Effect of radiotherapy target areas in the prognosis of esophageal cancer in the era of immunotherapy

doi:10.21203/rs.3.rs-5006934/v1

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Effect of radiotherapy target areas in the prognosis of esophageal cancer in the era of immunotherapy

https://doi.org/10.21203/rs.3.rs-5006934/v1

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Esophageal cancer is one of the most common malignancies. This study aimed to explore the influence of related factors such as immunotherapy, altitude level, radiotherapy target volume, and radiotherapy dose on the prognosis of patients with locally advanced and advanced esophageal cancer in the plateau region. We retrospectively collected data related to all patients with locally advanced and advanced esophageal cancer who completed definitive radiotherapy at Yunnan Cancer Hospital from January 2017 to January 2023. A total of 274 patients were included, with a median follow-up time of 54.8 months. The median OS and PFS were 15.0 months and 11.0 months, respectively. Immunotherapy significantly improved patient survival, especially for patients receiving immunotherapy after radiotherapy. Adjuvant therapy (including chemotherapy, immunotherapy, targeted therapy, P = 0.004) and GTV (P = 0.015) were independent predictors of OS, while body mass index (BMI, P = 0.037) was independent predictors of PFS. Patients with smaller target areas of PTV, CTV, GTV, GTVnd, and NEW had a better prognosis. The prognosis of recent efficacy is better than that of ineffective. Patients with disease progression within 3 months after radiotherapy have a worse prognosis. The altitude of the residence and the radiotherapy dose had no noticeable effect on the prognosis of patients with esophageal cancer. The lesion location, GTV, and simultaneous integrated boost (SIB) radiotherapy affected the occurrence of esophageal fistula.

Biological sciences/Cancer

Health sciences/Oncology

Esophageal cancer

immunotherapy

plateau

radiotherapy target volume

Esophageal cancer (EC) is one of the most common malignant tumors in China. Esophageal cancer ranks the 10th incidence in Yunnan Province, but the mortality rate ranks sixth¹. The prognosis of EC patients in Yunnan Province is worse than expected, which may be related to factors such as plateau hypoxia environment and poor living habits. The average altitude of Yunnan province is 2,000 meters, and the highest altitude is 6,740 meters, which belongs to the high altitude area. Studies have shown that the plateau hypoxia environment is associated with hypoxia-inducible factor (HIF)². Hypoxia activates the signaling pathway of HIF³, Further affecting vascular endothelial growth factor (VEGF) to stimulate angiogenesis⁴, thus improving the tumor hypoxia environment and promoting tumor growth and metastasis. Studies have found that altitude was directly proportional to the risk of cancer and death².

In Yunnan, most patients with esophageal cancer are treated when they have apparent dysphagia, and the stage at the diagnosis is locally advanced and advanced. Definitive chemoradiotherapy (dCRT) is the primary treatment, but the prognosis is still not ideal. The median survival of patients receiving dCRT was only 10.3–15.2 months^5–7, and the overall survival(OS) rate at three years was 12.4–39.3%^5,7,8. Immunotherapy is a therapeutic method to achieve anti-tumor effects by regulating the body's immune system. At present, immunotherapy has shown efficacy in the treatment of esophageal cancer^9,10. However, hypoxia affects the effectiveness of immunotherapy, and there is a correlation between hypoxia and the immunosuppressive microenvironment¹¹. Hypoxia has an effect in inhibiting CD4+ effector T cells and promoting immunosuppression of regulatory T cells¹².

Radiotherapy can change the body's immune microenvironment to enhance the anti-tumor effect of immunotherapy. The relevant mechanism may be radiation-induced tumor cell death and release of new tumor antigens, as well as upregulating the expression of PD-L1¹³. On the other hand, the application of immunotherapy could reduce the HIF-1 levels¹⁴. Therefore, immunotherapy combined with radiotherapy may bring more benefits to EC patients in the plateau area. Currently, the best combination pattern of radiotherapy and immunotherapy is not determined. It has been found that patients with smaller gross target volume (GTV) may benefit significantly from increased radiotherapy doses for local lesions (34.7 months versus 30.3 months)¹⁵. Clinical target volume (CTV) and planning target volume (PTV)¹⁶ can also affect the prognosis by affecting the completion rate of concurrent chemotherapy. The volume of radiotherapy targets has crucial predictive value for efficacy and prognosis and can provide a reference for the formulation of individualized treatment plans.

