Several PROs were identified in this review for capturing the humanistic burden of SCLC. The most commonly used PROs assessing HRQoL and symptoms were: the European Organization for Research and Treatment in Cancer Quality of Life Core 30 Questionnaire (EORTC QLQ-C30; n = 15), the Lung Cancer specific module (EORTC QLQ-LC13; n = 8), which is designed to be administered alongside the EORTC QLQ-C30, and the Lung Cancer Symptom Scale (LCSS; n = 5). Instruments identified only once include: London Lung Cancer Group (LLCG) Daily Diary Card (DDC), Functional Assessment of Cancer Therapy- General (FACT-G), Functional Assessment of Cancer Therapy- Lung (FACT-L), Questionnaire for patients with cancer treated with anticancer Drugs (QOL-ACD), Rotterdam Symptom Checklist (RSCL) modified to include additional lung cancer specific items, Rotterdam Symptom Checklist (RSCL), Hasegawa Dementia Scale-Revised (HDS-R), Sense of Coherence Questionnaire (SoC), Schedule for the evaluation of individual quality of life-direct weighting (SEIQoL-DW), and Patient Self-Assessment (PSA). See Figure 2 for a list of the most frequently used PROs identified and their frequency of use.

The majority of publications reported global or overall HRQoL (n = 21, 78%), with considerably fewer reporting specific domains of HRQoL: activities of daily living (ADL; n = 16, 59%), emotional functioning (EF; n = 14, 52%), cognitive functioning (CF; n = 13, 48%), physical functioning (PF; n = 13, 48%), and social functioning (SF; n = 11, 41%).

Global HRQoL (Giaccone et al., 2005; Jatoi et al., 2005; Thatcher et al., 2005; Eckardt et al., 2006, 2009; O'Brien et al., 2006; Reck et al., 2006, 2012; Fennell et al., 2007; Bottomley et al., 2008; Hermes et al., 2008; Rolke et al., 2008; Westerman et al., 2008; Araujo et al., 2009; Lee et al., 2009; Slotman et al., 2009; Le Pechoux et al., 2011; Nagel et al., 2011; Wolfson et al., 2011; Chen et al., 2012; Sekine et al., 2014) was most frequently measured using two items (overall health and overall QoL) in the EORTC QLQ-C30 (n = 13, 62%). In the LCSS, the second most frequently used PRO to measure the concept (n = 4, 19%, Jatoi et al., 2005; Eckardt et al., 2006, 2009; Chen et al., 2012), global QoL is assessed via a single item.

Most chemotherapy naïve LD and ED SCLC patients had EORTC QLQ-C30 Global health/quality of life mean baseline scores ranged between 44.7 and 55.4 (Reck et al., 2006; Hermes et al., 2008; Rolke et al., 2008; Lee et al., 2009). One study however reported baseline scores that were over 10 points higher, at 66 points. The main difference with this study was that patients provided their responses during an interview, rather than completing the questionnaire in the clinical site (Westerman et al., 2008). SCLC patients (both ED and LD) who had responded to treatment (67, Bottomley et al., 2008; Slotman et al., 2009) reported higher scores than patients who had not been treated. Systemic treatment naïve ED SCLC patients had the lowest scores overall (44.7, Hermes et al., 2008). As expected, all SCLC EORTC QLQ-C30 scores were lower the normative global health status/QoL scores provided by the EORTC of 71.2 (Scott et al., 2008). Real world EORTC QLQ-C30 data could be drawn from one study only, reporting a mean score of 49.6 (Rolke et al., 2008). This score falls within the range of clinical trial EORTC QLQ-C30 baseline scores (Reck et al., 2006; Bottomley et al., 2008; Hermes et al., 2008; Lee et al., 2009; Slotman et al., 2009), indicating no difference in scores between the population types.

A significant difference in HRQoL was reported between a cohort of LD and ED SCLC patients and matched controls free of lung cancer, using a combined LCSS and Linear Analog Self-Assessment (LASA) score (63.4 vs. 80.9, p < 0.0001) (Chen et al., 2012). Examining smoking behavior, the authors reported that SCLC patients who were “early quitters” and “never smokers” enjoy a better overall HRQoL than those who never quit or quit post-diagnosis. However, smokers who quit post-diagnosis also experienced a positive impact on HRQoL (Chen et al., 2012). This publication was the only SCLC study to examine the impact of smoking status on HRQoL. While three publications (out of all publications included in this review) included PD1/PD-L1 expression in their patient sample, (Giaccone et al., 2005; Bottomley et al., 2008; Eckardt et al., 2009) no publications examined global health status/QoL scores by PD1/PD-L1 expression.

