Clinical outcome of whole‐body gamma‐knife combined with pemetrexed concurrent chemoradiotherapy in elderly patients with locally advanced lung adenocarcinoma

Currently, concurrent chemoradiotherapy has become the standard treatment for locally advanced non‐small cell lung cancer, but it is often difficult for elderly patients to tolerate. In this study, we evaluated the curative effect, acute radiation reaction, and clinical application of stereotactic radiotherapy with whole‐body gamma‐knife combined with pemetrexed treatment in elderly patients with locally advanced lung adenocarcinoma.


INTRODUCTION
Recently, concurrent chemoradiotherapy has become a standard treatment for locally advanced non-small cell lung cancer (LA-NSCLC), but it is difficult for elderly patients to tolerate. When a double scheme with platinum-based drugs becomes the first-line treatment for LA-NSCLC, the improvement in prognosis in chemotherapy is within the platform period, and that in radiotherapy is also within the bottleneck area. 1,2 Therefore, there is no satisfactory standard treatment for elderly patients with lung cancer.
Based on three-dimensional conformal radiotherapy or intensitymodulated radiotherapy, proton therapy improved the 2-year survival rate to 57% in patients with stage III NSCLC. 3 Increasing the dose of local irradiation seems to reduce the incidence of late adverse reactions. However, because the normal tissue in front of the proton still has a high dose of irradiation and the treatment is expensive, the technology still has some challenges, so it is not suitable for most patients with LA-NSCLC. 4 The whole-body gamma-knife has been used in China for >20 years, and has been used to treat a large number of patients with cancer.
In the present study, we retrospectively analyzed 37 elderly patients with locally advanced lung adenocarcinoma, who received wholebody gamma-knife stereotactic body radiotherapy (SBRT) combined with pemetrexed concurrent chemotherapy in Hubei Provincial Armed Police Corps Hospital, which had good clinical effect.

Patient and characteristics
We selected 37 elderly patients with locally advanced lung adenocarcinoma who received whole-body gamma-knife (super-gamma-knife

Whole-body gamma-knife treatment system
The whole-body gamma-knife, also called super gamma-knife, which Zhongshan city, Guangdong province, China) 10 mg was administered during chemotherapy support symptomatic treatment.

Observation index and evaluation of curative effect 2.3.1 Short-term efficacy
After 2-3 months of radiotherapy, CT was carried out to evaluate efficacy. The RECIST 1.1 evaluation criteria were used for the short-term efficacy evaluation of solid tumor. 5 Local tumor control was classified as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) according to CT images. CR + PR is an effective index.

Long-term curative effect
The  SPSS 19 statistical software (IBM Corporation, Armonk, NY, USA) was used for data processing. The corresponding index was used to describe and analyze the counting data. The survival analysis was described using the Kaplan-Meier curve method. The log-rank test was used in the single-factor analysis of the prognosis. The multivariate analysis of prognosis was carried out using the Cox regression model, and the 2 -test was used to compare the count data groups. A P-value <0.05 was considered statistically significant.

