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Characteristics and clinical outcomes of pulmonary sarcomatoid carcinoma: experience from Tata Memorial Centre

Background Pulmonary sarcomatoid carcinoma (PSC) constitutes a heterogeneous group of poorly differentiated non-small cell lung cancers. Since these are rare tumours, we sought to determine the characteristics and clinical outcomes of these patients treated at our centre. Methods We did a retrospective evaluation of all patients diagnosed with PSC between January 2013 and September 2020 at the Tata Memorial Hospital, Mumbai, India. Baseline demographic and treatment data and outcomes were obtained retrospectively from electronic medical records and survival was calculated by using the Kaplan–Meier method. Results Out of 151 patients diagnosed with PSC during this period, 129 were included in the final analysis. The clinical stage was stage I in 3 (2.03%), stage II in 4 (3.1%), stage III in 35 (27.1%) and stage IV in 87 (67.4%). The median follow-up duration was 32 months (range, 15.0–48.9). The median overall survival (OS) of patients who received curative surgery was 18 months (95% confidence interval (95% CI), 2.59–33.4); concurrent chemoradiation was 11 months (95% CI, 2.99–19); palliative chemotherapy was 8 months (95% CI, 5.24–10.75) and best supportive care was 1 month (95% CI, 0.43–1.57, p = 0.001). On multivariate analysis, the presence of brain metastasis (p = 0.018; hazard ratio (HR), 2.47; 95% CI, 1.34–4.49) and the administration of chemotherapy (p = 0.037; HR, 2.2; 95% CI, 1.04–4.94) were the only factors impacting the OS. Conclusion PSC usually presents in advanced stages and is associated with a poor prognosis.

any cause before disease progression. The patients who were lost to follow-up were censored on the date of their last follow-up. The overall survival (OS) was defined as the interval from the date of diagnosis to the date of death. Patients who were alive at the end of the study were censored at the date of the last follow-up.

Statistical analysis
As this was a retrospective study of a rare tumour, the sample size was not calculated. We included all patients fulfilling the eligibility criteria during the study period. All statistical analyses were done using the SPSS software (Version 23, IBM Corp, Armonk, NY, USA), and the Kaplan-Meier curve was generated using R software (Vienna, Austria). The categorical variables were summarised by frequency and percentage and the continuous variables by median and range. Survival analysis was done using the Kaplan-Meier method [22] and the hazard ratio (HR) was calculated using the Cox proportional model [23,24]. Univariate and multivariate analyses were performed to compare the OS to various factors using the log-rank test and Cox regression analysis, respectively. All p values were two-sided with a 95% confidence interval (95% CI) level. A p-value of less than 0.05 was considered statistically significant.

Baseline patient characteristics
A total of 151 patients were diagnosed with PSC during the period between January 2013 and September 2020 ( Figure 1). Follow-up data were available for 129 patients and were included in the analysis. The baseline demographic, clinicopathological and imaging characteristics are summarised in Table 1. The median age was 63 years (range, . Almost half the patients presented with poor performance status (PS) of 2-4.

Molecular characteristics
The reports of EGFR mutation testing were available for 57 patients, out of which 4 (7%) patients had an EGFR mutation (two patients had exon 19 deletions, one had exon 21 L858R mutation and one had both exon 19 deletion and exon 21 L858R mutation). ALK reports were available in 40 cases [either Immunohistochemisty (IHC) or fluorescence in situ hybridisation (FISH)] and of these, two patients (5%) had ALK rearrangement. ROS1 rearrangement was not detected in any of the 40 patients who were tested. FISH for mesenchymal epithelial transition factor (MET) amplification was negative in all the six tested patients. Next-generation sequencing was performed in four patients which revealed TP53 mutation with EGFR amplification in one patient, Kirsten ras oncogene homolog (KRAS) exon 2 missense mutation (p.G12D) with PIK3CA (Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha) exon 1 mutation in one, BRAF (B-Raf Proto-Oncogene, Serine/Threonine Kinase) V600E and KRAS exon 2 mutation (p.G12V) in one patient each.

Surgery
Curative surgery was performed in 14 (10.9%) of the 129 evaluable patients. One patient had an R+ resection. One patient died in the immediate postoperative period due to aspiration pneumonia. The various treatment modalities are summarised in Table 2.
Post-operative staging as per the histopathological report according to the TNM classification was stage I in 3 (21.4%), stage II in 3 (21.4%) and stage III in 8 (57.1%) patients.
A total of six patients with locally advanced disease (three had an unresectable primary tumour and three had single station N2 on endobronchial ultrasonography) received neoadjuvant chemotherapy. Of these six patients, three subsequently underwent surgery; the remaining (Continued) three patients developed progressive metastatic disease following neoadjuvant chemotherapy. Platinum-based doublet combination was used in five patients; one patient who had pulmonary blastoma received an ifosfamide and doxorubicin combination. The response rate to neoadjuvant chemotherapy is summarised in Table 3. One patient received neoadjuvant chemo-radiotherapy and had a partial response.