The literature revealed a trend for global/overall HRQoL scores remaining relatively stable over time while patients were on treatment, often irrespective of type of treatment. For instance, an evaluation of amrubicin monotherapy in comparison with carboplatin/etoposide combination therapy as a 1st line treatment in patients aged ≥ 70 years with ED SCLC found that scores for the FACT-L and EQ-5D remained relatively stable over time, with no statistically significant differences either within or between groups (Sekine et al., 2014). However, two trials reported an impact of treatment on global/overall HRQoL. A trend toward a detrimental impact with patients who had undergone prophylactic cranial irradiation (PCI) (vs. observation) (Slotman et al., 2009), and patients taking cisplatin plus etoposide saw a significantly greater increase in HRQoL scores vs. patients taking oral topotecan plus cisplatin (Eckardt et al., 2006).

Sixteen publications presented findings specific to the impact on ADL (Thatcher et al., 2005; O'Brien et al., 2006; Reck et al., 2006, 2012; Chen et al., 2007, 2008; Fennell et al., 2007; Bottomley et al., 2008; Hermes et al., 2008; Rolke et al., 2008; Westerman et al., 2008; Araujo et al., 2009; Lee et al., 2009; Slotman et al., 2009; Le Pechoux et al., 2011; Nagel et al., 2011). The EORTC QLQ-C30 role functioning (RF) domain which assesses limitations in work, daily, and leisure activities and in hobbies, was most often used to asses ADL (n = 11). From the publications reviewed, most patients reported some degree of impairment to ADL.

Treatment naïve and chemotherapy/systemic treatment-naïve ED and LD patients' mean baseline scores ranged between 38.7 and 65.6 (Reck et al., 2006; Hermes et al., 2008; Rolke et al., 2008; Westerman et al., 2008; Lee et al., 2009). Studies reporting scores at the high end of this range (62, Westerman et al., 2008 and 65.6, Reck et al., 2006) included both LD and ED patients in their samples, while the lowest scores overall were in systemic treatment naïve ED patients (38.7) (Hermes et al., 2008). Overall ED and LD patient scores differed in the expected direction. LD patients who had a response to treatment reported a score of 74 (Bottomley et al., 2008), while in comparison, ED patients who had responded to treatment had a lower mean score of 65.5 (Slotman et al., 2009). All patient subgroups scored lower than normative data (84.7) (Scott et al., 2008). Two real world studies reported that over two thirds of patients who had completed first line treatment and then relapsed (74.3%, Chen et al., 2008 and 71.6%) (Chen et al., 2007) experienced some degree of interference with daily activities (Chen et al., 2007, 2008). A comparison of LD and ED patients' ADL scores from clinical trials (Reck et al., 2006; Bottomley et al., 2008; Hermes et al., 2008; Lee et al., 2009; Slotman et al., 2009) and real world evidence (Rolke et al., 2008) found similar scores in both types of studies. No publications examined ADL scores by PD1/PD-L1 expression.

Similar to global/overall HRQoL, the majority of publications reported that for patients on treatment the impact on ADL remained stable over time (Giaccone et al., 2005; Bottomley et al., 2008; Hermes et al., 2008; Le Pechoux et al., 2011; Nagel et al., 2011). However, one study highlighted a potential therapeutic benefit of triplet therapy consisting of cisplatin and etoposide plus celecoxib (Fennell et al., 2007), while two studies demonstrated a detrimental impact following treatment with PCI treatment on role functioning for LD and ED SCLC patients (Slotman et al., 2009; Le Pechoux et al., 2011). One publication reported that patients on a combination of Ifosfamide, carboplatin, etoposide, and vincristine had significantly worse impact on ADL at 6 months than those on standard control chemotherapy regimens (Thatcher et al., 2005; Rolke et al., 2008).

Thirteen of the publications reviewed presented findings on EF (Thatcher et al., 2005; Reck et al., 2006, 2012; Fennell et al., 2007; Westerman et al., 2007; Bottomley et al., 2008; Hermes et al., 2008; Rolke et al., 2008; Araujo et al., 2009; Lee et al., 2009; Slotman et al., 2009; Le Pechoux et al., 2011; Nagel et al., 2011). EF was most commonly assessed (n = 12) using the four items in the EORTC QLQ-C30 (felt tense, worried, irritable, or depressed). Other PROs assessing EF included the Rotterdam Symptom Checklist (RSCL) or a modified RSCL (n = 2) (Thatcher et al., 2005; Fennell et al., 2007) and Hospital Anxiety and Depression Scale (HADS; n = 2) (Thatcher et al., 2005; Rolke et al., 2008).

