The survival impact of concurrent chemotherapy and primary tumor radiotherapy on stage IV squamous non-small-cell lung cancer


 Objective: To analyse the impact of survival with three-dimensional radiotherapy for stage IV squamous non-small cell lung cancer (NSCLC). Methods: Data for 629 eligible patients who received three-dimensional radiotherapy between 2002 and 2016 were retrospectively analyzed.161 of 183 cases were included pre-protocol. Patients received platinum-doublet chemotherapy with concurrent irradiation of the primary tumour. Primary endpoints were overall survival (OS) and progress-free survival (PFS). Results: Of 161 patients, the 1-, 2-, 3- and 5-year OS rates and median survival time (MST) were 45.7%, 14.1%, 11.2%, 2.2% and 11months, respectively. Using contrastive analysis PTV dose ≥63 Gy and <63 Gy, the 1-, 2-,3- and 5-year overall survival (OS) rates and median survival time (MST)were 48.9% vs 43.3%, 21.8% vs 8.2%, 18.4% vs 4.4%, 5.1% vs 0%, and 12 months vs 11months ( χ 2 = 7.222, P=0.007). Contrastive analysis patients received radical concurrent chemoradiation therapy, and the 1-, 2-, 3- and 5-year overall survival (OS) rates and median survival time (MST) were 54.3% vs. 37.2%, 27.2% vs. 7.5%, 24.9% vs. 4.8%, 8.3% vs. 0%, and 14 months vs. 10 months ( χ 2 = 13.180, P=0.000). Multivariate analysis showed that PTV ≥63 Gy was an independent favourable factor for survival. Conclusion: Concurrent chemotherapy and three-dimensional radiotherapy to the primary tumour in stage IV squamous NSCLC could prolong survival, and with increasing intensity of comprehensive treatment, OS gradually improved. PTV ≥63 Gy is the independent prognostic factors for OS.
[Key Words] Stage IV; Squamous non-small cell lung cancer (NSCLC); Concurrent chemoradiotherapy; Overall survival

squamous cell, adenocarcinoma and other cell types. Squamous cell carcinomas account for 30% of NSCLC worldwide [2]. The majority of lung cancers (57%) are diagnosed at a distant stage, and the 5-year survival rate is approximately 4% for distant stage disease.
In recent years, first-line chemotherapy, including third-generation agents (including gemcitabine, paclitaxel, and pemetrexed), molecular targeted therapies or immunotherapy drugs, has improved overall survival (OS) of patients with advanced NSCLC [1,3,4].
For patients with non-squamous NSCLC without identified oncogenic drivers, bevacizumab, a recombinant humanized monoclonal antibody against vascular endothelial growth factor (VEGF), in combination with platinum-based chemotherapy, remains a valid first-line treatment option [5][6][7][8]. Cisplatin or carboplatin combined with pemetrexed and concurrent radiation therapy may also associated with more clinical benefits[9, 10]. However, none of the above treatments are suitable for patients with squamous NSCLC. The discovery of activating mutations of the epidermal growth factor receptor (EGFR) and the echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion has led to changing treatments for patients with NSCLC who harbour these drivers. Agents that inhibit the tyrosine kinase binding sites of these molecules have demonstrated improved PFS versus chemotherapy [11][12][13]. However, these mutations are very rare in squamous NSCLC [2,14].
For patients with squamous NSCLC, although some potentially targetable molecular lesions have been identified in tumours [2], including PIK3CA amplification, FGFR1 amplification, MET amplification, and DDR2 mutation, none of these biomarkers have yet been validated in this setting as predictive for targeted therapies, and available first-line regimens have remained essentially unchanged for the past two decades. In general, such regimens comprise a platinum-based doublet of cisplatin or carboplatin combined with gemcitabine, vinorelbine, or a taxane [2,15]. ECOG1594 study shows that the third-generation agents combined with platinum had similar efficacy in the treatment of advanced NSCLC.The median survival about 8 months, 1-year OS ~ 30% [4].The treatment with chemotherapy alone entered a plateau.Thus, new strategies involving combinations of chemotherapy with other treatment modalities should be explored.
Some studies have shown that controlling the primary tumour may be important in prolonging survival among patients with advanced NSCLC. Local control of the primary tumour has not only reduced symptoms but also improved overall survival (OS) [16,17].
More evidence suggests that some patients with stage IV disease could benefit from aggressive thoracic radiation therapy beyond palliative irradiation [18][19][20]. Moreover, the role of concurrent chemotherapy with thoracic radiation therapy for advanced NSCLC is not well-defined [19,21].
Our previous study showed that treatment of IV NSCLC with joint administration of four to five cycles of chemotherapy and three-dimensional radiotherapy may prolong survival especially for patients with single metastatic sites [22][23][24]. However, the role of chemotherapy given concurrently with primary tumor radiotherapy for stage IV squamous NSCLC patients is not well-defined, and the independent prognostic factors for OS in stage IV squamous NSCLC patients treated with concurrent chemoradiotherapy remains to be answered. Therefore, 164 eligible stage IV squamous NSCLC patients come from multiple cancer centers and tumor hospitals who received three-dimensional radiotherapy between 2002 and 2016 were retrospectively analyzed we assessed the impact of survival with primary tumour radiotherapy and concurrent chemotherapy for stage IV squamous NSCLC patients.