There are still a series of problems in the formulation of treatment plans for patients with esophageal cancer in plateau areas in the era of immunotherapy. For example, the impact of immunotherapy, altitude level, radiotherapy target volume, radiotherapy dose, and induction chemotherapy affects the prognosis. Our team has conducted systematic research on the above questions in order to provide more options for clinical decision-making.

The clinical data of all esophageal cancer patients who received radiotherapy at Yunnan Cancer Hospital from January 2017 to January 2023 were retrospectively analyzed. The inclusion criteria are the pathological diagnosis of esophageal malignancy, AJCC version 8 stage III-IV, and radiotherapy (total dose ≥ 50 Gy, 25–30 fractions, the single dose of 1.8-2.0 Gy). Exclusion criteria are incomplete radiotherapy, the irradiation site is non-esophageal, preoperative or postoperative radiotherapy, combined with other malignancies, incomplete medical records, and loss to follow-up. The short-term efficacy criteria were esophageal barium swallow combined with CT examination^17,18, and the effective rate = complete response + partial response/total population. NEW volume = CTV-GTV-GTVnd, representing the expanded range size of the CTV. Adjuvant therapy is chemotherapy, immunotherapy, and targeted therapy received after radiotherapy.

The X-Tile software was used to find the cut-off value of the target volume. SPSS26.0 software was used for data statistics and analysis. The Kaplan-Meier method was used to plot the survival curves of each group, and the Log-rank test was used to compare the median survival data and survival rate between the groups. Logistic regression analysis was used to analyze the influencing factors of esophageal fistula. The Cox proportional hazards regression model was used for prognostic correlation univariate and multivariate analysis, and the nomogram was drawn in the R programming language.

1. Overall population

A total of 274 patients were included in the final analysis according to the inclusion criteria and exclusion criteria(Fig. 1). The mean age was 60.7 (± 9.9) years old, the median body mass index (BMI) was 20.2 (18, 22.4), and the median altitude of the place of residence was 1750 (1420, 1891) meters. Most of the patients were male (266,97.1%) and squamous cell carcinoma (263,96%). The median length of the lesion was 5.6 (4,7.4) cm, primarily located in the middle-thoracic segment (126 patients, 46%), and only 13 patients (4.7%) in the cervical segment. All patients except one patient had an ECOG score of 0–1. There were 121 patients(44.2%) in Phase III, 95 patients(34.7%) in IVA and 58 patients(21.2%) in IVB. 263 patients(96%) received chemotherapy, 239 patients (87.2%) received induction chemotherapy, 167 patients(60.9%) received concurrent chemotherapy, and 101 patients(36.9%) received immunotherapy, and the specific baseline characteristics are shown in Table 1.

Table 1

Baseline characteristics
Feature	Number of people (%)		Feature	Number of people (%)
Age	< 60 years old	130(47.4)	Chemotherapy	yes	263(96)
Age	≥ 60 years old	144(52.6)	Chemotherapy	no	11(4)
Sex	man	266(97.1)	Synchronous chemotherapy	yes	167(60.9)
Sex	woman	8(2.9)	Synchronous chemotherapy	no	107(39.1)
Nation	the Han	241(88)	Targeted therapy	yes	15(5.5)
Nation	minority	33(12)	Targeted therapy	no	259(94.5)
SIB	yes	108(39.4)	Radiotherapy dose	high	152(55.5)
SIB	no	166(60.6)	Radiotherapy dose	standard	122(44.5)
ECOG grade	0	177(64.6)	Adjunctive therapy	yes	130(47.4)
	1	96(35)	Adjunctive therapy	no	144(52.6)
	2	1(0.4)	Clinical stages	III	121(44.2)
Pathology type	squamous cell carcinoma	263(96)		IVA	95(34.7)
Pathology type	non-squamous cell carcinoma	11(4)		IVB	58(21.2)
The length of the lesion(cm)		5.6(4, 7.4)	N position	mediastinal	216(78.8)
Location	cervical	13(4.7)		supraclavicular	100(36.5)
	upper-thoracic	55(20.1)		celiac	114(41.6)
	mid-thoracic	126(46)	M stages	0	214(78.7)
	lower-thoracic	80(29.2)		1	58(21.3)
Altitude		1750(1420, 1891)	BMI		20.2(18, 22.4)

