stage SCLC

OS according to treatment strategy for extensive-stage SCLC is summarized in Table 2 and Supplementary Table 5, https://links.lww.com/MD/G814 . The median OS for patients treated with CT alone [ 42 , 44 , 46 , 47 , 49 , 51–54 , 56 ] ranged from 6.4 to 16.5 months, with median OS exceeding 1 year in only 2 studies. [ 44 , 54 ] In these 2 studies, nearly all (91%) [ 54 ] or all patients [ 44 ] receiving platinum-based CT responded to treatment. The lowest OS was observed in a study enrolling patients ≥75 years old with BM (n = 238) from the NCDB. [ 52 ] Studies that primarily enrolled patients with 1 metastatic site [ 42 ] and those that excluded patients with disease progression [ 47 ] or nonresponse to CT [ 44 , 51 ] tended to report higher OS compared with studies enrolling primarily patients with polymetastases [ 53 ] or BM, [ 49 ] or studies without criteria requiring response to CT. [ 46 , 52 ] In the publications reporting information on CT regimens, [ 42 , 44 , 46 , 47 , 51 , 53 , 54 , 56 ] nearly all patients (84%–100%) received platinum-based therapy. In the studies (3 from China and 1 from the US) reporting receipt of specific agents, 86% to 100% of patients enrolled received cisplatin-etoposide or carboplatin-etoposide regimens; 3 publications did not report information on the specific CT regimen received. [ 49 , 51 , 52 ] Median OS for patients receiving CT and consolidative TRT (range: 12.1–18.0 months) [ 42 , 46 , 47 , 52–54 , 56 ] or CT and PCI (range: 12.0–16.5 months) [ 42 , 44 , 51 , 55 ] was ≥12 months ( Table 2 ).

There was general agreement across studies showing that consolidative TRT following CT resulted in superior OS outcomes compared with CT alone [ 42 , 47 , 52 , 53 ] ( Fig. 4 ). However, Zhang et al [ 54 ] found a significant benefit only for patients with oligometastases (median OS: 19.2 vs 15.6 months, P = .039), but not for those with brain/liver/multimetastasis. This contrasts with results from Xu et al, [ 53 ] which demonstrated a significant benefit in separate subgroups with oligometastases (2-year OS: 25.2% vs 12.7%, P = .002) and polymetastases (10.0% vs 6.8%, P = .030). Two studies enrolling patients without BM concluded that PCI following CT was beneficial compared with CT alone. In a study using the NCDB that excluded patients with OS <6 months as a proxy for lack of response to CT, median OS was 13.9 months for PCI versus 11.1 months for those who did not receive PCI ( P < .001). [ 51 ] Similarly, in a single-center study enrolling patients who had an initial response to CT, PCI significantly prolonged median OS from 12.6 to 16.5 months ( P = .033). [ 44 ] Another single-center study did not find a significant benefit favoring PCI. [ 42 ] However, this study enrolled only patients ≥65 years old and failed to exclude those with BM. Data from large US population-based studies indicated that only 16.3% and 11.1% of patients receive TRT and PCI, respectively ( Fig. 2B ). [ 51 , 52 ] Although, in single-center studies, TRT treatment rates were much higher (34.4%–80.6%).

In studies examining patients presenting with BM, median OS was consistently higher with SRS (range: 10.0–14.5 months) [ 45 , 48 , 50 ] compared with WBRT (5.6–8.7 months) [ 43 , 45 , 48–50 ] ( Table 2 ). Three studies compared WBRT to SRS, [ 45 , 48 , 50 ] 2 of which also assessed WBRT and boost [ 45 , 48 ] ( Fig. 4 ). A significant survival benefit for SRS compared with WBRT was observed in 2 studies using the NCDB; 1 enrolling patients from 2010 to 2014 (median OS: 10.8 vs 7.1 months, P < .001) [ 50 ] and the other from 2004 to 2013 (10.0 vs 8.2 months, P < .001). [ 45 ] Jiang et al [ 45 ] reported that SRS led to significantly better survival compared with WBRT and boost (10.0 vs 9.3 months, P < .001). Ni et al, [ 48 ] however, found that WBRT and boost significantly improved OS relative to SRS in the PSM analysis (21.8 vs 12.9 months, P = .040), but not in the overall sample. One study found that WBRT led to a modest increase in survival (1.9 vs 1.2 months, P < .0001) compared with no WBRT in the subgroup not treated with CT. [ 49 ]

4. Discussion

This review provides insights into RW treatment patterns and outcomes for patients with limited- or extensive-stage SCLC. Despite the limitations associated with RW data, many studies comparing treatment strategies generated evidence consistent with findings from RCTs and treatment guidelines. To our knowledge, this is one of the first reviews in SCLC summarizing the RW evidence separately for limited and extensive stages.

4.1. Limited stage

NCCN guidelines recommend surgical resection with lobectomy as the preferred radical therapy in T1-2N0 SCLC only, [ 9 ] which represents a small proportion of patients with SCLC. Consistent with this recommendation, we found that the surgery is infrequent in limited-stage SCLC (4.2%–10.8%). In recent years, investigators have shown that a multimodality approach including surgery may have benefits, particularly for stage I (cancer confined to 1 lung only) and II (cancer confined to 1 lung and nearby lymph nodes) patients, despite a lack of evidence from RCTs. [ 59–61 ] We identified 10 publications comparing multimodal therapy, including surgery to approaches using CT and/or RT only in limited-stage SCLC. Nearly all studies demonstrated significant survival benefits favoring treatment approaches including surgery; however, no improvement in OS following surgery was seen in patients with stage II–III SCLC.

For patients receiving CRT, median OS ranged from 15 to 45 months. Publications examining treatment with CT and/or RT (11–24 months) or CT alone (6–16 months) reported lower median OS relative to CRT. Concurrent CRT is the current SOC for limited-stage SCLC. Data from clinical trials found that concurrent CRT, where RT starts within the first or second cycle of CT, is more effective compared with sequential CRT. [ 62–64 ] Our review identified several RW studies examining the sequence and timing of RT with mixed results. Two showed a significant OS benefit favoring concurrent versus sequential CRT, [ 18 , 23 ] whereas the study by Ohara et al [ 24 ] did not. However, no statistical adjustment of outcomes was conducted in Ohara et al, despite notable differences between groups in patient characteristics.

BM commonly occurs in patients with SCLC. More than 50% will develop BM within 2 years. [ 65 ] Therefore, PCI is considered the SOC in patients with limited-stage SCLC. PCI was associated with longer OS in nearly all studies identified examining PCI following surgery. However, a survival benefit was not observed in subgroups with node negative or stage I SCLC. In the studies of patients comparing PCI with no PCI following CT or CRT, [ 19 , 20 , 22 , 26 ] all except Choi et al [ 41 ] observed a significant OS benefit for PCI. The authors noted that patients with an initial PET staging evaluation achieved long-term survival even without PCI.

4.2. Extensive stage

Consistent with treatment guidelines, [ 9 , 66 ] most extensive-stage patients included in this review received CT only. Most studies reported a median OS ≤12 months for patients treated with CT alone, indicating the poor prognosis of extensive-stage SCLC. The most common type of CT regimen was platinum-based, used in 84% to 100% of patients with extensive-stage disease, which aligns with the established SOC for the past several decades. Recently, atezolizumab and durvalumab have demonstrated improvement in survival when combined with platinum-based regimens for first-line treatment of extensive-stage SCLC. [ 13 , 14 ] However, we did not identify any RW studies examining these novel immunotherapies, which is likely a reflection of the review’s study period and the fact that it usually takes several years before records of these treatments show up in retrospective databases and cancer registries.

Historically, RT was reserved for palliation in extensive-stage SCLC. [ 67 ] The fact that many patients had recurrent or progressive intrathoracic disease led to clinical trial investigations and other observational studies examining the role of consolidative TRT in this population. In the first RCT examining consolidative TRT following CT, TRT led to significant OS improvements. [ 68 ] This review identified 6 studies comparing CT with or without consolidative TRT. A statistically significant OS benefit favoring TRT was reported in nearly all studies. Consolidative TRT is recommended in patients with complete response or good response following CT. Three studies examining PCI in extensive-stage SCLC were identified that reported mixed results. Two studies showed a significant OS improvement with PCI, [ 44 , 51 ] however, no OS benefit was observed with PCI in a study enrolling only elderly patients. [ 42 ] Mixed results in RCTs examining PCI in extensive-stage SCLC have also been reported. An RCT conducted by the European Organization for Research and Treatment of Cancer found that PCI improved survival, [ 69 ] while another from Japan found no improvement compared with routine surveillance magnetic resonance imaging and treatment of asymptomatic BM. [ 70 ] According to the NCCN guidelines, PCI is not recommended in patients with poor performance status or impaired neurocognitive function.