Patient selection
Inclusion criteria of patients are as follows: (1) Histologically or cytologically confirmed Squamous Carcinoma; (2) Newly diagnosed stage IV disease (staged according to the 2002 system of the American Joint Committee on Cancer); (3) No previous anticancer treatment; (4) 18 to 80 years of age; (5) Karnofsky performance status (KPS) score ≥ 70; (6) No contraindications to radiation therapy or chemotherapy; (7) Metastatic disease limited to ≤3 organs; and (8) Presumed ability to tolerate thoracic radiation therapy at a dose of ≥36 Gy in 20 fractions. Exclusion criteria were (1) a history of thoracic surgery, radiation therapy, or chemotherapy; (2) pregnancy or lactation at the time of enrolment; (3) previous malignancy or other concomitant malignant diseases.

Pre-treatment evaluations
All patients underwent fibrotic bronchoscopy and contrast-enhanced computed tomography (CT) of the chest to evaluate the extent of the primary tumour and regional lymph node status. All patients also underwent bone scintigraphy, contrast-enhanced CT of the abdominal region, and magnetic resonance imaging (MRI) of the head to detect distant metastases. Positive findings on positron emission tomography (PET)/CT or bone scintigraphy required additional radiologic confirmation (e.g., MRI or CT of the bone). Pretreatment evaluations were completed within 2 weeks before treatment started.

Thoracic radiotherapy protocol
All patients were immobilized in the supine position using a T bar, wing board, and Vaclock cradle. Images with contrast were obtained from the CT simulator for treatment planning purposes. All patients were scanned using serial 5-mm slices from the hyoid bone through the third lumbar vertebra. All patient 3D-CRT or IMRT treatment plans were performed using the ADAC pinnacle planning system (version 7.4f), and dose distribution was computed with a tissue heterogeneity correction.

Chemotherapy protocol
Platinum-based doublets chemotherapy(cisplatin in combination with docetaxel, paclitaxel or vinorelbine) was used for all patients, and concurrent thoracic radiation was given within 1 week following the start of chemotherapy. The commonly used regimens were as follows: 140 mg/m 2 of paclitaxel (P) or 75 mg/m 2 of docetaxel (D) on day 1, followed by 80 mg of cisplatinum (C) per square metre of body-surface area(mg/m 2 ) or carboplatin (Cb) at a dose calculated to produce an area under the concentration-time curve of 6.0 mg/ml/min were administered on day 2; gemcitabine was not given because of the risk of its increasing radiation-related toxicity. After completion of thoracic radiotherapy, patients demonstrating a response or stable disease continued chemotherapy up to 4-6 cycles, whereas patients who experienced progressive disease or unacceptable toxicity were transferred to second-line therapy. No maintenance therapy was given.
Patients who received at least 2 cycles of chemotherapy and thoracic radiation doses of ≥36 Gy were considered to have completed treatment according to the protocol.