EORTC QLQ-C30 mean baseline scores for ED and LD SCLC patients that had responded to therapy were comparable (80, Slotman et al., 2009 and 77 points, Bottomley et al., 2008, respectively). Both of which were numerically higher but similar to the EORTC QLQ-C30 normative population mean EF score (76.3, Scott et al., 2008). Furthermore, frequency distributions of baseline scores of LD patients in complete remission following treatment revealed that over half of patients had normal levels of EF (59 and 57%) (Le Pechoux et al., 2011). Scores on EF for treatment naïve LD patient scores were comparable to ED patient scores (59.9–65.7, Reck et al., 2006; Hermes et al., 2008; Lee et al., 2009). However, this range was lower than the range of scores of treated patients. In a study comparing groups of different types of lung cancer patients, newly diagnosed treatment naïve SCLC patients experienced higher levels of depression than NSCLC patients (Rolke et al., 2008). A comparison of LD and ED patients' EF scores from clinical trials (Reck et al., 2006; Bottomley et al., 2008; Hermes et al., 2008; Lee et al., 2009; Slotman et al., 2009) and real world evidence (Rolke et al., 2008) found similar scores. No publications examined EF scores by PD1/PD-L1 expression.

Four studies identified a treatment that demonstrated therapeutic superiority in terms of EF (Thatcher et al., 2005; Reck et al., 2006; Hermes et al., 2008; Lee et al., 2009), while five studies showed stability in EF over time (Bottomley et al., 2008; Araujo et al., 2009; Slotman et al., 2009; Le Pechoux et al., 2011; Nagel et al., 2011).

Thirteen publications reported findings for the impact of SCLC on CF (Reck et al., 2006; Fennell et al., 2007; Bottomley et al., 2008; Hermes et al., 2008; Rolke et al., 2008; Araujo et al., 2009; Lee et al., 2009; Slotman et al., 2009; Kohli et al., 2010; Le Pechoux et al., 2011; Nagel et al., 2011; Wolfson et al., 2011; Nakahara et al., 2015). The only PRO identified in this review assessing CF was the EORTC QLQ-C30, which assesses CF using two items, one of which asks about memory and the other about concentration.

Compared to EORTC QLQ-C30 normative scores of 86.1 (Scott et al., 2008), reported scores and frequency distributions indicate that CF is not necessarily impacted. This was true in treated and untreated LD and ED patients. Comparable or above normative scores were reported for LD (85, Bottomley et al., 2008) and ED (89, Slotman et al., 2009) SCLC patients who had responded to therapy and a sample of treatment naïve LD and ED patients (87, Reck et al., 2006). With the exception of one study (Reck et al., 2006), treatment naïve ED and LD patients' scores were generally lower than the scores of patients who had responded to treatment (ED: 75.3, Hermes et al., 2008 and LD: 76, Lee et al., 2009). Most untreated patients scores were also lower than mean EORTC QLQ-C30 normative scores of 86.1 (Scott et al., 2008). Frequency distributions of baseline scores showed that only 24% of LD SCLC patients in complete remission had below normal CF at baseline (Le Pechoux et al., 2011). The results from real world studies indicates that CF in LD and ED SCLC patients may be impaired with an EORTC QLQ-C30 score of 74.4 (Rolke et al., 2010). This is compared to the range of scores for LD and ED patients' clinical trial mean scores from 75.3 to 89 points (Reck et al., 2006; Bottomley et al., 2008; Hermes et al., 2008; Lee et al., 2009; Slotman et al., 2009). No publications examined CF scores by PD1/PD-L1 expression.

The impact of brain metastases on HRQoL was reported in a single study that investigated the effect of PCI in patients with and without brain metastases. Interestingly, this study reported that neurological deterioration was greater in those patients without brain metastases, compared to patients with brain metastases (Wolfson et al., 2011). The occurrence or development of brain metastases associated with SCLC was reported in seven publications; however no publications reported any effect on CF or any other domains of HRQoL (Eckardt et al., 2009; Le Pechoux et al., 2011; Wolfson et al., 2011; Reck et al., 2012; Satouchi et al., 2014; Sekine et al., 2014; Nakahara et al., 2015).

Thirteen publications presented findings for the impact on PF (Reck et al., 2006, 2012; Fennell et al., 2007; Bottomley et al., 2008; Hermes et al., 2008; Rolke et al., 2008; Westerman et al., 2008; Araujo et al., 2009; Lee et al., 2009; Slotman et al., 2009; Le Pechoux et al., 2011; Nagel et al., 2011; Satouchi et al., 2014). The EORTC QLQ-C30 was most commonly used PRO (n = 12) to assesses PF, which has five items that ask about the ability to undertake strenuous activities, personal care, and the ability to get around. Additional PROs used to assess PF were the FACT-G (n = 1), RSCL (n = 1), and QOL-ACD (n = 1).