NCCN guidelines state that WBRT should typically be used as treatment in patients who present with BM. Although WBRT is considered the SOC for BM, the optimal therapeutic approach remains controversial. [ 71 ] Two studies included in our review found that SRS was associated with significantly longer survival compared with WBRT. [ 45 , 50 ] Although the studies included in this review were observational and the data cannot be used to definitively conclude that survival would be improved with one approach over another, the data suggest that SRS may be appropriate and lead to favorable outcomes for certain patient subgroups. An RCT is being conducted to compare SRS to WBRT. [ 72 ]

4.3. Limitations

The searches for this systematic review were conducted in MEDLINE and Embase. Therefore, any publications that were relevant but not included in these databases were not captured in our search. As for any review, the current study is limited by the available literature and the possibility of publication bias. The systematic literature review included studies from a relatively short period of only ~4.5 years. However, the size of the literature on SCLC is very large and the time period was sufficiently long to identify multiple studies reporting outcomes for all the SOC treatment strategies across various geographic regions. In addition, the review period allowed for the identification of studies enrolling patients from more recent time periods increasing the usability of the data. Validation of level I abstract screening was only conducted for a random sample (15%) of abstracts, and some accuracy may have been compromised compared to double-screening. As a substantial proportion of the publications were retrospective chart reviews or secondary database analyses, the data from the studies also had important limitations. For example, many publications did not report information on performance status, an important variable affecting prognosis. Although many studies used statistical methods to control for imbalances in patient characteristics, residual confounding was likely an issue. Additionally, in cases where the survival data was extracted from a graph, the information is inherently less precise.

5. Conclusions

The RW evidence collected as part of this systematic review reveals a limited number of available SCLC treatment options. Overall, the recent RW evidence was in alignment with established treatment recommendations and clinical trial results for SCLC. In limited stage, higher OS rates may be achieved with treatment approaches including surgery (vs without), particularly for stage I SCLC and, in patients ineligible for surgery, concurrent CRT is preferable to sequential CRT and approaches using CT or RT alone. Additionally, PCI following CRT provides an OS benefit compared to CRT alone in limited stage. In extensive stage, consolidative TRT following CT results in higher OS compared to CT alone. Further study is needed to determine if PCI following CT prolongs survival in extensive stage and whether SRS is more effective compared to WBRT in patients who present with BM. Under the current SOC, which has remained relatively unchanged over the past few decades, prognosis remains dismal for many patients with SCLC. Recently approved immunotherapies may be the beginning of a new era where significant improvements in outcomes are observed. Our findings will enable healthcare decision-makers and other stakeholders to put RCT data on emerging therapies into context with RW outcomes achieved under the current SOC.

Acknowledgments

This study was funded by AstraZeneca. Copy-editing and medical writing support was provided by Michael Grossi, of Evidera. Lisa Mather, of Evidera, contributed to abstract/full-text screening and data extraction.

Author contributions

Conceptualization – MS, NB, AD.

Data curation – MS, NB, AD.

Formal analysis – MS, NB, AD.

Funding acquisition – OR, AF.

Investigation – MS, NB, AD.

Methodology – MS, NB, AD.

Project administration– MS, NB, AD.

Resources– MS, NB, AD.

Software– MS, NB, AD.

Supervision– MS, NB, AD,OR, AF, AG.

Validation– MS, NB, AD.

Visualization – MS, NB, AD.

Writing – original draft – MS, NB, AD.

Writing – review and editing – MS, NB, AD, OR, AF, AG.

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epidemiology; outcomes; overall survival; small cell lung cancer; treatment patterns

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White out hemithorax secondary to salivary gland type of lung cancer with metastasis in liver and bone: a case report

• Padma V. Badhe 1 ,
• M. Sivakumar 1 ,
• Swastika Lamture 1 ,
• Sanika Patil 1 ,
• Khushboo Tekriwal 1 &
• Khalid Ahmad Mohammad 1  

Journal of Medical Case Reports volume  18 , Article number:  288 ( 2024 ) Cite this article

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Salivary gland-type lung carcinomas are uncommon neoplasms of the lung, representing less than 1% of all lung tumors. The two most common among them are adenoid cystic carcinoma and mucoepidermoid carcinoma. Although they usually have an indolent behavior, adenoid cystic carcinomas can be more aggressive, with 5-year survival as low as 55%. Very few cases are reported in literature. We report a similar rare case of salivary gland type lung carcinoma that presented for the first time with unilateral opacification of left hemithorax.

Case presentation

A 38-year-old man of North Indian origin, who was a a nonsmoker, presented with complaints of shortness of breath and cough for 1 year, which has increased in the last 2 months and was associated with significant weight loss. A frontal radiograph of the chest and computed tomography of the chest were performed, which showed a mass in the left upper lobe of the lung with its epicenter in the left main bronchus. A bronchoscopic guided biopsy was performed, and histopathology confirmed the diagnosis of lung carcinoma of salivary gland type (adenoid cystic carcinoma). There was invasion of major vessels, hence the patient was offered and started on palliative management instead of surgical treatment.

In spite of palliative management of two cycles of chemotherapy and radiotherapy, the patient succumbed to the disease within 2 months from the time of diagnosis.

Lung carcinoma of the salivary gland type (especially adenoid cystic carcinoma) usually presents at a later stage. The resectability of the tumor depends on the involvement of the surrounding major vessels. Interestingly, these cancers have no association with smoking. The prognosis depends on the extent of the disease at the time of diagnosis. Hence, imaging plays a major role in deciding the further plan of management.

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Introduction

Primary salivary gland-type tumors of the lung occur primarily in the central airways and originate from the submucosal glands. These include adenoid cystic carcinomas (ACCs), mucoepidermoid carcinomas (MECs), and epithelial−myoepithelial carcinomas (EMECs) [ 1 ]. Most ACCs in the lung occur in the distal trachea or mainstem bronchi, a peripheral or segmental location are uncommon (10% of cases). Lung ACCs tend to have submucosal extension within the airway [ 2 , 3 ]. MECs most commonly occur in segmental bronchi compared with the trachea or main bronchi, and appear as sharply marginated, either ovoid or lobulated, intraluminal nodules that adapt to the branching features of the airways [ 4 ]. A much less common entity is primary pulmonary EMEC, which appears to be a low-grade malignant neoplasm with a low risk of recurrence after surgical excision [ 5 , 6 ].

Primary salivary gland-type tumors of the lung differ from the more common types of lung cancer (adenocarcinoma and squamous cell carcinoma) in that the former tend to occur in younger patients [ 7 , 8 , 9 ] to affect the central airways and to have a more indolent nature [ 10 , 11 ]; however, staging and treatment of primary salivary gland-type tumors does not differ from the staging and treatment of adenocarcinoma or squamous cell carcinoma. Unlike staging of adenocarcinoma and squamous cell lung cancers, which are predominantly affected by positive nodal and metastatic disease, staging of the primary salivary gland-type tumors of the lung are usually affected most by primary local tumor invasion. Failure to identify tumor growth along the airways or in the submucosa leads to incorrect delineation and staging of the primary salivary gland-type tumors of the lung, which impacts surgical and radiation planning. Inadequate planning can affect patients negatively because local recurrence is likely if complete surgical resection is not achieved [ 11 ].

A 38-year-old man of North Indian origin, who was a nonsmoker, presented with complaints of shortness of breath grade I (NYHA, New York Heart Association) and cough for 1 year, which was initially dry and was later associated with mucoid expectoration for the last month. The patient had a history of 5–6 episodes of hemoptysis per day with 5–10 cc/day in the last month. The patient had a history of approximately 8 kg of weight loss in the last 2 months associated with loss of appetite. The patient also complained of lower back pain in the last 2 months. He had no history of tuberculous contact or tuberculosis.

On physical examination, he had normal vital signs and was cachectic. On respiratory examination, he had decreased air entry on the left side. A chest radiograph revealed a heterogeneous opacification of left hemithorax, ipsilateral shift of mediastinum, elevation of left hemidiaphragm, crowding of ribs on left, and hyperinflation of the right lung (Fig.  1 ). These features were suggestive of volume loss of the left lung. There was a bronchial cut-off sign on the left. There was minimal blunting of the left costophrenic angle. The right costophrenic angle was normal.

Chest radiograph shows heterogeneous opacification of the left hemithorax with an ipsilateral shift of mediastinum and loss of left lung volume. There is an elevation of the left hemidiaphragm with crowding of ribs and hyperinflation of the right lung

A differential diagnosis of bronchogenic carcinoma and tuberculosis was considered.

High-resolution computed tomography (HRCT) of the chest in the lung window shows cut off of the left main bronchus with a soft tissue lesion in the upper lobe of the left hemithorax (Fig.  2 a). Contrast enhanced CT (CECT) of the chest axial section shows a well-defined lobulated heterogeneously enhancing mass of size 9 × 8 × 7 cm in the left upper lobe with its epicenter in the left main bronchus with complete occlusion of the left main bronchus (Fig.  2 b). CECT chest coronal section shows a complete collapse of the left upper lobe with an ipsilateral shift of mediastinum and compensatory hyperinflation of the right lung with minimal left-sided pleural effusion (Fig.  2 c). There was no mediastinal lymphadenopathy. CECT axial section shows complete encasement of the aortic arch (Fig.  3 a), 150° encasement of the right pulmonary artery with its narrowing (Fig.  3 b), and sagittal section shows > 180° encasement of the descending aorta (Fig.  3 c).