The median follow-up for all patients was 54.8 months, and the median OS and progression free survival(PFS) were 15.0 and 11.0 months, respectively. The rates of OS and PFS at 1, 2, and 3 years were 57%, 34.3%, 27%, 46.1%, 19%, and 12.5%, respectively. Relevant factors such as clinical baseline characteristics and treatment status were included for Cox univariate and multivariate analyses. Body mass index (BMI, P = 0.018), lesion location (P = 0.036), adjuvant therapy (P < 0.001), immunotherapy (P = 0.011), and GTV (P = 0.026) were the influencing factors of OS. The above factors of P < 0.05 were included in the multivariate Cox proportional hazards model, and the results showed that adjuvant therapy (P = 0.004, HR = 1.871) and GTV (P = 0.015, HR = 1.005) were independent predictors of OS (Table 2). Univariate Cox regression analysis showed that immunotherapy (P = 0.012) and adjuvant therapy (P = 0.004) were the influencing factors for PFS (Table 3). The multivariate analysis of P < 0.1 showed that BMI (P = 0.037, HR = 0.946) was an independent predictor of PFS. Adjuvant therapy, lesion location, ECOG score, and BMI were screened out as independent variables, and a nomogram model of OS was constructed using R programming language (Fig. 2A). The ECOG score (P > 0.05) was included because the AIC criterion of R programming language used a stepwise backward method to filter the independent variables rather than the P-value to filter the independent variables. Adjuvant therapy and BMI were screened out as independent variables, and a nomogram model of PFS was constructed (Fig. 2C).

Table 2

The results of univariate and multivariate analysis affecting OS
Factor		Univariate analysis			Multivariate analysis
Factor		P	HR	HR95.0%CI	P	HR	HR95.0%CI
Age	< 60 years old	0.060	0.744	0.546–1.013
Age	≥ 60 years old	0.060	0.744	0.546–1.013
BMI		0.018	0.936	0.887–0.989	0.078	0.821	0.652–1.036
ECOG grade	0	0.116	1.300	0.937–1.804
	1
	2
The length of the lesion(cm)		0.548	1.019	0.957–1.086
Location	cervical	0.036	0.826	0.690–0.988	0.096	0.821	0.652–1.036
	upper-thoracic
	mid-thoracic
	lower-thoracic
Adjunctive therapy	yes	< 0.001	2.028	1.480–2.779	0.004	1.871	1.222–2.866
Adjunctive therapy	no	< 0.001	2.028	1.480–2.779	0.004	1.871	1.222–2.866
Clinical stages	III	0.844	0.980	0.801–1.199
	IVA
	IVB
M stages	0	0.808	0.953	0.644–1.409
M stages	1	0.808	0.953	0.644–1.409
N position	mediastinal	0.459	1.151	0.794–1.668
	supraclavicular	0.191	0.810	0.591–1.110
	celiac	0.946	0.989	0.724–1.352
Synchronous chemotherapy	yes	0.553	0.910	0.667–1.242
Synchronous chemotherapy	no	0.553	0.910	0.667–1.242
Immunotherapy	yes	0.011	1.567	1.107–2.217	0.965	1.010	0.643–1.586
Immunotherapy	no	0.011	1.567	1.107–2.217	0.965	1.010	0.643–1.586
Radiotherapy dose	high	0.666	1.074	0.777–1.483
Radiotherapy dose	standard	0.666	1.074	0.777–1.483
PTV (cm³)		0.141	1.001	1.000-1.001
CTV (cm³)		0.105	1.001	1.000-1.002
GTV (cm³)		0.026	1.004	1.001–1.008	0.015	1.005	1.001–1.010
GTVnd (cm³)		0.148	1.006	0.998–1.013
NEW (cm³)		0.204	1.001	1.000-1.002