Evaluation of treatment-related toxicity and response
Treatment-related acute toxicity was scored according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. During treatment, a routine blood test was performed at least once per week; and routine blood, liver function, renal function tests and electrocardiograms were examined prior to chemotherapy. If necessary, a chest X-ray or CT examination and barium meal radiography were used to evaluate radiation pneumonitis and oesophagitis. Treatment response was assessed by extramural reviewers using the Response Evaluation Criteria in Solid Tumours (RECIST).
Patients were also classified as having a response if they had CR or PR and no response if they had SD or PD. The conventional response criteria were measured at each individual institution and verified by the central principal investigator (PI). Disease-free survival and OS were calculated from the time of registration.

Follow-up
After the completion of treatment, an intravenous contrast CT scan of the chest and upper abdomen was obtained, and tumour response was assessed at 1 month after the completion of treatment. Patients were followed monthly for the first 3 months, every 3 months for 2 years, and then every 6 months thereafter.

Statistical analyses
Intent-to-treat analyses were performed on data from all patients who entered the study.
The endpoints of this study included overall survival (OS) and progress-free survival (PFS).
The overall survival time was measured from the first day of concurrent chemoradiotherapy to the date of death or the last follow-up. The progress-free survival time was measured from the first day of concurrent chemoradiotherapy to the date on which the tumour progressed or the date on which the patient died from any cause. The Statistical Package for Social Sciences, version 13.0 (SPSS, Chicago, IL, USA) was used for statistical analysis. The Kaplan-Meier method was used to calculate the OS. The logrank test was used to compare the survival curves. Multivariate Cox regression analysis was used to test independent significant prognostic factors for OS. All statistical tests were two-sided, and a P-value <0.05 was considered statistically significant.

Patient Clinical characteristics
In total, 629 patients were enrolled in this study. The last follow-up was in January 2019.

Cox regression analyses for overall survival
According to multivariate analyses, patient age, metastatic lesions and treatment response were not related to survival, but the primary tumour radiation dose the patient received was an independent predictor of survival (HR, 0.703; 95% CI, 0.498-0.991; P=0.044). (Table 4)