High-resolution computed tomography chest coronal section ( a ) shows cut off of the left main bronchus, loss of left lung volume with hyperinflation of the right lung, and herniation across the midline. Contrast enhanced computed tomography chest axial section ( b ) shows a well-defined lobulated heterogeneously enhancing mass in the left upper lobe with its epicenter in the left main bronchus with complete occlusion of the left main bronchus. Contrast enhanced computed tomography chest coronal section ( c ) shows a complete collapse of the left upper lobe with a shift of mediastinum and compensatory hyperinflation of the right lung with minimal left pleural effusion

Contrast-enhanced computed tomography axial section shows complete encasement of the arch of aorta ( a ), 150° encasement of the right pulmonary artery with narrowing ( b ), and sagittal section shows > 180° encasement of descending aorta ( c )

The CECT axial section of the abdomen shows two hypoenhancing lesions in segments VI and VIII of the liver, the largest of which is 3.8 × 4 cm in size in segment VIII, suggestive of metastasis in the liver (Fig.  4 a–c). However, a positron emission tomography scan was not done.

The contrast enhanced computed tomography axial section of the abdomen ( a Plain, b arterial phase c venous phase) shows two hypoenhancing lesions in segment VI and VIII of the liver, the largest of which is 3.8 × 4 cm in size in segment VIII, suggestive of metastasis in the liver

The bone algorithm of the lumbar spine in the sagittal section shows a focal lytic lesion in the left pedicle of the L5 vertebra suggestive of bony metastasis (Fig.  5 ).

The bone algorithm of the lumbar spine in the sagittal section shows a focal lytic lesion in the left pedicle of the L5 vertebra suggestive of bony metastasis

Bronchoscopic guided biopsy was done, which showed nests of cells with cylindromatous microcystic spaces that contained basophilic mucoid material suggestive of a cribriform pattern of high-grade adenoid cystic carcinoma (ACC) of the salivary gland type (Fig.  6 ). Immunohistochemistry was not done. There was involvement of major vessels, hence the patient was offered and started on palliative management of chemotherapy and radiotherapy instead of surgical treatment. After a total of two cycles of chemotherapy and two sessions of radiotherapy, the patient’s hemoglobin dropped from 11.2 gm/dl to 8.6 gm/dl. He had further loss of appetite and became more emaciated. The patient succumbed to the disease within 2 months from the time of diagnosis.

Bronchoscopic guided biopsy shows nests of cells with cylindromatous microcystic spaces suggestive of a cribriform pattern of adenoid cystic carcinoma of the salivary gland type

Adenoid cystic carcinoma (ACC) is the most common type of lung cancer of salivary gland origin in the central airway [ 12 ]. ACC commonly occurs in the fourth and fifth decades of life and has an equal sex distribution [ 12 ]. Metastases are very unusual, with recurrence more often being local [ 13 ]. ACC tends to occur in the central airways, such as the trachea, main bronchus, or lobar bronchus, a peripheral or segmental location is uncommon [ 12 , 14 , 15 ]. These tumors tend to have submucosal extension and manifest with circumferential and infiltrative growth [ 12 , 14 , 15 ]. ACC tends to have an intact epithelium and a smooth contour, because of its submucosal origin [ 12 , 14 ]. The cephalocaudal extent of the tumor requires evaluation with three-dimensional (3D) or multiplanar reconstruction because it is underestimated with CT [ 16 ]. The optimal management of ACC of the lung is surgical resection, which has favorable outcomes. To control residual disease and recurrences, radiotherapy is indicated for unresectable tumors and incomplete resection. So, imaging plays a major role in evaluating the extent of the tumor, major vessel invasion, and deciding the line of management. Most ACCs should be distinguished from bronchogenic carcinoma [for example, squamous cell carcinoma (SCC)], carcinoid tumors, and benign airway tumors because they manifest as central airway tumors. ACCs that occur in the central airways and show avid FDG uptake may be difficult to differentiate from bronchogenic carcinoma, particularly SCC [ 12 ] Primary pulmonary ACC can have three main architectural growth patterns, in keeping with ACC of the salivary glands. The most common pattern is the cribriform or cylindromatous pattern characterized by nests and islands of tumor cells with well-circumscribed luminal spaces containing mucinous or basement membrane-like material. The tubular pattern consists of cells forming small, scattered gland-like spaces with wide lumina lined by cuboidal cells two to three layers thick. Finally, the solid variant is composed of nests of cells with only rare intercellular spaces, the absence of cystic areas, and a limited stromal matrix. Cytologically, tumor cells consist of bland cells with round nuclei, dense chromatin, and scant eosinophilic or amphophilic cytoplasm. There is no significant pleomorphism or mitotic activity and areas of necrosis and hemorrhage are rare. The solid variant may show an increased mitotic count, and prominent perineural, bronchial mucosal, and cartilage invasion may be seen with all patterns.

Mucoepidermoid carcinoma (MEC) in the tracheobronchial tree is rare, accounting for only 0.1–0.2% of all pulmonary malignancies [ 17 , 18 ]; it is thought to arise from the minor salivary glands in the tracheobronchial tree [ 19 ]. This tumor is classified as either low-grade or high-grade on the basis of histologic criteria [ 9 ]. Low-grade MEC shows minimal or no mitoses, nuclear pleomorphism, or necrosis within the tumor [ 18 ]. High-grade tumors show increased mitoses (more than four per ten high-power fields), nuclear pleomorphism, hyperchromasia, and cellular necrosis [ 9 , 18 , 20 ]. MEC has been reported to occur in patients from 4 to 78 years of age, nearly one-half of whom are under 30 years old [ 9 , 21 ]. Most MECs occur in the lobar or segmental bronchi rather than the trachea or main bronchi and manifest at CT as an intraluminal nodule adapting to the branching features of the airways [ 12 , 18 ]. When the tumor is in the segmental bronchi, obstructive pneumonia, atelectasis, and mucus plugging are frequently associated findings. MECs have been reported to show variable amounts and patterns of FDG uptake [ 12 ]. Mild FDG uptake was found in low-grade MECs, while high and homogeneous FDG uptake has been reported in high-grade MECs [ 9 ]. As with ACCs, MECs in the central airways with high FDG uptake may be difficult to differentiate from bronchogenic carcinoma, especially SCC [ 12 ].

Primary pulmonary epithelial–myoepithelial carcinoma (EMEC) is the least common type of lung cancer of salivary gland origin. They are well-circumscribed but nonencapsulated polypoid endobronchial lesions with an average size of 3.2 cm. The lesions are often covered by intact bronchial epithelium and on the cut surface have a tan or white color. On low-power microscopic examination, the tumors have a striking biphasic appearance with duct-like structures that are formed by an inner layer of epithelial cells and a surrounding outer layer of myoepithelial cells. High-power examination reveals that the epithelial cells are flat, cuboidal, or columnar-shaped and contain eosinophilic cytoplasm and round to oval nuclei. Significant cytologic atypia or mitotic activity is not a common feature. The myoepithelial layer is composed of polygonal cells with eccentric nuclei, clear cytoplasm, and indistinct cell borders. Brightly eosinophilic, sometimes colloid-like deposits can fill the ductular lumina and the stroma can show fibrotic or myxoid changes. Some cases may show more solid tumor patterns or foci of squamous metaplasia.

Salivary gland-type lung cancers are a group of low-aggressive entities, usually present at a later stage with a higher tendency of recurrence/metastasis. Intensive clinical, radiological, and pathological examinations are essential to estimate risk stratification and management. The prognosis depends on the extent of the disease at the time of diagnosis. Hence, imaging plays a major role in deciding the management plan.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Abbreviations

Adenoid cystic carcinomas

Mucoepidermoid carcinomas

Epithelial-myoepithelial carcinomas

Squamous cell carcinoma

Computed tomography

High resolution computed tomography

Contrast enhanced computed tomography

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Acknowledgements

We would like to thank our institution that is Seth GSMC and KEM hospital, my colleagues, my seniors, and last but not the least our patient, without whom this case report would not have been possible.

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Padma V. Badhe, M. Sivakumar, Swastika Lamture, Sanika Patil, Khushboo Tekriwal & Khalid Ahmad Mohammad

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PVB is the primary author and contributed to the manuscript by analyzing and interpreting patient data, organizing the case report, and was a major contributor in writing the manuscript and performing the literature search; SK was a major contributor in writing the manuscript, performing the literature search, analyzing the patient data, study conceptualization, and the editing process; SL was a major contributor in writing the manuscript and analyzing and interpreting the figures with their descriptions; SP was a major contributor in reading and approving the final manuscript; KT was a major contributor to validation; KAMA was a major contributor to interpreting patient data. All authors read and approved the final manuscript.

