Pulmonary pleomorphic carcinoma (PPC) is defined as a coexistence tumor of a carcinomatous tumor with a sarcomatoid tumor component of at least 10%, according to the World Health Organization (WHO) histological classification of lung tumors 2004 [1]. This subtype of sarcomatoid carcinoma has been considered to be characteristic of worse prognosis than other histological types. Some recent retrospective studies have suggested that PPC is usually resistant to standard chemotherapeutic regimens for non-small cell lung cancer (NSCLC) [2-6]. Because of a low incidence of less than 0.4% of all pulmonary malignancies [7], there were limited reports on the efficacy of palliative chemotherapy and was no established treatment for advanced PPC. In this study, we retrospectively investigated 31 palliative chemotherapy regimens for 16 patients with advanced PPC. This study aimed to clarify the efficacy of palliative chemotherapy for this rare type of aggressive tumor.

Patient selection and study design

We collected data on patients who had been diagnosed of PPC between June 2007 and December 2014 at our hospital. PPC was diagnosed according to the WHO classification report 2004 [1]. A diagnosis was based on the light microscopic findings of histological specimens and, if necessary, confirmed by immunohistochemical examinations. The pathological diagnosis was made as a routine work by agreement of two independent pathologists. For this study, we did not review the past diagnosis. Our institutional ethics committee approved this study and waived the requirement for informed consent from each patient.

Assessment

Clinical staging and response to chemotherapy was assessed according to the seventh edition of TNM classification for malignant tumors by the International Union Against Cancer and the American Joint Committee on Cancer [8] and to the Response Evaluation Criteria for Solid Tumors, version 1.1 [9], respectively. Response classification required two radiological assessments of over 6 weeks interval after the start of chemotherapy, unless confirmation of objective progressive disease (PD). We defined progression-free survival (PFS) and overall survival (OS) as the interval from the first day of chemotherapy to PD or death from any cause, and to the last day on which the patient was confirmed to be alive or dead from any cause, respectively. The Kaplan–Meier method estimated survival. We closed the data collection by December 31, 2015. All statistical analyses were performed with EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria). More precisely, it is a modified version of R commander designed to add statistical functions frequently used in biostatistics [10].

Among a total of 1461 primary lung cancers at our institution between June 2007 and December 2014, 29 patients (2.0%) were histologically diagnosed with PPC. Among 17 and 7 patients whose epidermal growth factor receptor (EGFR) mutation status and anaplastic lymphoma kinase (ALK) gene rearrangement were examined, respectively, none harbored positive activated mutation status. Except for 3 non-smokers and 2 unknown smoking habit, 24 patients were current or ex-smokers. Among 19 patients with stage IIIB or IV at diagnosis, three did not receive chemotherapy. Among 10 patients with stage IB-IIIA, nine received surgery, and one patient with stage IIIA transferred to another hospital for aggressive treatment immediately after confirmed diagnosis. Among 5 patients who experienced post-surgical recurrence, two transferred to other hospitals for aggressive treatment, two received best supportive care alone, and one received palliative chemotherapy. Clinical characteristics of the 17 patients who received palliative chemotherapy at our institution are listed in Table 1.

Table 1: Patient Characteristics.

Table 2 presents the details in the first-line chemotherapy. Twelve patients received platinum-based regimen, while the remaining 5 patients were treated with monotherapy. The response rate (RR), disease control rate (DCR), median PFS, median OS and 1-year survival rate of the first-line chemotherapy were 5.9% (95% confidence interval; 0.1-28.7%), 35.3% (14.2-61.7%), 45 days (35-115 days), 179 days (64-303 days) and 19.0% (4.7-40.6%) among 17 patients, and 8.3% (0.2-38.5%), 25.0% (5.5-57.2%), 44 days (35-161 days), 179 days (48-374 days) and 27.8% (6.7-54.5%) among 12 patients who received platinum-based regimens, respectively. Partial response (PR) was observed in a patient treated with a triplet of carboplatin, paclitaxel and bevacizumab.

Table 2: First-line chemotherapy.

Table 3 shows the details in the second- and further-line chemotherapy. Among 15 regimens per 9 patients in the second- and further-line settings, four regimens were combination doublets of two non-platinum drugs, but the remaining 11 regimens were monotherapy. No regimen was responsive. The RR, DCR, median PFS, median OS and 1-year survival rate of the second-line chemotherapy (N=9) were 0% (0-28.3%), 33.3% (7.5-70.1%), 77 days (3-142 days), 144 days (5-331 days) and 11.1% (0.6-38.8%), respectively.

Table 3: Second- and further-line chemotherapy.

This retrospective study reported on the efficacy of palliative chemotherapy for patients with advanced PPC, a rare histological subtype of lung tumor. As the previous reports suggested (Table 4), our study also showed that PPC was aggressively resistant to any regimens and resulted in poor prognosis. Thus, our study failed to propose any promising regimens for PPC.

Table 4: Review of previous case series reports of the first-line palliative chemotherapy for patients with pulmonary pleomorphic carcinoma.

Regarding carboplatin plus paclitaxel in our study, this combination doublet provided little response and was unsatisfactory for PPC. Except for a case report in which carboplatin plus paclitaxel successfully achieved tumor size reduction and long-term survival in two patients [11], no case series detected a responsive case treated with this doublet regimen [2-6]. We experienced an exceptional case in which bevacizumab-containing regimen achieved PR and provided favorable PFS, approximately six months. Three case reports described carboplatin, paclitaxel plus bevacizumab regimen achieved PR in four patients [12-14]. In addition, another case report described a case in which weekly paclitaxel plus bevacizumab was highly effective in the brain metastases after the completion of whole brain radiotherapy, but moderately effective in the thoracic lesions [15]. Although bevacizumab should be used for the highly aggressive tumor with careful attention to characteristic adverse effects of hemorrhage, this antibody drug may deserve further evaluation for PPC.

Cytotoxic chemotherapy containing platinum and gemcitabine is also debatable. Several case reports have described cases of PPC that responded to platinum plus gemcitabine. Hong et al. experienced two PR and two SD among eight patients treated with platinum plus gemcitabine as the first-line regimen [3]. Kaira et al. also found a case which achieved PR in the second-line carboplatin plus gemcitabine regimen [5]. Tamiya [16] and Yamanashi [17] et al. also reported successful cases in which cisplatin plus gemcitabine and carboplatin plus gemcitabine provided long-term response and survival, respectively. In contrast, the studies by Bae and Tamura et al. found no responder among 6 and 2 patients treated with platinum plus gemcitabine [2,6]. In our institution, gemcitabine was not used in the first-line regimen, and was not effective in combination with vinorelbine in the later-line setting.

This study has several limitations. First, this study was retrospective and our population was small sample size. Considering the rarity of this histology, a prospective and large scale study would be impossible. Our study was one of the largest studies which evaluated the palliative chemotherapy for advanced PPC. Second, our study included 11 cases in which pathological diagnosis was based on tiny specimens obtained by trans-bronchial biopsy or CT-guided biopsy. Except for post surgical recurrence, it is usually difficult to obtain a sufficient amount of specimens from patients with already advanced stage of lung cancer at the diagnosis.

Palliative chemotherapy was futile for advanced PPC. Further investigation of a new approach to this unfavorable tumor is required.

We thank Moto Yaga, Kentaro Masuhiro, Yumi Mitsuyama, Son-Ho Kim, Sou Takada, Narumi Noda, Yuki Nakatani, Kanako Nishimatsu and Shouko Ikuta at Department of Respiratory Medicine, Osaka Police Hospital for their detailed medical charts, diagnosis, treatment and care of their patients.