Table 3

The results of univariate and multivariate analyses affecting PFS
Factor		Univariate analysis			Multivariate analysis
Factor		P	HR	HR95.0%CI	P	HR	HR95.0%CI
Age	< 60 years old	0.130	0.794	0.590–1.070
Age	≥ 60 years old	0.130	0.794	0.590–1.070
BMI		0.051	0.950	0.902-1.000	0.037	0.946	0.898–0.997
ECOG grade	0	0.199	1.230	0.897–1.686
	1
	2
The length of the lesion(cm)		0.868	0.995	0.937–1.057
Location	cervical	0.087	0.861	0.725–1.022	0.233	0.900	0.756–1.070
	upper-thoracic
	mid-thoracic
	lower-thoracic
Adjunctive therapy	yes	0.004	1.555	1.150–2.103	0.058	1.385	0.989–1.941
Adjunctive therapy	no	0.004	1.555	1.150–2.103	0.058	1.385	0.989–1.941
Clinical stages	III	0.477	0.931	0.763–1.135
	IVA
	IVB
M stages	0	0.926	0.982	0.676–1.427
M stages	1	0.926	0.982	0.676–1.427
N position	mediastinal	0.795	1.049	0.729–1.509
	supraclavicular	0.217	0.825	0.607–1.120
	celiac	0.692	0.941	0.695–1.273
Synchronous chemotherapy	yes	0.327	0.861	0.638–1.162
Synchronous chemotherapy	no	0.327	0.861	0.638–1.162
Immunotherapy	yes	0.012	1.520	1.094–2.111	0.189	1.280	0.885–1.851
Immunotherapy	no	0.012	1.520	1.094–2.111	0.189	1.280	0.885–1.851
Radiotherapy dose	high	0.934	0.987	0.725–1.344
Radiotherapy dose	standard	0.934	0.987	0.725–1.344
PTV (cm³)		0.617	1.000	0.999–1.001
CTV (cm³)		0.528	1.000	0.999–1.001
GTV (cm³)		0.643	1.001	0.997–1.005
GTVnd (cm³)		0.184	1.005	0.998–1.012
NEW (cm³)		0.670	1.000	0.999–1.002

2. Immunotherapy

According to whether the patients received immunotherapy, they were divided into an immunotherapy group (101 people, 36.9%) and a non-immunotherapy group (173 people, 63.1%). The proportions of concurrent chemotherapy (P = 0.015), targeted therapy (P = 0.014), adjuvant treatment (P < 0.001), standard radiotherapy dose (P = 0.002), and metastasis (P = 0.010) in the immunotherapy group were higher than those in the non-immunotherapy group. There was no statistically significant difference in other baseline characteristics. The median OS and PFS between the two groups were 22.0 months, 12.0 months, 14.0 months, and 10.0 months, respectively, and the difference was statistically significant (P = 0.010, and P = 0.010).

The immunotherapy group was divided into a pre-radiotherapy group (N = 47, 46.5%) and a post-radiotherapy group (N = 54, 53.5%) according to the time of immunotherapy. The post-radiotherapy group includes people who use immunotherapy during and after radiotherapy. There was no significant difference in baseline characteristics between the two groups. The OS (25.7 months versus 14.0 months, P = 0.039) and PFS (16.0 months versus 11.0 months, P = 0.079) in the post-radiotherapy group were better than those in the pre-radiotherapy group. The 1-year OS and PFS were 79.5%, 64.7%, 69.1%, and 44.9%, respectively, and the survival curves are shown in Fig. 3.