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Correspondence to Khalid Ahmad Mohammad .

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Badhe, P.V., Sivakumar, M., Lamture, S. et al. White out hemithorax secondary to salivary gland type of lung cancer with metastasis in liver and bone: a case report. J Med Case Reports 18 , 288 (2024). https://doi.org/10.1186/s13256-024-04607-y

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Pleomorphic carcinoma of the lung revealed by uncommon colonic metastasis: An exceptional case report with literature review

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• 1 Department of Pathology and Research Laboratory LR18SP10, Habib Bourguiba University Hospital, University Hospital, University of Sfax, Sfax, Tunisia.
• PMID: 38444383
• DOI: 10.1177/02184923241237315

Lung pleomorphic carcinoma is a rare and aggressive cancer that uncommonly metastasizes to the colon and only a few case reports have been published thus far. We present an exceptional case of colon metastasis from lung pleomorphic carcinoma in a 68-year-old man which was revealed by large bowel perforation, and we review the previous three published cases. Metastasis to the bowel from primary lung malignancy often lacks specific symptoms which result in delayed diagnosis. Bowel metastasis is a poor prognostic factor in patients with lung pleomorphic carcinoma, regardless of management strategy.

Keywords: Lung cancer; case report; colon metastasis; perforation; pleomorphic carcinoma.

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Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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An annual review of the remarkable advances in lung cancer clinical research in 2019

1 Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, Guangzhou 510120, China;

Hengrui Liang

Zisheng chen.

2 Department of Respiratory Medicine, the Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital, Qingyuan 511500, China

Wenhua Liang

Jianxing he.

In recent years, lung cancer has become the most common cancer and the leading cause of deaths attributed to cancer. In China, lung cancer is the third leading cause of death after strokes and ischemic heart disease. This review aimed to provide an up-to-date summary of studies in regard to lung cancer in 2019 and to present the remarkable progress seen in lung cancer clinical research. A systematic search of PubMed and Web of Science for research published in 2019 was conducted using the search terms “lung cancer”, “early stage”, “advanced”, “diagnosis”, “treatment”, or any combination of these terms. We selected 56 studies that we considered to be significant and have presented their major findings. In summary, survival among lung cancer patients was significantly improved compared with historical controls, turning lung cancer from an incurable disease into a chronic disease. In addition, treating lung cancer has become increasingly comprehensive, diversified, and individualized. Exploring the accurate biomarkers in immunotherapy and the mechanism of drug resistance in targeted therapy constitutes the greatest challenge at this stage.

Introduction

The diagnosis and treatment of lung cancer became a hot spot of research due to the disease’s increased morbidity and mortality in recent years. Therefore, more and more novel diagnosis methods for early-stage lung cancer and plenty of clinical trials have been conducted. Over past 12 years, China has seen a significant increase in the 5-year survival rates of various cancers, among which the 5-year survival rate of lung cancer has increased by an average of 1.3% every year and has achieved 19.7% so far ( 1 ). In terms of different patient characteristics, a series of treatment modes have been adopted, such as combination therapy, sensitization of drugs, and targeted therapy on various driver mutations. The aim of this review is to provide an up-to-date summary of lung cancer studies in 2019 and to present the remarkable progress made in lung cancer clinical research.

A systemic search of PubMed and Web of Science was conducted to find studies or conference abstracts published in English in the period between January 1, 2019 and December 31, 2019. The search terms included “lung cancer”, “early stage”, “advanced”, “diagnosis”, “treatment”, or any combination of these terms. The articles published in The New England Journal of Medicine ( NEJM ), The Lancet , JAMA , BMJ , and some other journals in the oncology field, as well as the abstracts reported in the conferences of the American Society of Clinical Oncology (ASCO), the World Conference on Lung Cancer (WCLC), and the European Society for Medical Oncology (ESMO) were included. Additionally, we reviewed in detail the survival of patients, the efficacy of drugs and drug-related adverse events in each enrolled study.

Early-stage lung cancer

The trends and risk of morbidity in lung cancer, lung cancer has become the third leading cause of death in china.

In June 2019, The Lancet published China’s burden of disease data online, covering a period of nearly 30 years ( 2 ). The data, which was reported by Professor Xiaofeng Liang from the Chinese Center for Disease Control and Prevention, revealed lung cancer to have become the third leading cause of death in China after strokes and ischemic heart disease (IHD). Between 1990 to 2017, increases of 28.2% and 12.6%, respectively, were seen in age-standardized mortality and years of life lost (YLLs) in lung cancer, leading to a change in ranking from 13th in 1990 to third in 2017.

This trend and current situation suggest that the prevention and control of lung cancer needs to be carried out with reference to the management mode of common diseases such as diabetes and hypertension, including the popular science and screening activities for lung cancer which are increasingly valued in China. How to balance the goals of early diagnosis and concerns regarding the health economy will be an important challenge.

Dietary fiber and yogurt consumption were associated with reduced risk of lung cancer

In October 2019, JAMA Oncology published a meta-analysis of data from ten prospective cohort studies performed by Xiao-Ou Shu’s team at Vanderbilt University ( 3 ), which involved a total of 1.44 million people and 8.6 years of follow-up. The results showed that dietary fiber and yogurt consumption were associated with a lower risk of lung cancer. The two groups with the highest intake of fiber and yogurt had a lower risk (17% and 19% lower, respectively) of lung cancer than the group with the lowest intake. For individuals who reported high yogurt consumption along with the highest fiber intake, the risk of lung cancer was reduced by 33% compared with those who did not consume yogurt and had the lowest fiber intake. In addition, young people may benefit more from the consumption of dietary fiber and yogurt.

Early screening and diagnosis of lung cancer

Genetic risk of lung cancer in chinese and its measurement.

In July 2019, a large multicenter study of the Chinese population conducted by Professor Hongbing Shen and his team from Nanjing Medical University was published in The Lancet Respiratory Medicine ( 4 ). This study systematically identified 19 susceptibility loci to be significantly associated with risk of non-small cell lung cancer (NSCLC) in the Chinese population through a cohort involving nearly 55,000 people and built a polygenic risk score (PRS) for Chinese people based on it. Meanwhile, this research, which was verified by an independent prospective cohort of about 100,000 individuals from the China Kadoorie Biobank (CKB), indicated that the incidence of lung cancer in the highest risk group was nearly double that of the lowest risk group. Moreover, PRS was an independent, effective predictive indicator of risk beyond age and smoking, which could provide an important reference for the screening and accurate prevention of lung cancer for high-risk individuals.

Liquid biopsy (LBx) is expected to be used as an early diagnosis tool for lung cancer

The preliminary results of Circulating Cell-free Genome Atlas (CCGA) Study were released at the conference of the ASCO and the ESMO ( 5 , 6 ). By combining three prototype assays [whole-genome bisulfite (WGBS), whole-genome sequencing (WGS), and targeted (507 gene) sequencing], signals from 12 cancers including lung cancer can be detected at an early stage. The overall detection rate (sensitivity) of this method for all stages and types of cancers was 55%, and the tissue of origin (TOO) localization could also be identified with high accuracy. The detection results of early-stage cancer (stage I–III) were favorable, with a sensitivity of 32%, 76%, and 85% for stages I, II, and III, respectively. This is consistent with the preliminary results relating to lung cancer of the CCGA study announced by ASCO annual meeting last year, which showed a diagnostic sensitivity of 38–51% for stage I lung cancer.

In addition, Professor Jianxing He and his team from Guangzhou Institute of Respiratory Health developed a non-invasive diagnostic tool for early-stage lung cancer using high-throughput targeted DNA methylation sequencing of circulating tumor DNA (ctDNA), which had a sensitivity of more than 70% for stage I lung cancer ( 7 ). Moreover, this assay was being validated through two national multicenter studies ( {"type":"clinical-trial","attrs":{"text":"NCT03181490","term_id":"NCT03181490"}} NCT03181490 and {"type":"clinical-trial","attrs":{"text":"NCT03651986","term_id":"NCT03651986"}} NCT03651986 ) in current stage, including the “Thunder Project” which involves more than 10,000 cases.

The treatment of stage I–III lung cancer

Immunotherapy joins the “neoadjuvant family”.

Three important neoadjuvant immunotherapy studies were presented at the ASCO annual meeting in June 2019: LCMC3 ( 8 ), NEOSTAR ( 9 ), and NADIM ( 10 ).