Discussion
In the present series, squamous cell carcinomas accounted for 30% of patients, and in this study, squamous cell carcinomas accounted for approximately 29% of patients. The ratio of males to females in squamous cell carcinoma was 7.3: 1, which is higher than that for non-squamous cell carcinoma (2.1: 1), and the incidence of squamous cell carcinoma was higher in men [3]. The incidence of squamous cell carcinoma was 46% in patients ≥65 years of age. In the entire group, T3-4 squamous cell carcinoma accounted for approximately 68.9% of patients, which is slightly higher than 62.3% being adenocarcinoma. This may be because squamous cell carcinomas easily infiltrate the surrounding large blood vessels, similar to the epidemiological characteristics of NSCLC.
Regarding the lymph node metastasis rate, the N2-3 stage accounted for approximately 85.8%, with adenocarcinoma being 85.7%. Regarding the organ metastatic rate, 60.1% had single organ metastasis, which was lower than the IV NSCLC metastatic rate of 69.5% [25], but when it was defined by metastatic lesions, for less than 5 lesions, 57.9% of squamous cell carcinoma was oligometastatic, and the non-squamous cell carcinoma rate Platinum-based two-dose chemotherapy is still the standard treatment of squamous IV NSCLC [15]. In this study, the results of three-dimensional radiotherapy with concurrent chemotherapy of the primary tumour showed that the 1-year OS, MST and PFS were 45.7%  (Table 3), the 1 year OS and PFS were 8.3% and 0 for <36 Gy, but for 36-44.9 Gy and 45-62.9 Gy patients, the 1 and 2-year OS rates were 31.7% and 45.5% and 5.3% and 7.1%, respectively. The median PFS was 8 and 11 months, and for ≥ 63 Gy patients, the 1, 2, 3 and 5-year OS rates were 46.1%, 21.3%, 17.9% and 5.0%, respectively, and the median PFS was 5 months. Further analysis of the 161 cases that completed the study programme showed that the OS was significantly prolonged with increased dose, suggesting that for squamous IV NSCLC, the OS gradually extended with increases in the primary tumour dose. With a dose ≥ 63 Gy, the extension OS were more pronounced than at <63 Gy, indicating that higher dose improves local control, which was the main failure pattern in squamous NSCLC [32]. These results were similar to a previous report of primary tumour radical dose three-dimensional radiotherapy with IV NCSLC (including squamous cell carcinoma and non-squamous cell carcinoma) [23].In our study there are no significant difference in PFS and LRPFS with increased dose in squamous NSCLC.However, there are significant differences in the overall patients and nonsquamous NSCLC patients, which may be due to radiosensitivity and the need for radiation therapy doses vary between pathological types of tumors.Adenocarcinoma may require higher local control dose.
It is commonly agreed that a primary treatment of stage IV NSCLC with systemic chemotherapy will improve OS and PFS for stage IV NSCLS patients. In this study, concurrent chemo-radiotherapy was the main treatment mode, and the OS and PFS after 4 cycles of chemotherapy for stage IV squamous NSCLC were significantly longer than after 2-3 cycles. This was similar to IV NSCLC patients receiving chemotherapy [34], indicating that chemotherapy and its intensity can interfere with the results of comprehensive treatment. Thus, for the patients who received 4-6 cycle chemotherapy, the OS of the primary tumour at ≥ 63 Gy trend to longer than at <63 Gy, but the PFS was not statistically different (P = 0.356). Radiotherapy as a local treatment would treat the primary tumour, and chemotherapy would control not only primary tumours but also metastases. New metastases or small metastases can reduce PFS, but patients can survive with the tumour. Three-dimensional radiotherapy to the primary tumour may affect the OS, and the emergence of new metastatic lesions is not a direct death factor for patients [25]. Systemic and local treatment may be more important for squamous stage IV NSCLC.
Therefore, different intensities of combined chemotherapy and radiotherapy were analysed (Table 3). Four cycles of chemotherapy with a primary tumour dose ≥ 63 Gy were defined as radical treatment. The results showed with intense chemo-radiotherapy, the MST were 3, 8, 10, and 14 months, the OS gradually increased, and the PFS was no significant difference (P = 0.377). For radical treatment, the 1-, 2-, 3-, and 5-year OS rates were 54.3%, 27.2%, 24.9%, and 8.3%, respectively, and the PFS was 5 months. These results demonstrated that the increase in the chemotherapy cycle and radiotherapy dose may prolong OS and PFS in IV NSCLC. If the patients tolerate the radio-chemotherapy toxicity, adequate chemotherapy and radical radiation therapy will control not only the metastatic disease but also the primary tumour. The combined treatment contribution to improved survival may be important [24].
Compared to patient age and number of metastatic lesions, the response after comprehensive treatment multivariate analysis showed that primary tumour radiation dose was an independent prognostic factor, and ≥63 Gy provided better OS and LRPFS.
This was similar to the results from previous studies with IV NSCLC [23].
We acknowledge several limitations to the current study. Although we found that a dose of 63 Gy was associated with better OS, the range of doses for the thoracic lesions was broad, from 36 to 72 Gy, and the choice of dose depended on factors such as PS and tumour burden, leading to possible selection bias. Moreover, we found that radiation dose remained a predictor of improved survival outcomes even when patient and treatment factors were considered in the multivariate analyses. Finally, we recognize that the limited number of patients means that additional studies and patients will be needed in the future.

Conclusions
In summary, chemotherapy given concurrently with 3D-RT to the primary tumour may improve survival in stage IV squamous NSCLC. The radiation dose to the primary tumour was the main contributor to OS. Consistent with conclusions from previous studies we reported [22][23][24], we found that aggressive radiation to the primary tumour improved survival outcomes for a subset of patients with metastatic NSCLC. Further randomized trials and more patients are warranted to evaluate the optimal thoracic radiation dose

Availability of data and material
All data generated or analysed during this study are included in this published article.