Univariate analysis showed that age (P = 0.024, HR = 2.058) and the order of immunotherapy and radiotherapy (P = 0.044, HR = 0.509) were the influencing factors of OS, and age (P = 0.021, HR = 2.025) was the influencing factors of PFS. Multivariate analysis showed that age (P = 0.004, HR = 0.328) and the order of immunotherapy and radiotherapy (P = 0.007, HR = 0.308) were independent predictors of OS in patients receiving immunotherapy. Age (P = 0.032, HR = 0.487), GTV (P = 0.028, HR = 2.062), and the order of immunotherapy and radiotherapy (P = 0.017, HR = 0.428) were independent predictors of PFS in patients receiving immunotherapy.

3. Volume of radiotherapy target

Due to different physician delineation habits and missing partial data, the collected volume of PTV, CTV, GTV, GTV-nd and NEW were 228, 192, 214, 149, and 191, respectively. The volume of the PTV is 334.24 (230.76,485.46) cm³, the CTV is 187.25 (114.21,286.16) cm³, the GTV is 36.95 (22.80,64.32) cm³, the GTV-nd is 10.98 (4.26,25.86) cm³, and the NEW volume is 137.13 (72.18,212.12) cm³。

Using X-Tile software, the cut-off values of PTV, CTV, GTV, GTVnd, and NEW were 300 cm³, 178 cm³, 35 cm³, 10 cm³ and 117 cm³, respectively. The analysis showed that patients with PTV < 300 cm³, CTV < 178 cm³, GTV < 35 cm³, GTVnd < 10 cm³, and NEW < 117 cm³ had a longer median survival time. The smaller the target volume, the better the patient prognosis (Table 4).

Table 4

Survival of the differentiated groups with different radiotherapy targets volume.
Variable		Median OS(month)	P
PTV	< 300cm³	20	0.514
PTV	≥ 300cm³	14.5	0.514
CTV	< 178 cm³	19	0.234
CTV	≥ 178 cm³	14	0.234
GTV	< 35cm³	24	0.002
GTV	≥ 35cm³	14	0.002
GTVnd	< 10cm³	17	0.176
GTVnd	≥ 10cm³	14	0.176
NEW	< 117cm³	20	0.272
NEW	≥ 117cm³	14	0.272

4. Radiotherapy dose and altitude

The patients were divided into a high-dose group (> 54 Gy, 152 patients) and a standard-dose group (≤ 54 Gy, 122 patients) with 54 Gy as the cut-off. There was no significant difference in OS (14.0 months versus 15.0 months, P = 0.662) and PFS (10.4 months versus 11.4 months, P = 0.932) between the two groups(Fig. 4A-B). To rule out the effect of immunotherapy on outcomes, we performed subgroup analyses of people who received and did not receive immunotherapy. It was found that there was no statistically significant difference in OS (P = 0.899, P = 0.186) and PFS (P = 0.760, P = 0.160) between the two groups. The altitude of the patient's residence was 1750 (1420, 1891) meters, and the patients were divided into a high altitude group (> 1500 meters, 195 patients, 71.2%) and a low altitude group (≤ 1500 meters, 79 patients, 28.8%). The two groups had no statistically significant difference in OS and PFS ( Supplemental Table 1).