• The LCMC3 study assessed the efficacy and safety of atezolizumab used as neoadjuvant therapy for patients with stages IB to selected IIIB resectable NSCLC. The interim analysis showed that 7% of patients achieved partial response (PR), 18% achieved major pathological response (MPR), and 5% achieved pathological complete response (pCR). Pathological response was also observed in some patients with positive epidermal growth factor receptor (EGFR)/ALK mutations. Neither PD-L1 expression nor tumor mutational burden (TMB) level was correlated with pathological response. This regimen was tolerated.
• NEOSTAR confirmed that nivolumab (NV) plus ipilimumab showed better efficacy as a neoadjuvant therapy for resectable NSCLC patients than NV monotherapy. Patients received neoadjuvant therapy for three cycles before surgery and underwent surgery within three to six weeks after treatment. The results revealed that the MPR rate was 17% in the monotherapy group vs. 33% in the combination group, and the pCR rate was 9% vs. 21% in the monotherapy and combination groups, respectively. For imaging evaluation, the objective response rate (ORR) was 22% and 19% in the monotherapy group and the combination group, respectively, and the ORR was positively correlated with MPR (P<0.001). Subgroup analysis presented that the higher expression of PD-L1, the benefit of imaging, and the pathological response of patients would be greater. Additionally, this combination could increase the lymphocyte infiltration of the tumor and enhance cell diversity and reactivity-related function. No unacceptable toxicity or increased perioperative morbidity or mortality was found.
• NADIM was the first multicenter study on conventional chemotherapy (CT) combined with immuno-oncology agent (IO) in a neoadjuvant setting for stage IIIA patients. Participants received three cycles of NV + paclitaxel + carboplatin as preoperative treatment, followed by adjuvant NV treatment for 1 year after the surgery. The chemotherapy combined with immunology was well tolerated, and 41 patients ultimately underwent surgery, with R0 resection in all cases. Downstaging was seen in 90% of cases after neoadjuvant CT+IO, the MPR rate was 83%, and the pCR rate was 71%. According to RECIST (Response Evaluation Criteria in Solid Tumors), the imaging PR rate was 71%, and the CR rate was 7%. No patients withdrew from the study before surgery due to progressive disease (PD) or safety problems.

Neoadjuvant immunotherapy, especially combined with chemotherapy, achieved a surprising pathological response rate, which will largely change the treatment model of early- and middle-stage lung cancer. However, a series of questions relating to, for example, response evaluation criteria, surgery time, and postoperative treatment choices also surfaced and need to be answered.

Treatment strategy options for early-stage lung cancer

• Stereotactic body radiotherapy (SBRT) was widely used to treat inoperable stage-I NSCLC. The Lancet Oncol ogy published the phase 3 randomised controlled trial (RCT) “TROG 09.02 CHISEL”, the results of which indicated that SBRT compared to standard radiotherapy could reduce the local recurrence rate (14% vs. 31%, respectively), which supports the use of SBRT in treating early-stage NSCLC ( 11 ).
• In relation to adjuvant treatment options for stage-I NSCLC patients, as defined by the eighth edition TNM staging system, Jianxing He and Wenhua Liang’s research group from Guangzhou Institute of Respiratory Health established a risk prediction model based on data from a large sample size, which was published on Annals of Surgical Oncology ( 12 ). This research found that 21.7% of stage IB patients (7.5% of all stage I) were categorized into the high-risk of recurrence group, and verified that these patients can benefit from chemotherapy. Furthermore, in regard to the optimal treatment for stage IIIA-N2 NSCLC, the same team published a network meta-analysis based on 18 RCTs in The Annals of Thoracic Surgery ( 13 ), finding that neoadjuvant chemotherapy followed by surgery and adjuvant chemotherapy or radiotherapy holds the greatest potential to become the optimal treatment with the best efficacy and safety. This paper was included in the recommended literature on the F1000Prime platform.

The treatment of locally advanced NSCLC

Immunology consolidation therapy after concurrent chemoradiotherapy.

The PACIFIC study is a milestone to rewrite the therapeutic method of locally advanced NSCLC, the results of which were published in NEJM for twice in 2018 and confirmed that treatment with PD-L1 antibody durvalumab after concurrent chemoradiotherapy for unresectable stage III NSCLC can significantly prolong progression free survival (PFS) and overall survival (OS) compared with the placebo group. The PACIFIC study presented the 3-year updated OS data at the 2019 ASCO annual meeting ( 14 ). The median duration of follow-up was 33.3 months, and the median OS (mOS) of the treatment group was significantly longer than that of the placebo group [not reached (NR) vs. 29.1 months]. The 3-year OS rate in these two groups was 57% vs. 43.5%, respectively. Compared with the placebo group, patients in the treatment group received subsequent therapies for a longer period of time, with the first subsequent treatment continuing for twice as long (21.2 vs. 10.4 months), and the second subsequent treatment lasting for 30.2 vs. 17.8 months.

Furthermore, the PACIFIC study updated the information of patient-reported outcomes (PROs) in The Lancet Oncology ( 15 ), proving that with the consolidation therapy of durvalumab, OS could be greatly improved in patients with unresectable stage III NSCLC and patients’ quality of life was not compromised.

Immunotherapy plus concurrent chemoradiotherapy

The current concerned point is whether immunotherapy can be used concurrently with chemoradiotherapy. The treatment of atezolizumab combined with concurrent chemoradiotherapy had favorable safety for locally advanced NSCLC patients, as reported at ASCO annual meeting 2019, suggesting that concurrent chemoradiotherapy plus immunotherapy does not increase toxicity compared with chemoradiotherapy followed by immunotherapy. At present, the PACIFIC2 study is also under way, and the impact on efficacy due to bringing immunotherapy forward to the same stage as chemoradiotherapy is anticipated.

Whether patients with locally advanced NSCLC need prophylactic cranial irradiation (PCI)

An update of a prospective, randomized, multicenter phase 3 study of locally advanced NSCLC patients (RTOG 0214 trial) was published in JAMA Oncology ( 16 ). In patients without disease progression after local therapy, despite PCI therapy significantly decreasing the incidence of brain metastasis (BM) and remarkably improving disease-free survival (DFS) compared with the observation group, there was no significant difference in terms of OS (the 5- and 10-year rates were 24.7% and 17.6% vs. 26.0% and 13.3%, respectively).

Advanced lung cancer

First-line immunotherapy for advanced lung cancer, io monotherapy.

(I) KEYNOTE-024

Keynote-024 updated 3-year OS data at the WCLC conference 2019 and showed that the superior efficacy of PD-1 antibody monotherapy compared to CT. There was a significant difference in the 3-year OS rate between the treatment group and the control group (43.7% vs. 24.9%, respectively) ( 17 ).

(II) KEYNOTE-042

This important phase 3 study was formally published in The Lancet , and its results confirmed that for locally advanced or metastatic NSCLC patients without sensitizing EGFR/ALK alterations and with PD-L1 positive [tumor proportion score (TPS) ≥1%], first-line pembrolizumab treatment could obviously extend the OS compared to chemotherapy (16.7 vs. 12.1 months; HR, 0.81; 95% CI, 0.71–0.93; P=0.0018) and was safer ( 18 ).

(III) IMpower 110

The interim OS analysis announced on the ESMO congress demonstrated that, compared to standard chemotherapy, atezolizumab significantly improved the mOS (20.2 vs. 13.1 months, respectively; HR, 0.59; 95% CI, 0.40–0.89; P=0.0106) of untreated stage IV patients with PD-L1 high expression (TC3/IC3-WT). Median PFS was 8.1 vs. 5.0 months (HR, 0.63; 95% CI, 0.45–0.88; P=0.007) for atezolizumab and standard chemotherapy, respectively. ORR and duration of response (DoR) had notable benefits with atezolizumab ( 19 ).

Throughout the current research data for IO monotherapy, the level of patients’ PD-L1 expression has been the key to selecting IO monotherapy. Existing evidence demonstrates that IO monotherapy should be preferentially considered for patients with PD-L1 high expression (≥50%), whereas a combination of immuno- and chemo-therapy should be considered for patients with PD-L1 expression <50%.

The long-term survival outcome of PD-1 monoclonal antibody treatment

• The Lancet Oncology published the long-term survival outcome of NV as a second-line treatment for advanced NSCLC patients ( 20 ). A pooled analysis from the Checkmate 017 and 057 studies showed the 4-year OS rate with NV was 14% for all patients, and 19% for those with positive PD-L1 expression (at least 1%), which was far higher than the 5% of docetaxel chemotherapy. This confirmed that PD-1 antibody immunotherapy can achieve a clinical cure for some patients.
• The ASCO annual meeting presented the long-term outcomes of the KEYNOTE-001 trial ( 21 ). With pembrolizumab monotherapy treatment, the estimated 5-year OS rates were 23.2% for treatment-naive advanced NSCLC patients and 15.5% for patients who had been previously treated.

