Ethical approval

The study was approved by the Ethics Committee of Shandong Cancer Hospital and Institute. All procedures performed in the studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Written informed consent was obtained from all patients before their participation in this clinical research, and their data are used for future research.

Grouping


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Of the 115 patients, the 15 (13%) patients who composed group A received PORCT and had EGFR mutations, the 31 (27%) patients who composed group B received PORCT and had wild-type EGFR, the 21 (18%) patients who composed group C received POCT alone and had EGFR mutations, and the 48 (42%) patients who composed group D received POCT alone and had wild-type EGFR.

EGFR mutation detection

The test specimens were collected during surgery; EGFR mutations were detected by fluorescence quantitative polymerase chain reaction (PCR), and the positive specimens were confirmed by gene sequencing. Exons 18, 19, 20 and 21 of the EGFR gene were tested in 115 surgical specimens.

Patient evaluation

The pretreatment assessments typically included clinical evaluations, blood tests, CT scans of the chest, bronchoscopy, ultrasound or abdominal CT, brain magnetic resonance imaging (MRI), and bone scans. The patients were followed up every 3 months for 2 years after surgery and then followed up every 6 to 12 months. The regular follow-up evaluations included a physical examination, determination of World Health Organization (WHO) Performance Status (PS), biological assessment, chest X-ray, chest CT scan, bronchoscopy, abdominal ultrasound or CT scan, and bone scan.

Disease recurrence at the surgical margin, ipsilateral hilum, and/or mediastinum was considered a local-regional failure.14 All other sites of failure, including the supraclavicular zone, contralateral hilum and distant organs, were considered distant metastasis.15,16

Surgery

In our analysis, positron emission tomography (PET)-CT scans were used as part of the routine preoperative work-up. All thoracic surgeons performed thoracotomy and mediastinal lymphadenectomy in a similar manner. All patients underwent systematic and complete mediastinal lymph node dissection or sampling. Systematic sampling was defined as the routine removal of at least one lymph node from each of the lowest levels. The lymph nodes at levels 5, 6 and 7 (at least) were sampled during the left thoracotomy or dissected completely, while those at levels 4 and 7 were sampled during the right thoracotomy. A total of 3~20 N2 lymph nodes were taken, with an average of 6 lymph nodes.

Postoperative chemotherapy

Platinum-based chemotherapy was administered with a median of four cycles and was given with radiotherapy or alone. A total of 63 patients received gemcitabine (1,000 mg/m2 intravenously on days 1 and 8) and cisplatin (40 mg/m2 intravenously on days 1–3) for a median of four cycles (range, two to five); 52 patients received pemetrexed (500 mg/m2 intravenously on day 1) and cisplatin (40 mg/m2 intravenously on days 1–3) for a median of four cycles (range, two to five). Platinum-based chemotherapy was administered with a median of four cycles and was given with radiotherapy or alone.

Postoperative radiotherapy

Of the 115 patients, 46 received adjuvant PORT. Radiation was delivered with 6 to 8 MV X-rays at 1.8–2Gy per fraction, 5 days per week, for a total dose ranging from 48Gy to 54Gy and a median dose of 50Gy. The clinical target volume (CTV) for treatment generally included the mediastinum and ipsilateral portal (based on a postoperative CT scan of the anatomical markers). The planning target volume (PTV) was defined as the CTV plus 0.5–0.8 cm margins. The tumor bed was included only if invasion of the parietal pleura was documented in the operative report. The exact location of the visual field boundaries varied from case to case and depended on the postoperative displacement of the mediastinal structures. The respective 99% PTVs had to be covered by the 95% prescription dose, and the 95% PTVs had to be covered by the 100% prescription dose14 The dose limits for the peripheral normal organs were as follows: the maximum dose for the spinal cord was less than 45Gy; the mean lung dose was less than 15Gy, and less than 25% of the lung volume received 20Gy (V20); and the mean cardiac dose was less than 30Gy.

Statistical analyses

All statistical analyses were conducted using SPSS for Windows, version 20.0 (IBM Corporation, Armonk, NY, USA). OS was measured from the day of surgery to the date of death from any cause or the last follow-up. Progression free survival (PFS) was calculated from the day of surgery to the date of confirmed progression or death from any progression. If the complete survival time of a patient was impossible to obtain or if the disease did not progress, the patient status was assumed at the last known survival and/or contact date.

The PFS and OS rates were estimated using the Kaplan-Meier method, and log-rank tests were used for the univariate analysis. Variables that showed significant associations in the univariate analysis (p<0.05) were included in a multivariate stepwise backward Cox regression model to validate their independent prognostic values. Differences were assumed to be significant when a p-value of <0.05 was achieved.

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