5. Induction chemotherapy

Induction chemotherapy was defined as chemotherapy received before radiotherapy, and 239 patients received induction chemotherapy. According to whether or not they received concurrent chemotherapy after induction chemotherapy, 147 patients (61.5%) were divided into the concurrent chemoradiotherapy group and 92 patients (38.5%) in radiotherapy group. Median OS and PFS were 15 and 11 months in the total induction chemotherapy population. There was no statistically significant difference between the concurrent chemoradiotherapy and mono-radiotherapy groups in median OS (15.0 months versus 14.0 months, P = 0.773) and PFS (12.0 months versus 11.0 months, P = 0.656). Multivariate findings showed that age (P = 0.028), adjuvant therapy (P = 0.020), and short-term efficacy (P = 0.043) were independent predictors of OS. Adjuvant therapy (P = 0.023) and short-term efficacy (P = 0.018) were independent predictors of PFS. Esophageal fistula occurred in 22 patients (9.2%) of the induction chemotherapy population, and the higher the PTV (7.8% versus 6.8%, P = 0.016), CTV (7.5%% versus 5%, P = 0.021), GTV (9.5%% versus 3.4%, P = 0.240), and NEW (7.1%% versus 5.4%, P = 0.144), the higher the incidence of esophageal fistula.

6. Esophageal fistula

In the total population, 24 patients (8.8%) developed esophageal fistula, and the median survival of patients with esophageal fistula was shorter than that of patients without fistula (8.4 months versus 15.0 months, P = 0.003). Logistic regression equations were constructed by including related factors. The results showed that the effects of lesion location (OR = 0.382, 95.0%CI 0.171–0.854, P = 0.019), GTV (OR = 1.016, 95.0%CI 1.003–1.030, P = 0.014) and SIB (OR = 17.309, 95.0%CI 1.725-175.653, P = 0.015) on esophageal fistula were statistically significant. The lower the location of the lesion, the lower the risk of esophageal fistula. For every 1 cm³ increase in GTV, the risk of esophageal fistula increases by 0.01 times. The risk of esophageal fistula in SIB patients was increased by 16.309 times ( Supplemental Table 2). The GTV, lesion location, and SIB were screened out as independent variables, and a nomogram model of esophageal fistula was constructed (Fig. 4E-F).

7. Short-term efficacy and progression

A combination of CT and barium meal was used to evaluate the short-term outcomes of 91 patients. There was 1 patient with complete remission, 53 patients with partial remission, and 37 patients with no remission or disease progression, with an effective rate of 59.3%. Those who responded to short-term efficacy had better OS and PFS than those who did not (median OS 22.0 months versus 11.0 months, P = 0.004; median PFS 14.5 months versus 8.4 months, P = 0.001). According to the location, the patients were divided into a local progression group (41 patients, 59.4%) and a distant metastasis group (28 patients, 40.6%), and local recurrence included recurrence of primary esophageal lesions and regional lymph nodes. There was no statistically significant difference in median OS (16.0 months versus 12.7 months, P = 0.567) and PFS (13.0 months versus 11.4 months, P = 0.298) between the local recurrence group and the distant metastasis group(Fig. 4C). The prognosis of patients with disease progression within three months of radiotherapy was much lower than that of patients with disease progression after three months of radiotherapy (median OS 11.0 months versus 16.0 months, P = 0.005), and the time to disease progression was an influencing factor for prognosis(Fig. 4D).

Immunotherapy is a prognostic factor in patients with esophageal cancer¹⁹. In the phase Ib study of radiotherapy (60 Gy) combined with PD-1 antibody camrelizumab, the objective response rate was as high as 74%²⁰. Patients treated with radiotherapy and immunotherapy achieve a better prognosis than those treated with concurrent chemoradiotherapy²¹. Treatment combined with anti-PD-1 antibody therapy promoted the migration of dendritic cells (DCs) and macrophages closer to tumor cells²², which could be a potential mechanism for enhancing the anti-tumor immune response. In terms of survival, the results of this study were consistent with the above studies, and the median OS (22 months versus 12 months, P = 0.010) and PFS (14 months versus 10 months, P = 0.010) were better in patients who received immunotherapy than those who did not receive immunotherapy.