IO plus chemotherapy

(I) KEYNOTE-189 ( 22 )

At the 2019 ASCO annual meeting, the KEYNOTE-189 study updated the OS results after follow-up time was extended and, for the first time reported the results of PFS2 (progression after the next line of therapy). For nonsquamous NSCLC, persistent OS and PFS benefit was still observed in the combination arm of pembrolizumab and chemotherapy. For the combination and control arms, mOS was 22.0 vs. 10.7 months, respectively (HR, 0.56; 95% CI, 0.45–0.70; P<0.00001), and median PFS (mPFS) was 9.0 vs. 4.9 months, respectively (HR, 0.48; 95% CI, 0.40–0.58; P<0.00001). In the intention-to-treat (ITT) population, PFS2 in the combination arm was significantly higher than in chemotherapy alone arm. In these two groups, the mPFS2 was 17.0 vs. 9.0 months, respectively (HR, 0.49; 95% CI, 0.40–0.59; P<0.00001). The benefit of all endpoints was independent of the PD-L1 TPS level of patients.

(II) KEYNOTE-407 ( 23 )

The study’s updated outcome at the ESMO congress 2019 indicated that for squamous NSCLC, first-line treatment with pembrolizumab plus chemotherapy significantly prolonged PFS2. In the chemotherapy alone group, 49.1% of the patients received the subsequent treatment of PD-1/PD-L1 antibody, and the combination of pembrolizumab and chemotherapy still brought continuous OS benefit to patients. In the ITT population, mOS attained 17.1 months (range, 14.4 to 19.9 months), compared to 11.6 months (range, 10.1 to 13.7 months) in the chemotherapy alone group, and the mortality risk was reduced by 29% with combination treatment (HR, 0.71; 5% CI, 0.58–0.88). In comparison with chemotherapy alone, combination treatment also significantly improved the PFS of patients. Regardless of the level of PD-L1 expression of patients, pembrolizumab plus chemotherapy continued to demonstrate improved end points including OS, PFS, ORR, and PFS2 as the first-line treatment, compared with chemotherapy alone for advanced squamous NSCLC, with a manageable safety profile.

(III) IMpower130

The results published in The Lancet Oncology showed a significant and clinically meaningful improvement in OS and PFS with atezolizumab plus chemotherapy versus chemotherapy alone as first-line treatment for patients with stage IV nonsquamous NSCLC and no ALK or EGFR mutations ( 24 ), with acceptable safety and tolerability. This was the first PD-L1 inhibitor to be successfully used as first-line treatment for advanced NSCLC.

These study results further consolidated the status of pembrolizumab as well as atezolizumab combined with chemotherapy as the first-line standard treatments for advanced NSCLC patients with negative driver genes, and suggested once again that the earlier the use of immunotherapy, the more effective it was, and its use as a first-line treatment combined with chemotherapy was superior to its use as a second-line salvage therapy.

The sensitization of first-line immunotherapy

Io plus radiotherapy.

In 2019, JAMA Oncology published two consecutive studies related to the treatment of oligometastatic NSCLC with immunotherapy plus radiotherapy.

• A single-arm phase 2 study ( 25 ) demonstrated that after the completion of locally ablative therapy (LAT) such as surgery or stereotactic radiotherapy for oligometastatic NSCLC (≤4 metastatic sites), the mPFS of patients subsequently treated with pembrolizumab was 19.1 months, significantly longer than the historical median of 6.6 months (P=0.005), with no new safety signals and no reduction in quality of life.
• Another important randomized controlled trial, the PembroRT study ( 26 ), was designed to evaluate the tolerability and efficacy of SBRT prior to pembrolizumab treatment on a single metastatic site. The ORR of the control arm and the experimental arm was 18% (n=40) and 36% (n=36), respectively, and the mPFS was 1.9 and 6.6 months, respectively (HR, 0.71; 95% CI, 0.42–1.18; P=0.19). Due to reasons including experimental design, the PembroRT study did not meet its prespecified end point, but it clearly showed the powerful sensitization effect of radiotherapy, which is worthy of further examination.

At present, all of the first-line studies are aiming to compare whether immunotherapy should be added on the basis of chemotherapy. Therefore, it is still controversial whether to add chemotherapy on the basis of immunotherapy for a population which is suitable for immunotherapy, especially for those with PD-L1 expression >50%. Through an indirect comparison of 11 first-line RCTs, Jianxing He and Wenhua Liang’s research group from Guangzhou Institute of Respiratory Health found that adding chemotherapy on the basis of immunotherapy could further significantly improve PFS/OS in the overall population and in the high PD-L1 expression population ( 27 ). This provides evidence for treatment selection, whereas the optimal sensitization model still needs to be optimized and confirmed.

PD-1 monoclonal antibody plus CTLA-4 monoclonal antibody

In September 2019, NEJM once again published the results from the CheckMate 227 study ( 28 ), confirming that for patients with NSCLC, nivolumab plus ipilimumab resulted in a longer OS duration than platinum-containing chemotherapy, providing a “chemo-free” first-line treatment regimen for these patients. The researchers enrolled more than 1,700 untreated advanced NSCLC patients who were EGFR and ALK mutation negative.

First, the patients were stratified according to their expression of PD-L1, and divided into the PD-L1 positive group (PD-L1 expression ≥1%) and the PD-L1 negative group (PD-L1 expression <1%). Each group was further divided into three subgroups: the PD-L1 positive group was divided into the dual immunotherapy (nivolumab plus ipilimumab), single immunotherapy (nivolumab alone group), and chemotherapy groups (standard chemotherapy regimen). The grouping of the PD-L1 negative group was similar to that of the PD-L1 positive group, except the single immunotherapy group was combined with chemotherapy in PD-L1 negative group, while the other two subgroups were the same as the in the PD-L1 positive group.

There were two primary end points: (I) patients with a high TMB (TMB ≥10 mutations per megabase): PFS with dual immunotherapy versus with chemotherapy; and (II) PD-L1 positive patients (PD-L1 expression level of 1% or more): OS with dual immunotherapy versus with chemotherapy. NEJM reported the PFS in patients with a high TMB in 2018, with the dual immunotherapy group being obviously superior to the chemotherapy group. A second primary end point was simultaneously reported by ESMO congress and NEJM in 2019, showing that the OS of PD-L1 positive patients was significantly longer with dual immunotherapy (NV plus ipilimumab) than with chemotherapy. Furthermore, regardless of the level of PD-L1 expression and TMB, the mOS of the dual immunotherapy group was longer than that of the chemotherapy group, especially in the PD-L1 negative group (17.2 vs. 12.2 months; HR, 0.62). Additionally, the median DoR (mDoR) was also significantly longer in the dual immunotherapy group than in the chemotherapy group (23.2 vs. 6.2 months).

IO plus antiangiogenic agents

Following the Impower150 study’s report in 2018 of the efficacy of chemotherapy + atezolizumab + bevacizumab, a multicenter, phase Ib study that aimed to assess the preliminary antitumor activity of the inhibitor of vascular endothelial growth factor receptor (VEGFR) ramucirumab plus pembrolizumab in multiple types of cancer (including lung cancer) patients was published in The Lancet Oncology in 2019 ( 29 ). Patients with NSCLC attained ORR of 30% and a disease control rate (DCR) of 86%, which suggests this is a regimen worthy of further exploration.

The first-line treatment for EGFR-mutated advanced NSCLC

The third-generation tyrosine kinase inhibitor of the egfr (egfr-tki) consolidated its status in first-line treatment.

NEJM once again published the FLAURA study, the foremost research into targeted therapy of lung cancer ( 30 ). This trial was designed to compare the efficacy of third-generation EGFR-TKI osimertinib as the first-line treatment with first-generation EGFR-TKI. The analysis of the FLAURA study, which was reported for the first time in 2017, showed that the PFS of the osimertinib group was significantly longer than that of the control group, and the mPFS was 18.9 and 10.2 months (HR, 0.46; P<0.001), respectively.

As announced in NEJM and at the ESMO congress 2019, the mOS of the osimertinib group and the comparator group was 38.6 and 31.8 months, respectively (HR, 0.8; P=0.046), achieving a reduction of 20% in disease mortality risk in the osimertinib group (HR, 0.80; 95% CI, 0.64–1.00; P=0.046). The 12-, 24-, and 36-month OS rates in the osimertinib group were all better than those in the first-generation EGFR-TKI group, and osimertinib also extended the time to first and second subsequent therapy. An OS benefit with osimertinib was observed across most of the predefined subgroups, apart from the Asian subgroup (HR, 1.00; 95% CI, 0.75–1.32).

In addition, Journal of Clinical Oncology published the results of the BLOOM study, which investigated osimertinib treatment in patients with EGFR-mutated NSCLC and leptomeningeal metastases (LMs) ( 31 ). The LM ORR and DoR were 62% (95% CI, 45–78%) and 15.2 months (95% CI, 7.5–17.5 months), respectively. The FLAURA study established the treatment mode of putting third-generation TKI as a priority option in first-line treatment, but its results in Asian populations remain controversial.

