Discussion
To the best of our knowledge, this is the first study that addresses the impact of LC on IPF patients in the Middle East and Egypt. Results showed that LC has significant impacts on clinical outcomes and survival of patients with IPF in Upper Egypt. Demographic features of patients with IPF and/or LC could be different in our locality. Mohamed and Ibrahim [
11], in their study of 568 patients with IPF in Upper Egypt, concluded that IPF has a different age and sex distribution in Upper Egypt, compared to international data. It was observed that 43% of patients with IPF developed their disease before the age of 50, with a mean age of 48.6 ± 12.9 years at the time of diagnosis [
12]. In a recent study for primary LC in Upper Egypt, it was observed that the incidence of adenocarcinoma surpassed that of squamous cell carcinoma, and it was common that the patients presented with their illness at later stages [
13].
Our data revealed that the prevalence of LC in IPF patients is 13.8% in all (8.9% in LC onset during the IPF follow up). The cumulative incidence of LC among IPF patients at 1 and 3 years was 37.2 and 62.5%, respectively. Our results are consistent with the worldwide reported prevalence range of 4.8 to 48% [
3‐
5,
7]. Moreover, these data represent the third report; after those of Ozawa et al. [
19] and Tomassetti et al [
4], documenting that cumulative incidence of LC increases remarkably overtime after the initial diagnosis of IPF. Furthermore, these data confirm the crucial importance of a prospective protocol for follow up of IPF patients with annual HRCT scanning.
It has been observed that LC was more common among IPF patients who are older, males, and smokers. These findings are consistent with those of previous reports enrolling different populations [
3‐
7,
9,
10]. For these reasons, we think that those particular populations with IPF should receive intensified follow up protocols for the development of LC. Despite that tumor location in LC-IPF patients was different among studies [
3‐
7], results of the current study are in agreement with the majority of other studies of LC in IPF [
3‐
10]. Most of the cancerous lesions were peripherally located, in the lower lobes, and in IPF-associated lesions. These findings add more support to the theory that the inflammatory process is associated with bronchiolar metaplasia in the pathogenesis of LC [
20]. Again, we believe that those populations deserve more attention during their follow up protocols. It is necessary to raise awareness of LC risk among patients with IPF.
Similarly, there was no consensus regarding the most prevalent histologic type of LC-IPF [
3‐
10]. Squamous cell carcinoma was the most common histological type encountered by some authors [
4,
5,
10], while adenocarcinoma was encountered by others [
21,
22]. Squamous cell carcinoma and adenocarcinoma were found in 44 and 41% of our LC-IPF cohort, respectively. In a recent systemic review, Wang et al. concluded that adenocarcinoma and squamous cell carcinoma are the most common types in IPF-associated LC patients [
23].
Considering the clinical, radiologic, and pathologic findings of our cohort together may support the current hypothesis that considers IPF as a disease of premature aging with several links to LC [
4,
5,
8,
24]. However, the pathogenesis of combined IPF and LC is not so simple. Recently, it has been proposed that perturbed signaling pathways, epigenetic and genetic changes, oxidative stress, and fibroblast growth factor receptor (FGFR) signaling pathways are all thought to be involved in the pathogenesis of IPF-associated LC [
23].
Previous studies have highlighted the clinical risk factors associated with LC development in IPF patients [
3‐
7,
25]. It was consistently shown that elderly male IPF patients with a history of smoking are more likely to develop LC. In this context, we observed that pack/years and male gender were significant independent predictors of LC in IPF patients. A study from England suggested that the incidence of LC is significantly increased in IPF patients compared to the general population, and that smoking is an independent predictor of LC development [
26].
Survival analysis of our cohort showed interesting results. Survival time was significantly different between LC-IPF and IPF only (p = 0.000). LC accompanying IPF was one of the most significant independent predictors of survival in IPF patients (HR 5.431, CI 2.186–13.492, p = 0.000).
Notably, the difference in mortality seen in our study was not attributable to worsening of pulmonary fibrosis, but mainly to both LC progression and complications of LC therapies. Similar to the findings observed by Tomassetti et al. [
4], this is the second report that confirms such significant findings.
Our results are in strong agreement with previous reports [
3‐
7]. Lee and coworkers [
3] concluded that LC was the most predictor for mortality among IPF patients (HR 2.441, CI 1.373–4.339;
p = 0.002), while Tomassetti et al [
4], observed a statistically significant difference in survival of patients with LC-IPF compared with IPF only, with an adjusted HR of 7 (95% CI, 3.81–12.90;
p = 0.001).
The majority of deaths among LC-IPF patients seen in the current study was not due to worsening of pulmonary fibrosis, but to both LC progression and complications of LC treatment; in 36 and 22% of patients, respectively. Moreover, it was observed that 50% of AEs in patients with LC were triggered by therapies for LC. These risks make the decisions about LC management in IPF, despite undertaken by a multidisciplinary team, still challenging to the clinician.
Furthermore, two-thirds of patients with LC-IPF (23/34, 67.6%) had advanced cancer and received either chemotherapy (with a high rate of complications) or best supportive care. Despite improvements in our understanding of pathogenetic mechanisms for the development of LC among IPF patients [
23], the current treatment strategies for combined IPF and LC, including medications and surgery are still controversial, complex and thorny [
4,
23,
27].
Several studies had addressed the impact of surgical resection of LC in patients with IPF. Early postoperative mortality ranged from 0 to 18.2% and postoperative morbidity ranged from 7.1 to 40.7% [
27,
28]. Notably, we reported surgery-related complications in 75% of operated patients, mainly pneumonia. Kreuter and colleagues reported an incidence of 67% for surgery-related complications and a 30-day mortality of 25% among the operated patients with LC-IPF [
10].
This high rate of surgery-related complications, again highlights the importance of annual HRCT for patients with IPF, for early detection of LC which might give the patient better surgical therapeutic options, hence better outcomes.
There are only sparse data concerning radiotherapy in LC with IPF [
10]. Despite those patients who received radio-, or radio-chemotherapy had non-fibrotic ground in HRCT still, the reported rates of radiation pneumonitis and pulmonary infections were high, but with no impact on mortality. Local tumor ablation might be an attractive option in some of those severely pulmonary compromised patients, while it has been used safely in patients with severe emphysema [
29]. Disappointingly, it seems that chemotherapy is not a safe therapeutic option for patients with LC-IPF. Chemotherapy-related toxicities were reported in 77% of our cohort, mainly pneumonia, and pancytopenia. Previous studies reported chemotherapy-related toxicities in 63% [
10] and 50% [
4] of patients with LC-IPF.
Acute exacerbations have significant impact on IPF patients, particularly those with LC-IPF, with considerable morbidity and mortality. In the literature, the incidence of treatment-related AEs in patients with LC-IPF ranged between 12.5 and 30% and mortality of treatment-related AE ranged between 9 and 16% [
30,
31]. However, our results revealed a higher incidence of treatment-related AEs (50%) and their related mortality (50%). Careful monitoring of patients for these AEs, and if possible, their prediction [
32], are warranted.
Despite the current study is the first one in Egypt and the Middle East that describes the impact of LC on IPF in a unique group of populations, yet it is to be considered that the inherent disadvantage of being a retrospective study, together with its single-center design, and the relatively limited number of patients are important limitations. The impact of LC on IPF and the optimal management of LC in patients with IPF needs to be addressed in larger prospective multicenter studies. Finally, our data from Upper Egypt are generally similar to those previously reported from Western and Asian populations.