Side-effects
The V 20 of both lungs in 37 patients were all <20%; the maximum irradiation BED 10  In elderly patients with lower body function, immunity is significantly lower, and the adverse reaction resistance is poorer. A reduction in the side-effects of chemoradiotherapy and improvement in the quality of life are the focus of clinical treatment. 9 PEM is a new kind of multiple target for folic acid-resistant agents, and is important in the clinical treatment of NSCLC, first-line treatment, secondary treatment, and maintenance treatment, and treatment with other chemotherapy drugs, such as molecular target drugs, and radiation therapy plays an important role. 10,11 Studies confirm that PEM possibly interferes with the balance of nucleic acids in cells by inhibiting adenosine triphosphate synthesis and damage to the accurate replication of DNA, and preventing cell block in radiation-sensitive G1/S phase boundary, joint genome DNA damage caused by radiotherapy, and cell apoptosis, and thus plays a role in radiotherapy sensitization. 12 In the present study, we used whole-body gamma knife SBRT combined with PEM concurrent chemoradiotherapy in the treatment of locally advanced lung adenocarcinoma in elderly patients.  13 It is higher than the results of the simultaneous treatment with PEM/carboplatin with a short-term efficiency in LA-NSCLC (CR + PR) of 83.33%, which is higher than the results of 3-D conformal radiation therapy, intensity-modulated radiation therapy, or combined chemotherapy in most studies. [15][16][17] The local control rate for 1 year in this group was 67.57%. The total survival rates for 1, 2, and 3 years were 86.49%, 45.45%, and 25%, respectively, which were similar to those reported by most studies using gamma-knife, 3-D conformal radiation therapy, and intensity-modulated radiation therapy or combined chemotherapy in the treatment of LA-NSCLC. 13,14,16 The adverse reactions, such as leukocyte count reduction, thrombocytopenia, radiation-induced esophagitis, and radiation-induced pneumonia, are also mild, obviously superior to the results of the same study with other single-or double-drug regimens. 18,19 In conventional radiotherapy technology, increasing the radiation dose of the tumor cannot improve the patient's OS. 20 The present study suggests that this might be related to a single low dose of radiation, prolonged course of radiation, and increased side-effects associated with increased tumor dose. The whole-body gamma-knife, as a special method of SBRT, adopting the high-dose treatment mode to improve the target dose and better protect the normal tissues, simultaneously reducing the number of segmentation, significantly shortens the treatment period, inhibits tumor cell repopulation, and improves local control rate of the tumor. The results of the present study showed that the whole-body gamma-knife SBRT is a good treatment for elderly patients with locally advanced lung adenocarcinoma. Its advantage is that it overcomes the disadvantages of conventional radiotherapy.
First, it shortened the 6-7 weeks conventional radiotherapy treatment duration to 2 weeks. It is critical for the elderly patients to actively accept successful complete treatment. More importantly, the treatment was completed within a short period, and there was no accelerated repopulation of tumor cells, which greatly improved the local control rate. 21 Furthermore, gamma-knife SBRT has a higher degree of conformal dose distribution of target, and the radiation center has high doses, allows rapid decrease in the outside dose, and guarantees target therapeutic doses that can effectively reduce the surrounding normal tissue dose, increasing the enhancement ratio. Furthermore, it can selectively reduce lymph node exposure without affecting the efficacy, and is simple and feasible. 21 Finally, the shorter course of SBRT is better combined with chemotherapy to improve patient tolerance.
In the present study, single-factor and multifactor analysis found that N staging and radiotherapy dose are both related to the prognosis.
The median survival time of N 0∼1 patients in this group was 10 months longer than that of N 2∼3 patients (P = 0.011). Therefore, the higher the N stage is, the greater the invasiveness of the tumor and easier the dissemination. These results are similar to the results of the study by Speicher et al. 22 The 1-year local control rate and median survival time in the GTV >120 cm 3 subgroup were lower than those in the GTV <120 cm 3 subgroup, but the difference was not statistically significant.
The results were different from those of patients with GTV >130 cm 3 , as reported by Yu et al. 23 Eliminating the interference factors of clinical stages, the difference in the results might be related to more target placement of gamma-knife therapy for large-volume tumors. Because of the multitarget arrangement, if the radiation therapy physiologist is not well controlled in designing the treatment plan, the dose distribution will be uneven, and the cold point will affect the curative effect.
The present study agrees with the view that the size of the focus should not be a limiting factor for SBRT. 21 The relationship between the size of GTV and optimal fractional dose, total dose, and treatment course has no definite biological theoretical basis and unified clinical research conclusion.
The whole-body gamma-knife SBRT combined with PEM curative chemoradiotherapy has a significant effect on the prognosis of senile locally advanced lung adenocarcinoma, with minor side-effects. It is a good choice for elderly patients with locally advanced lung adenocarcinoma who cannot or are unwilling to undergo surgery because of medical reasons. The time-dose-fraction model requires a large sample of clinical randomized controlled trials for further study.

CONFLICT OF INTEREST
The authors declare that they have read the article and there are no