First-generation EGFR-TKI plus chemotherapy

• A phase 3 randomized controlled trial NEJ005 was released at the 2019 ASCO annual meeting, with the purpose of comparing gefitinib plus chemotherapy with gefitinib alone as the first-line treatment ( 32 ). In this trial, estimated mPFS was significantly longer with gefitinib plus chemotherapy than gefitinib alone (16 vs. 8 months; HR, 0.5; 95% CI, 0.39–0.65; P<0.001). Moreover, patients treated with gefitinib plus chemotherapy had longer mOS than those treated with gefitinib alone (NR vs. 18 months; HR, 0.45; 95% CI, 0.31–0.66; P<0.001). In terms of adverse events, the incidence of adverse events ≥ grade 3 was 51% for the gefitinib plus chemotherapy arm and 25% in the gefitinib group, with significant difference between the arms (P<0.001). The NEJ009 study presented its results at the ASCO annual meeting 2018, and these two studies were published successively in the Journal of Clinical Oncology .
• At the WCLC conference 2019, Professor Baohui Han and his team from Shanghai Chest Hospital affiliated to Shanghai Jiao Tong University verbally reported the efficacy and safety of first-generation EGFR-TKI gefitinib combined with chemotherapy as the first-line treatment for advanced EGFR-mutated NSCLC ( 33 ). Updated data of the clinical trial showed that the mOS in the combinational group was obviously extended to 37.9 months (95% CI:17.3–58.6). Multiple studies have confirmed that first-generation EGFR-TKI combined with chemotherapy shows significant survival benefit. However, the comparison of first-generation EGFR-TKI plus chemotherapy with third-generation EGFR-TKI, and the mechanism of first-line treatment resistance are yet to be fully explored.

First-generation EGFR-TKI plus antiangiogenic agents

• The ARTEMIS study is a Chinese multicenter, randomized, controlled phase 3 clinical trial aiming to investigate the efficacy and safety of erlotinib with or without bevacizumab as the first-line treatment for EGFR-mutated NSCLC patients. The study was verbally presented by Professor Qing Zhou from Guangdong Provincial People’s Hospital at ESMO congress 2019 ( 34 ). The mPFS evaluated by the Independent Review Committee (IRC) was 18 months in the combinational group and 11.3 months in the erlotinib group (HR, 0.55; P<0.001), and PFS benefited significantly in the combinational group. In addition, the analysis of drug resistance showed a similar proportion of T790M mutation between these two groups (P=0.732).
• The RELAY study was a worldwide, randomized, double-blind, and placebo-controlled study which evaluated ramucirumab plus erlotinib versus placebo plus erlotinib as first-line treatment for advanced NSCLC patients ( 35 ). There was a significantly statistical and clinical improvement of PFS in the treatment group compared to the placebo group (mPFS, 19.4 vs. 12.4 months; HR, 0.59; 95% CI, 0.46–0.79; P<0.0001), and the frequencies of EGFR-T790M mutation were similar between the groups. The related results were published in the The Lancet Oncology .

The combination of first-generation EGFR-TKI with antiangiogenic agents can delay the occurrence of drug resistance, but the long-term survival benefit has not yet been confirmed, and, at present, there is not enough evidence which demonstrates that this treatment model can change the biological activity of tumor.

Comprehensive comparison of first-line treatment regimens

Regarding the numerous options currently available for first-line treatment for EGFR mutations, Jianxing He and Wenhua Liang’s research group from Guangzhou Medical University conducted a network meta-analysis involving a total of 4,628 patients from 18 RCTs ( 36 ). This meta-analysis found that gefitinib plus chemotherapy and third-generation EGFR-TKI osimertinib ranked highest and equal in efficacy among all regimens. Furthermore, the meta-analysis indicated that these two regimens were the optimal therapy for the two major mutation types of EGFR L858R and exon 19 deletion, respectively.

This study was the first study related to the treatment of lung cancer to be published in the BMJ in China, providing evidence for the optimization and individualized options of first-line regimens for patients with EGFR mutations.

Third-generation EGFR-TKI showed efficacy on uncommon mutations

A multicenter, open-label, single-arm, phase II trial published in the Journal of Clinical Oncology demonstrated that patients with NSCLC harboring EGFR mutations (other than the exon 19 deletion, L858R and T790M mutations, and exon 20 insertion) achieved an ORR of 50% (95% CI, 33–67%, 18/36) after receiving osimertinib treatment ( 37 ). The mPFS was 8.2 months (95% CI, 5.9–10.5 months) and the mDoR was 11.2 months (95% CI, 7.7–14.7 months), with manageable toxicity.

Anaplastic lymphoma kinase-positive (ALK-positive) advanced NSCLC

The ALESIA study, led by Professor Caicun Zhou from Shanghai Pulmonary Hospital Affiliated to Tongji University School of Medicine, was published in The Lancet Respiratory Medicine ( 38 ). This trial aimed to compare the first-line treatment of alectinib and crizotinib head-to-head in Asian patients with advanced ALK-positive NSCLC. The mPFS was NR in the alectinib group compared with 11.1 months in the crizotinib group. (HR, 0.22; 95% CI, 0.13–0.38; P<0.0001). OS data are currently immature for both groups (HR, 0.28; 95% CI, 0.12–0.68; P=0.0027), but the results showed that the prognosis of both groups of patients with or without central nervous system (CNS) metastatic lesions was superior in the alectinib group, and alectinib can significantly delay the progression of CNS (HR, 0.14; 95% CI, 0.06–0.30). Additionally, the incidence of grade 3–5 adverse events in the alectinib group was lower than that in the crizotinib group.

A phase 2 clinical trial led by Professor Li Zhang/Yunpeng Yang from Sun Yat-sen University Cancer Center which assessed the efficacy and safety of ensartinib in ALK-positive NSCLC patients who underwent crizotinib treatment failure was published in The Lancet Respiratory Medicine ( 39 ). A total of 156 patients, 62% of whom had BMs, were included in the final analysis. Data showed that 52% of patients attained a response after treatment, the DCR reached 93%, and the mPFS was 9.6 months. Among the patients with BMs, the intracranial ORR was 70%, and the DCR of intracranial lesions reached 98%. Moreover, ensartinib had significant efficacy with varieties of ALK-resistant mutations, including those of other second-generation ALK inhibitors.

ROS1 fusion-positive advanced NSCLC

Entrectinib.

An integrated analysis of three phase 1–2 clinical trials published in The Lancet Oncology showed that entrectinib was effective and well tolerated for advanced ROS1-fusion positive NSCLC ( 40 ). The outcomes from trials ALKA-372-001, STARTRK-1, and STARTRK-2 indicated that the ORR of 53 ROS1-fusion positive NSCLC patients treated with entrectinib was 77%, the mPFS was 19 months, and the mDoR was 24.6 months.

The Lancet Oncology published the results of a phase 1–2 clinical trial of lorlatinib in advanced ROS1-positive NSCLC which included a total of 69 ROS1-positive NSCLC patients ( 41 ). For 21 TKI-naive patients who had not received ROS1 inhibitors treatment before, the ORR and DCR were 62% and 90%, respectively, and the mPFS and mDoR were 21 and 25.3 months, respectively. Among the 11 patients with CNS metastases, the overall ORR was 45%, the intracranial response rate was 64%, and the median intracranial DoR was not reached. For the 40 patients previously treated with crizotinib as their only TKI, the ORR and DCR were 35%, and 75%, respectively, and the mPFS and mDoR were 8.5 and 13.8 months, respectively. Among the 24 patients with CNS metastases, the ORR rate was 25%, the intracranial response rate was 50%, and the median intracranial DoR was not reached.

Advanced NSCLC with KRAS mutation

A study evaluating the efficacy of AMG 510 in patients with advanced KRAS G12C mutant solid tumors was reported at ASCO annual meeting 2019 ( 42 ). Tumor response was assessable in 29 patients, including 10 NSCLC and 19 colorectal cancer (CRC) patients. All of these patients had previously received ≥2-line treatment regimens. The results indicated that the ORR and DCR of the patients overall were 17.24% and 79.31%, respectively, and the response lasted for a long duration. In particular, in the ten NSCLC patients, the ORR was 50% and the DCR reached 100%.

Advanced NSCLC with other mutations

A study evaluating the efficacy and safety of a novel MET (MET exon 14 skipping mutations) inhibitor tepotinib in advanced NSCLC was presented at the 2019 ASCO annual meeting ( 43 ). This single-arm, phase 2 clinical trial was planned to enroll more than 120 patients, who would receive tepotinib 500 mg once a day. At the time the data was released, 85 patients were enrolled, including 55 identified by LBx and 52 by tumor biopsy (TBx). A total of 35 and 41 patients in these two groups were evaluable for efficacy (≥2 post-baseline assessments or discontinuation for any reason), respectively. The ORR of the two groups assessed by IRC was 51.4% and 41.5%, respectively, and the mDoR was 9.8 and 12.4 months, respectively.

A phase 1 clinical trial was reported at the 2019 ASCO annual meeting ( 44 ). It included patients with advanced EGFR-mutated NSCLC who had previously experienced disease progression after receiving the treatment of EGFR-TKI (including first-/second-generation EGFR-TKI and osimertinib) and were subsequently treated with U3-1402. The outcome showed that out of 13 evaluable patients, all but 1 had a decrease in sum of longest diameter of lesions (median best change −29%, range, +10% to −67%), and the DCR reached 100%. In addition, U3-1402 was also effective on different pathways which were activated secondary to EGFR-TKI resistance, including EGFR C797S, HER2, and CDK4.