The order of radiotherapy and immunotherapy affects the prognosis. A study²³ found that the patients treated with sintilimab within three months after radiotherapy had good median OS and PFS, and three months may be an important time cutoff. In our study, OS (25.7 months versus 14.0 months, P = 0.039) and PFS (16.0 months versus 11.0 months, P = 0.079) in the post-radiotherapy immunotherapy group were superior to those in the pre-radiotherapy group, which is consistent with the above study. Radiotherapy may improve the body's immune microenvironment and thus enhance the anti-tumor effect of immunotherapy, and it is recommended to receive immunotherapy after radiotherapy.

The size of the irradiation range affects the efficacy.It can be measured by the volume of the target area of the radiotherapy. Irradiation of regional lymph nodes is controversial over elective nodal irradiation (ENI) or involved-field irradiation (IFI). IFI means that irradiation range are smaller than ENI. There was no significant difference in median PFS (20.3 months versus 21.4 months) and OS (32.5 months versus 34.9 months) between the ENI and IFI groups²⁴. Expanded exposure may also increase the occurrence of related adverse events, which may affect survival. Higher PTV has been found to increase the incidence of grade 4 lymphopenia²⁵, which is associated with a worse prognosis. PTV > 521.2 cm³ is an independent risk factor for lymphopenia²⁶. The current trend for regional lymph node irradiation is to irradiate the involved field.

In our study, the smaller the target volume, the better the prognosis. This is consistent with the above studies, especially in the immunotherapy population, where the smaller the NEW volume, the longer the median survival is (33.0 months versus 14.0 months, P = 0.134, HR = 1.680). The survival prognosis of the post-radiotherapy group was significantly better than that of the pre-radiotherapy group (P = 0.039). It may be related to the fact that the proportion of NEW volume < 117cm³ in the post-radiotherapy group was greater than that in the pre-radiotherapy group (53.2% versus 21.6%, P = 0.004), suggesting that narrowing the range of CTV may reduce the damage of radiotherapy to the body's immune system and improve the prognosis of patients.

In this study, the higher the incidence of esophageal fistula, the larger the PTV (P = 0.016) and CTV (P = 0.021) in the patients receiving induction chemotherapy. The effect of radiotherapy target size on prognosis is not absolute. It is necessary to fully consider the dose of radiotherapy, the impact of radiation range on the body's immune environment, and the intensity of the overall treatment regimen. Whether low-dose and large-scale irradiation can improve the body's immune microenvironment and thus improve the efficacy of immunotherapy still needs to be confirmed by many clinical experiments.

The dose of radiotherapy also affects the prognosis, and the current internationally recommended standard dose is 50-50.4 Gy. Both the INT0123 study²⁷ and the ARTDECO study²⁸ found that high-dose radiotherapy did not improve local control and survival, and recommended 50.4 Gy as the standard radiation dose. Our study concluded similarly to the above research that increasing the radiotherapy dose did not significantly improve patient survival. However, a study²⁹ found that patients who received simultaneous integrated boost radiotherapy (SIB-RT, GTV 66 Gy) had better local tumor control and survival than those who received standard-dose radiotherapy. In this study, 108 patients received SIB-RT, and the median survival was longer than that of patients who did not receive SIB-RT(16.0 months versus 14.5 months, P = 0.547). The difference between the two groups was insignificant, which may be related to the fact that the SIB-RT was not high enough, with only 28 patients (25.9%) receiving a dose ≥ 66 Gy. In a phase 1b study³⁰ in which camrelizumab and chemoradiotherapy (60 Gy) were used simultaneously, 65% of patients experienced an objective response after 40 Gy irradiation. When combined with immunotherapy and chemotherapy, a series of questions, such as the optimal dose of radiotherapy and how to formulate the dose of individualized radiotherapy, still plague us.

