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 was 50.2%. This may show that the metastasis of squamous cell carcinoma was later and more limited than adenocarcinoma[26].
After three-dimensional radiation therapy of the primary tumour, the OS of single organ metastasis was trend of improved, especially for the patients with 1-5 metastatic lesions. The OS was significantly prolonged, showing that 75% of squamous lung cell carcinoma patients died of primary tumour progression[27]. Local treatment may be more important for squamous carcinoma, and more oligometastatic patients would have survival benefits from local treatment. However, there was no difference in PFS between single organ metastasis and 2-3 organ metastasis,also no difference in 1-5 metastatic lesions and >5 lesions.The reason may be due to insufficient follow-up time. There was no difference in OS and PFS in the T and N stages between squamous cell carcinoma and non-squamous cell carcinoma[28].
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% and 13.8% and 11 months and 6 months, respectively, similar to the standard treatment of 33% and 11% and 8 months and 4 months (part of the case IIIB period) [29], indicating that radiotherapy for stage IV squamous cell carcinoma will result in PFS extension. However, recent retrospective and prospective clinical studies of IV NSCLC in patients with squamous cell carcinoma have shown a significantly longer survival period than with chemotherapy alone, particularly for the patients who received 4 cycles of chemotherapy and a concurrent dose of ≥ 63 Gy radiotherapy. The 1 year OS rate, MST and PFS were 59%, 16 months and 9 months [23, 24], respectively, for patients who had 5 or fewer oligometastatic lesions, and the OS, PFS and local control were improved when the primary tumour received a high dose of radiation, ≥63 Gy[21, 22]. Therefore, in stage I-III NSCLC, a primary tumour irradiation dose from 40 Gy to 60 Gy gradually extended the OS, and local recurrence of squamous cell carcinoma after treatment was the main failure [30-32]. Large data results of IV NSCLC radiotherapy alone showed that the OS after a dose lower than 36 Gy was significantly lower than 36-50 Gy and did not further improve at doses higher than 50 Gy [33]. According to the primary tumour dose stratification analysis in 183 patients of this study (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 non-squamous 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.