An integrated analysis of phase 1–2 clinical trials was published in The Lancet Oncology and showed that entrectinib was effective and well tolerated in advanced NTRK fusion-positive NSCLC patients ( 45 ). Among 54 NTRK fusion-positive NSCLC patients, 31 (57%; 95% CI, 43.2–70.8%) patients had an objective response, with an mPFS of 11.2 months and mDoR of 10.4 months.

The 2019 ASCO annual meeting reported the efficacy and safety of TAK-788 (an inhibitor of EGFR/HER2) in advanced NSCLC patients with EGFR exon 20 insertions ( 46 ). In a phase 1/2 multicenter clinical study, patients who met the inclusion criteria were first subjected to dose escalation and then an expansion cohort. A total of 101 patients were enrolled in the study, 76% of whom had previously received at least two therapies, and 53% of whom had BMs. The treatment dose was 5–180 mg once a day, and the recommended phase 2 dose (RP2D) was 160 mg once a day. Twenty-eight patients received this dose (during dose escalation or in the expansion cohort). The ORR and DCR of 26 patients in the extended cohort were 54% (95% CI, 33–73%) and 89% (95% CI, 70–98%), respectively.

BLU-667 is a highly potent and selective RET inhibitor, and the data of its efficacy and safety was released at the 2019 ASCO annual meeting ( 47 ). A total of 79 patients (21 of dose escalation and 58 of dose expansion) were enrolled and treated with BLU-667, and 39% of these patients had baseline BMs. Among the 57 patients who received at least one follow-up disease assessment, the ORR was 56% (95% CI, 42–69%), the DCR was 91%, and 6 patients had a DoR of more than 6 months. Among 30 patients treated at the RP2D, the ORR was 60%, and responses occurred regardless of prior treatment or RET fusion genotypes. Only 3% of patients discontinued because of the adverse event of drug.

Small-cell lung cancer (SCLC)

The CASPIAN study was a randomized, open-label, worldwide, multicenter phase 3 clinical trial that aimed to explore the efficacy of anti-PD-L1 antibody durvalumab, with or without anti-CTLA-4 antibody tremelimumab, in combination with etoposide plus either cisplatin or carboplatin (platinum-etoposide) in treatment-naive patients with extensive-stage SCLC (ES-SCLC). The results, which were published in The Lancet ( 48 ), demonstrated that the mOS was significantly longer in the durvalumab plus platinum-etoposide group compared to the platinum-etoposide alone group (13.0 vs. 10.3 months; HR, 0.73; 95% CI, 0.59–0.91; P=0.0047).

To date, there are two PD-L1 monoclonal antibodies (atezolizumab and durvalumab) which have obtained positive results in first-line combination treatment of SCLC, establishing the special status of PD-L1 monoclonal antibodies in the treatment of SCLC.

Related research on PD-1 antibodies independently developed in China for lung cancer

The chinese-developed pd-1 antibody and related research have entered onto the international stage, camrelizumab.

• SHR-1210-303 was an open, randomized, multicenter phase 3 clinical trial presented at the WCLC conference 2019 ( 49 ), which included patients with advanced non-squamous NSCLC with negative EGFR or ALK and was designed to explore the efficacy of adding camrelizumab (200 mg) on the basis of chemotherapy. The mPFS was 11.3 months (95% CI, 9.5–NR) in the camrelizumab plus chemotherapy arm and 8.3 months (95% CI, 6.0–9.7) in the chemotherapy arm (HR, 0.61; 95% CI, 0.46–0.80; P=0.0002). For other secondary endpoints including ORR, DCR, DoR, and OS, related data of the camrelizumab plus chemotherapy arm were also superior to the chemotherapy arm.
• Another study reported at the 2019 ASCO annual meeting showed that for nonsquamous NSCLC patients treated with camrelizumab plus apatinib as second-line and above treatment, the ORR and DCR in 91 evaluable patients were 29.7% and 81.3%, respectively, providing a “chemo-free” option for patients who received second-line treatment ( 50 ).
• At the WCLC conference 2019, Professor Baohui Han from Shanghai Chest Hospital affiliated to Shanghai Jiao Tong University reported the relevant data of PD-1 monoclonal antibody sintilimab combined with anlotinib in the first-line treatment of advanced NSCLC ( 51 ). Treatment-naive, stage IIIB/IV NSCLC patients were eligible, and patients with EGFR, ALK or ROS1 mutations were excluded. A total of 22 patients were enrolled in this study, and the results showed that the ORR was 68.2%, the DCR was 100%. At the data cutoff, 81.8% of the patients were still receiving treatment; the proportion of patients with PFS of at least 6 months was 93.8%.
• At the WCLC conference 2019, Professors Jie He and Shugeng Gao from Cancer Hospital, Chinese Academy of Medical Sciences released the research results of sintilimab in resectable NSCLC as a neoadjuvant therapy ( 52 ). The MPR reached 40.5% and the pCR reached 16.2%, with manageable safety. This study also designed three postoperative adjuvant treatment cohorts (chemotherapy, PD-1 antibody, and chemotherapy plus PD-1 antibody) synchronously, which are expected to answer the question of postoperative treatment options.
• Jianxing He and Wenhua Liang’s research group from Guangzhou Institute of Respiratory Health launched a clinical study (CCTC-1901) in relation to sintilimab treatment in early-stage multiple primary lung cancer (MPLC) with ground-glass density ( 53 ). This is a single-center, single-arm, prospective Simon’s two-stage design phase II clinical trial, aimed at assessing the efficacy of sintilimab in very early-stage (“stage 0”) lung cancer.

Toripalimab

At the WCLC 2019 conference, Professor Caicun Zhou from Shanghai Pulmonary Hospital presented the latest results of a study on toripalimab plus chemotherapy in advanced NSCLC patients with EGFR activating mutations for whom prior EGFR-TKI therapies have failed ( 54 ). A total of 40 patients are included in this study and the ORR reached 32.5% at the 12th week. As of July 25, 2019, the ORR was 50.0%, the DCR was 87.5%, PR had occurred in 20 patients, 15 patients (including 1 unconfirmed PR) performed SD, the mDoR was 7.0 months, and the mPFS was 7.0 months.

Biomarkers for the drug efficacy

• In a study published in JAMA ( 55 ), Flatiron Health and Foundation Medicine (FMI) confirmed the associations between clinical and genomic characteristics of NSCLC patients through the data of real-world study and demonstrated that targeted therapy could prolong the OS of patients with driver mutations compared to without targeted therapy (18.6 vs. 11.4 months; P<0.001), and that patients with TMB-high (TMB-H, ≥20 mutations/Mb) attained longer OS after receiving IO therapy compared to the patients with TMB-low/intermediate (TMB-L/I, <20 mutations/Mb) (16.8 vs. 8.5 months).
• An analysis of the FDA database was published in JAMA Oncology ( 56 ), indicating that a lung immune prognostic index (LIPI) derived from neutrophils/(leukocytes minus neutrophils) ratio (dNLR) and lactate dehydrogenase (LDH) was significantly correlated with the PFS and OS of immune checkpoint inhibitor (ICI) therapy, targeted therapy, and chemotherapy in advanced NSCLC patients.
• Professor Jie Wang and Zhijie Wang from Cancer Hospital, Chinese Academy of Medical Sciences evaluated the feasibility of blood-based TMB (bTMB) as a predictor of efficacy in advanced NSCLC treated with immunotherapy in the Chinese population ( 57 ). The results showed that the response rate and response duration of advanced NSCLC patients treated with anti-PD-1/PD-L1 monoclonal antibody could be predicted by adopting a NCC-GP150 panel based on 150 genes to estimate bTMB based on ctDNA.

Conclusions

With the incidence of lung cancer increasing, various centers worldwide have gradually started to value early screening and diagnosis of lung cancer. The survival of lung cancer patients has significantly improved compared with historical controls, turning lung cancer from an incurable disease into a chronic disease and suggesting that lung cancer prevention and control need to be carried out with reference to the management mode of common diseases, including popular science and screening activities. Systemic therapy, especially immunotherapy in stage I–III lung cancer, reached a new milestone. Treatment of lung cancer tended to be comprehensive, diversified, and individualized. It is of great importance to explore a biomarker that can accurately predict the efficacy of immunotherapy in the treatment of lung cancer patients. In addition, the mechanism of drug resistance in targeted therapy and how to overcome it is deserving of further investigation in the future.

Acknowledgments

Funding: None.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Conflicts of Interest: JH serves as the unpaid Executive Editor-in-Chief and WL serves as the unpaid editorial board member of Journal of Thoracic Disease . The other authors have no conflicts of interest to declare.