Adjuvant therapy
Nine patients received adjuvant chemotherapy. Three received adjuvant postoperative radiotherapy (two due to N2 disease, one due to a positive margin). Platinum-based doublet combination was the most common regimen used in the adjuvant setting.

Radical radiotherapy
Five patients received radical intent radiotherapy with concomitant chemotherapy -indication being N2/N3 disease in three patients and unfit for surgery in two patients. Weekly paclitaxel 80 mg/m 2 and carboplatin area under curve 2 mg/mL/minute were used as the concurrent chemotherapy regimen in all patients. One patient received stereotactic body radiation therapy to the lung as the primary treatment modality because of poor lung function.

Palliative therapy
Of the 129 evaluable patients, palliative intent systemic therapy was given to 66 patients (51.2%), of which six patients received therapy post-progression on curative intent therapy. The systemic therapy regimens used were platinum-based chemotherapy in 50 (75.8%), nonplatinum based in 9 (13.6), tyrosine kinase inhibitors in 5 (7.6%) and ICIs in 2 (3.0%). Four patients had an EGFR mutation, of which two patients received targeted treatment with gefitinib; one patient died due to sepsis and another patient defaulted before any targeted therapy could be given. The PFS for the two patients who received EGFR tyrosine kinase inhibitors (TKI) was 5 and 11 months. One patient had ALK rearrangement and received crizotinib in the first line; this patient progressed on crizotinib within 2 months. Two patients who received erlotinib on a compassionate basis in the first-line setting due to poor PS went on to receive second-line chemotherapy. One patient who had metastatic disease with BRAF V600E mutation was treated with only palliative chemotherapy as BRAF inhibitor was not feasible. Second-line chemotherapy could be administered in 15 (22.7%) patients. Gemcitabine was the most frequently used second-line agent. Only about 6 (9.1%) patients could receive third-line therapy. The response rates to the different lines of palliative chemotherapy are summarised in Table 4. The objective response rate (ORR) for first, second and third-line chemotherapy was 15.2%, 13.3% and 0%, respectively. Two patients received ICIs in the first line with pembrolizumab and the PFS were 4 and 8 months. One patient who received ICIs in the second-line setting with nivolumab had a PFS of 3 months. Forty-one (31.8%) patients were unfit for any form of therapy due to poor PS. These patients have been advised the best supportive care (BSC) alone.

Survival outcomes
One hundred and twenty-nine patients were included in the survival analysis ( Figure 1). The median follow-up duration for the whole cohort was 32 months (range, 15.0-48.9). The median OS for the entire patient cohort was 5 months (95% CI, 3.4-6.5) (Figure 2). The median OS of patients who received curative-intent treatment (surgery or concurrent chemo-radiotherapy (CTRT)) was 14 months (95% CI: 6.5-21.4) and the corresponding 1-and 5-year survivals were 56% (Standard error (SE): 11.1) and 23% (SE: 9.9), respectively. The median OS for patients treated with palliative intent was 4 months (95% CI: 2.6-5.3, p = 0.00052) (Figure 2), and the corresponding 1-and 5-year survival rates were 20% (SE: 4.5) and 6% (SE: 3.2), respectively. The median OS according to the various treatment modalities is summarised in The factors significantly affecting the survival outcomes in the univariate analysis were Eastern Cooperative Oncology Group PS (ECOG PS), the intent of treatment, stage of the disease, T stage, M stage, presence of brain metastasis and the type of initial treatment received. On multivariate analysis, only brain metastasis and administration of palliative chemotherapy were found to be significant. The univariate and multivariate analyses are summarised in Supplementary Table 1.