All publications measuring PF in SCLC patients using the EORTC QLQ-C30 reported lower than normative scores (89.8) (Scott et al., 2008). Patients with LD SCLC who had responded to treatment (78) (Bottomley et al., 2008), and a combined sample of treatment naïve LD and ED SCLC patients (77.4) (Reck et al., 2006) reported the highest overall baseline PF scores. Patients with ED SCLC who responded to chemotherapy at trial enrolment had a slightly lower mean score of 66 points (Slotman et al., 2009). Treatment naïve LD and ED patients had EORTC QLQ-C30 comparably lower mean scores (54.7–62) (Hermes et al., 2008; Rolke et al., 2008; Westerman et al., 2008; Lee et al., 2009), with exception to one clinical trial of treatment naïve LD and ED patients (Reck et al., 2006). Treatment naïve ED SCLC patients reported the lowest score overall (54.7) (Hermes et al., 2008). Comparison of real world and clinical trial evidence show that ED and LD real world mean scores are at the low end of the range of LD and ED patients' clinical trial mean scores (56.1, Rolke et al., 2008 vs. 55–78) (Reck et al., 2006; Bottomley et al., 2008; Hermes et al., 2008; Lee et al., 2009; Slotman et al., 2009). No publications examined PF scores by PD1/PD-L1 expression.

Four studies reported that physical functioning either remained stable or increased over time while on treatment, irrespective of type of treatment (Giaccone et al., 2005; Bottomley et al., 2008; Hermes et al., 2008; Satouchi et al., 2014). Two studies reported a potential therapeutic benefit in terms of physical functioning (Reck et al., 2006; Nagel et al., 2011).

Eleven of the publications reviewed presented findings specific to the impact of SCLC on SF (Reck et al., 2006, 2012; Fennell et al., 2007; Bottomley et al., 2008; Hermes et al., 2008; Rolke et al., 2008; Araujo et al., 2009; Lee et al., 2009; Slotman et al., 2009; Le Pechoux et al., 2011; Nagel et al., 2011). Most studies (n = 9) used the EORTC QLQ-C30, which assesses SF using a single item that examines interference with family life and with social activities. One study used the Functional Assessment Cancer-Therapy General (FACT-G) to assess social well-being (SWB) (Reck et al., 2006).

In comparison to normative scores (87.5, Scott et al., 2008), LD and ED treated and treatment naïve patients are impacted by SCLC. Treated ED patients and LD patients who have undergone at least first line treatment and responded to therapy (74.5, Slotman et al., 2009 and 74, Bottomley et al., 2008, respectively) were least impacted of all groups. Similar baseline scores were reported between ED SCLC and LD SCLC patients who were already treated. Scores in SCLC ED and LD patients who were treatment/chemotherapy naïve ranged from 58.5 (Hermes et al., 2008) to 72.5 (Reck et al., 2006). While the scores ranged considerably, no difference in scores was found between combined samples of treatment naïve LD and ED patients (Reck et al., 2006; Rolke et al., 2008; Lee et al., 2009) and treatment naïve ED patients (Hermes et al., 2008). A study reported that 58% of LD SCLC patients who were in complete remission following treatment have below normal SF scores (Le Pechoux et al., 2011). Similar to PF, the SF mean score of LD and ED patients taking part in a real world study was at the low end of the range of LD and ED patients' clinical trial scores (58.5, Rolke et al., 2008 vs. 58.3–74.5 Reck et al., 2006; Bottomley et al., 2008; Hermes et al., 2008; Lee et al., 2009; Slotman et al., 2009). No publications examined SF scores by PD1/PD-L1 expression.

SF was usually shown to be consistent over time. However, some impact was demonstrated with treatment, with one author reporting statistically significant improvements in both LD and ED SCLC patients following combination treatment of chemotherapy and Darbepoetin alfa (Nagel et al., 2011). Two publications reported on the effect of PCI in SCLC patients, with one study identifying an improvement in the social functioning of LD SCLC patients over time while on treatment (p = 0.009) (Le Pechoux et al., 2011) and the other study reported a decline in social function of ED SCLC patients (p < 0.05) (Slotman et al., 2009).

BB, JW, and CP work at Adelphi Values who were employed by BMS as expert consultants to carry out the review described in this manuscript. YY and JP are employees of BMS who funded this work.