The treatment of locally advanced NSCLC remains controversial [11
] due to the heterogeneity of this patient population. Surgery alone is not recommended as the standard therapy, because the prognosis of these patients varies according to the status of mediastinal lymph node involvement. Additionally, primary surgery has been shown to have poor outcomes in certain subgroups of patients with this disease [12
]. The most common treatment approaches are concurrent chemoradiation (CRT) [13
], or in some cases trimodality therapy, which involves CRT followed by surgical resection [15
]. Thoracic irradiation may cause a bronchovascular fistula, which results either from the rapid regression of the tumor or from necrosis of the bronchial mucosa and the vessel wall by radiotherapy itself with the attendant endothelial damage causing vascular abnormalities. As the pathogenesis of PH involves bronchovascular fistulae and vascular abnormalities [5
], thoracic irradiation is a potential cause of PH, and its toxicity may be enhanced when combined with chemotherapy [18
This study was conducted to identify the risk factors for fatal PH in patients with locally advanced NSCLC treated with chemoradiotherapy. Risk factors for fatal PH in this set of patients have not yet been established. In the current study, risk factors were determined by multiple logistic regression of variables that included patient demographics, baseline hemoptysis, tumor location, histological type, and baseline tumor cavitation, all of which could influence the occurrence of PH. We identified 2 independent significant risk factors for fatal PH: the presence of baseline major cavitation and squamous cell histology. The presence of baseline major cavitation proved to be a powerful risk factor (OR, 17.878) for fatal PH. Chaudhuri et al. examined cavitating lung cancer and reported that vascular invasion by tumor cells causes intratumoral ischemia [19
], which induces hypoxia-inducible transcription factors and several angiogenic factors such as vascular endothelial growth factors [20
]. The mechanism of PH in tumors with cavitation remains unclear, but disruption of the abnormal intratumoral vasculature by these transcription factors or cytokines may be one of the causes of PH in case of tumors with cavitation.
While the incidence of PH appeared to be high in patients with squamous cell carcinoma, it remains unclear whether squamous cell carcinoma contributed directly to the hemorrhage. For example, the risk of PH observed in the first phase I clinical trial of bevacizumab rendered antiangiogenic therapies inaccessible to patients with squamous cell carcinoma; [21
] nevertheless, bevacizumab was added to standard frontline chemotherapy for NSCLC and has shown a survival benefit in these patients compared to chemotherapy alone [22
]. However, it was not clear whether histology alone was the central risk factor for PH since squamous cell tumors differed from adenocarcinomas in that they were more frequently centrally located and had a greater tendency to cavitate. In the current study, we showed that squamous cell histology was associated with PH, independent of tumor location or the presence of cavitation.
Interestingly, the tumors of all patients with fatal PH who had major tumor cavitation before treatment had squamous cell histology. The incidence of fatal PH in patients having both risk factors, baseline major cavitation and squamous cell histology, was 33.3%; in contrast, the overall incidence in the study cohort was 2.1%. This findings shows that use of a combination of independent significant risk factors may enable the identification of patients at high risk of fatal PH.
Considering the risk factors for fatal PH identified here, primary surgery may be one of the treatment options for patients with operable locally advanced NSCLC, with baseline major cavitation and squamous cell histology. For the management of massive and recurrent hemoptysis, bronchial artery embolization (BAE) is also a demonstrated treatment option [24
]; however, the bleeding recurrence rate among patients with BAE-treated lung cancer can reach 50% [32
]. Surgical intervention, in contrast, is curative [33
] and an established treatment for PH. A surgical approach may be beneficial for these patients at high risk of fatal PH with regard to local control of the potential source of the hemorrhage. In addition, although it remains unclear whether chemoradiation contributes directly to the occurrence of fatal PH in this study, primary surgical resection may help avoid potentially unfavorable primary chemoradiation.
The present study was retrospective and had limitations. It was not designed to evaluate the association between therapeutic modality and fatal PH risk. To our knowledge, no definitive information evaluates the direct association between therapeutic modality and fatal PH risk. Accordingly, it remains unclear which therapeutic modality among surgery, chemotherapy, and radiotherapy should be selected for patients identified as being at high risk of fatal PH in our study. We consider primary surgery to be a potential treatment option for patients with operable locally advanced NSCLC, who have both baseline major cavitation and squamous cell histology. However, further studies are required to compare the risk of surgery and the risk of fatal PH that accompanies chemotherapy or radiotherapy. Additionally, a considerable number of patients with locally advanced NSCLC are inoperable. For these patients, further studies are required in order to compare the differences between therapeutic modalities with regard to treatment benefit and the risk of fatal PH accompanying each therapy. Furthermore, since patients with fatal PH were all ≤ 70 years of age or had stage III tumors, we could not evaluate the correlation between age or stage and risk of fatal PH in this study. Despite these limitations, this is the first study to identify the statistically significant independent risk factors for fatal PH in patients with locally advanced NSCLC treated with chemoradiotherapy. We believe that our data will be helpful for future trials and for clinicians when determining therapeutic strategies for patients with locally advanced NSCLC.