Discussion
Our study represents one of the largest single-institution case series of patients with PSC.
In our study, the majority of the patients were smokers (70.6%), which is similar to that reported in other studies [25]. However, in an earlier study from our group, we found that 52% of patients with NSCLC were non-smokers; thus, smoking appears to be more common in patients with PSC than NSCLC in our patients [26]. However, we found that smoking did not significantly influence the survival of our patients with PSC. PSC was also seen more frequently in males than females (81.5% in males) [2,11,27]. The majority of patients who had metastatic disease had poor PS and the proportion of patients who received first-line or subsequent lines of therapy was low, which reflects the aggressive disease biology.   We found that the median SUV max of the tumour on the baseline PET-CT was 20.2, which is similar to that reported in other studies which reported that PSC has intense SUV uptake values [28,29]. This suggests that PSCs are F-fluorodeoxyglucose (FDG)-avid tumours and that performing a PET-CT scan would be an appropriate staging test, especially in patients who are being planned for radical therapy. The median tumour size was 7.5 cm and the majority presented with advanced T stages (about 91.4 % were of T3 and T4). In a similar study of 51 cases of PSC, the median T size was 6 cm and the incidence of T3/T4 disease was 60.7%. However, this frequency was relatively higher in our study when compared with case series from other countries. Interestingly, only three patients had T1 disease in our study. Similarly, the percentage of stage III and IV disease was 95.3%, which was markedly higher in contrast with other case series [10,30].
Most studies on PSC have reported that PSC carries a poor prognosis with the caveat that these are small case series or single-institution studies. In one study from the Mayo Clinic, a matched comparison between PSC and typical NSCLC demonstrated that PSC histology was associated with significantly poorer survival than other NSCLC histologies. In this study, the median OS was 9.9, 25.2 and 16.8 months for PSC, adenocarcinoma and squamous cell carcinoma, respectively [9]. Similarly, a study from the Surveillance, Epidemiology and End Results database on PSC also revealed a significantly worse OS for patients with PSC compared with matched NSCLC controls [31]. The survival in our study was markedly lower when compared to other published case series which had reported a median survival range of 10-19 months.
The poor survival in our study, when compared to the other case series, may be attributed to a multitude of causes. A high percentage of patients presented with a very advanced stage, with early-stage disease (stage I and II) accounting for only 4.7%. The percentage of patients who could receive curative-intent therapy was also markedly lower in comparison with other reported case series: surgery in 9.3% and CTRT in 3.3% of patients [9,31]. Other reasons include a higher percentage of patients with poor PS, high nodal stage, higher incidence of brain metastasis, higher rates of upfront BSC, lower incidence of targetable driver mutation and the lower use of ICIs.
There are conflicting reports on the prevalence of EGFR mutation in sarcomatoid carcinoma of the lung. In a study by Jiang et al [32], the EGFR mutation was seen in 9 out of 32 patients (28.1%). In another study of 22 patients by Italiano et al [33], none had EGFR mutations. Likewise, the efficacy of EGFR TKIs in PSC is unknown. Few reports have suggested that PSC with EGFR mutations respond poorly to TKIs [32,34]. In our study, the frequency of EGFR mutation was 7% (4/57 patients) and two patients had a reasonable response to EGFR TKI. The prevalence of EGFR mutation in lung sarcomatoid carcinoma is lower than that reported in our patients with adenocarcinoma but similar to that reported in our patients with squamous cell lung cancer [35]. Similarly, the prevalence of ALK rearrangement in PSC is not clear [36]. Chen et al [37], in a study of 82 patients with PSC, found that ALK rearrangement was seen in three patients (3.6%). Gelibter et al [38] reported a case of PSC with ALK rearrangement who had a PFS of 15 months with alectinib. Two patients in our study had ALK rearrangement by IHC and the only patient who received crizotinib had a poor response with a PFS of 3 months.   PSC was historically considered to be resistant to chemotherapy [39][40][41][42]. Our study also revealed a poor response of PSC to chemotherapy. The response rates to first-line chemotherapy in our study were 15.2%, 13.3% for the second line, and 0% for the third line. This is similar to a study by Vieira et al [15], in which platinum-based chemotherapy was given to 73% of patients (n = 97), the response rate to chemotherapy was just 16.5% and about 69% of the patients had progressive disease at the time of first evaluation after the initiation of chemotherapy. These rates are much higher when compared with conventional NSCLC. For instance, in a combined analysis of three randomised controlled trials from the Southwest Oncology Group, the response rate to first-line platinum-based chemotherapy was 27% and the progression rate was 38% for NSCLC [43]. Molecular analysis of PSC has revealed a high frequency of mutation in certain genes like TP53 in 60%-80% [20,44] and KRAS in 30%-35% of the cases [44,45] and this may be the reason for resistance to chemotherapy [46]. The role of antiangiogenic therapy has been explored in the treatment of PSC. Apatinib, an antiangiogenic TKI which targets the vascular endothelial growth factor receptor 2 (VEGFR2) has been reported to cause a sustained response of 14 months in a case report by LI et al [47]. TP53 mutation has been postulated to be a predictive biomarker of response to antiangiogenic agents [48,49]. Since these tumours have a high prevalence of TP53 mutations, further studies are required to evaluate the role of VEGF targeting agents.
Very little progress has been made in the treatment of PSC to date. Given the high incidence of KRAS and MET mutation in PSC and with the arrival of novel drugs to target these mutations [50][51][52], the survival is expected to improve in the future [53,54]. Bringing down the cost of ICIs would go a long way to improve the outcomes in lower-middle-income countries like India [55]. Ongoing studies in recurrent or metastatic PSC are evaluating the role of dual ICIs like nivolumab + ipilimumab (NCT02834013), durvalumab + tremelimumab (NCT03022500), chemotherapy combined with ICIs (ifosfamide + doxorubicin + durvalumab, NCT04224337), the combination of chemotherapy, ICIs and anti-VEGF agents (toripalimab + bevacizumab + nab-paclitaxel and carboplatin, NCT04725448) and savolitinib in MET exon 14 mutated PSC (NCT02897479).
The limitations of our study include the retrospective nature subject to an inherent bias, a lack of central pathological review and the heterogeneous nature of the chemotherapies used. We also were limited in our ability to perform extensive molecular testing in all patients; hence, we do not have information on the molecular profiles of all the tumours.

Conclusion
PSC presents in advanced stages, has a poor response to the current chemotherapeutic drugs, and is associated with poor survival outcomes. Further studies using molecular characterisation, ICIs and targeted therapy will be indispensable to improve the survival of these patients.