The hypoxic environment reduced oxidative damage to DNA, and the median tumor-free survival of the mice studied was increased by approximately 50%³¹. Plateau hypoxic environment will also activate HIF to stimulate angiogenesis and improve the tumor hypoxic environment. On the other hand, hypoxia / HIF-1 α / A2 adenosine can mediate immunosuppression³², and hyperoxic therapy can improve the tumor's immune microenvironment. Hypoxic environment and HIF are also factors that influence treatment resistance³³. There was no statistical difference in outcomes of patients with different altitudes of residence in this study, and the altitude of residence did not affect recent efficacy. However, from the perspective of long-term survival, the 3-year OS rate of patients living in high altitudes is lower than that in low altitudes, and the long-term survival curve of the two is significantly separated. This may be because the survival of EC patients is short, and the effect of residence altitude on survival may not be shown. On the other hand, among the 91 patients with recent efficacy data collected in this study, only one patient achieved complete response (1.1%), much lower than previous studies(12.9% -24%)^7,34. The evaluation criteria used are relatively strict and cannot exclude the effects of the hypoxic environment of the plateau. The hypoxic environment here refers to the altitude of the hospital during the treatment rather than the altitude of the residence, which needs more experiments to confirm.

A phase II clinical trial³⁵ compared definitive chemoradiotherapy (CRT) treatment effects after induction chemotherapy with CRT alone. The ORR was similar between the two groups (74.5% versus 61.8%, P = 0.152), and further analysis showed that the survival rate of patients who responded to induction chemotherapy was improved. In this study, induction chemotherapy did not improve survival (median OS 15 months versus 16 months, P = 0.890), consistent with the above research. Induction therapy before radiotherapy can be combined with immunotherapy, and the objective response rate of Pembrolizumab combined with chemotherapy is as high as 87.2% after induction therapy³⁶. In another ongoing multicenter, prospective clinical study³⁷, patients with immunotherapy combined with chemotherapy were treated with induction therapy, patients significantly respond after treatment were treated with definitive chemoradiotherapy, and patients who did not respond significantly were treated with surgery.

Until the optimal combination of radiotherapy, chemotherapy, and immunotherapy has been determined, induction therapy is a good option. If the induction therapy is effective, the original treatment regimen can be continued, and the chance of other treatments, such as surgery, is also increased. Patients who are insensitive to induction therapy may need to increase the intensity of the original regimen, prolong the duration of treatment, or change to another treatment.

Immunotherapy can significantly improve survival, especially in patients who receive immunotherapy after radiotherapy. Adjuvant therapy and GTV were independent predictors of OS. Patients with smaller radiotherapy target volume have a better prognosis. Altitude of residence and dose of radiotherapy had no significant effect on prognosis. In the era of immunotherapy, many clinical trials are still needed to explore individualized treatment plans for patients based on relevant influencing factors such as radiotherapy target volume, radiotherapy doses, immunotherapy, plateau hypoxic environment, and chemotherapy.

Acknowledgements

We thank colleagues from the Yunnan Cancer Hospital for their valuable suggestions and discussions. This manuscript is original, has not been published or presented elsewhere in part or entirety, and is not under consideration by another journal.

Author contributions

L.W., Y.X. and J.Z. contributed to the conception and design of the study; H.B. and D.Z. collected data; F.H., J.Z. and F.L. analysis and interpretation of the data; J.Z. and L.W. wrote sections of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.

Funding

Young talents of Yunnan Xingdian Talents Support Program (XDYC-QNRC-2023-0189).

Competing interests statement

The authors declare no competing interests.

Data availability statement

The data are available from the corresponding author on reasonable request.

Ethics declarations

This study was approved by the Ethics Committee of Yunnan Cancer Hospital (approval number: KYLX2024-029). All methods were carried out in accordance with relevant guidelines and regulations. Informed consent was obtained from all subjects and/or their legal guardian(s).

Consent to publish

Consent for publication was obtained from all authors and participants in this article.

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No competing interests reported.

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Effect of radiotherapy target areas in the prognosis of esophageal cancer in the era of immunotherapy

Status:

Version 1

Abstract

Figures

Introduction

Materials and methods

Results

1. Overall population

2. Immunotherapy

3. Volume of radiotherapy target

4. Radiotherapy dose and altitude

5. Induction chemotherapy

6. Esophageal fistula

7. Short-term efficacy and progression

Discussion

Conclusion

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1