Neoadjuvant PD-1 blockade combined with chemotherapy or chemotherapy alone for patients with resectable locally advanced esophageal carcinoma: A real-world data analysis

doi:10.21203/rs.3.rs-2114958/v1

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Neoadjuvant PD-1 blockade combined with chemotherapy or chemotherapy alone for patients with resectable locally advanced esophageal carcinoma: A real-world data analysis

https://doi.org/10.21203/rs.3.rs-2114958/v1

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published 03 Feb, 2023

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Background

Neoadjuvant concurrent chemoradiotherapy with surgery was the standard of therapy for esophageal cancer. But many patients refused or abandoned radiotherapy because of the intolerable adverse effects in China. Neoadjuvant immunochemotherapy (nICT) followed by surgery has become an emerging treatment in patients with esophageal cancer. There was still no consensus on whether neoadjuvant immunochemotherapy was superior to neoadjuvant chemotherapy (nCT) alone in patients with esophageal cancer.

Methods

In this retrospective study, patients with resectable esophageal cancer received surgery after neoadjuvant immunochemotherapy (nICT) (n = 26, 40%) or neoadjuvant chemotherapy (nCT) alone (n = 39, 60%) were included. The patients were classified as nICT or nCT arm. The primary end points were pathological tumor response (PTR) and event-free survival (EFS). The different clinic-pathological features were compared by the Kruskal-Wallis test for continuous variables and the Chi-square (χ2) test for categorical variables. Kaplan-Meier curves were used to estimate EFS from the date of treatment to recurrence or death. All tests were 2-sided with a significative P-value defined < .05.

Results

Three (11.5%) of the 26 patients achieved pathological complete remission (pCR) in the nICT group, and four (10.3%) of the 39 patients achieved pCR in the nCT group, respectively (P = 1.0). Six (23.1%) of the 26 patients achieved major pathological response (MPR) in the nICT group, and eleven (28.2%) of the 39 patients achieved MPR in the nCT group, respectively (P = 0.645). Downstaging was achieved in 13 (44.8%) patients in the nICT group and 16 (55.2%) patients in the nCT group, respectively (P = 0.732). To verify the TRG results, we compared them with MPR and pCR, which showed a significant dependency (P < 0.001). Patients who achieved downgrading showed better MPR and pCR rates (P<0.001 and P = 0.010). There was no significant difference in EFS between nICT and nCT group (HR = 1.011, 95%CI: 0.421–2.425, P = 0.981).

Conclusions

Anti-programmed death-1 (PD-1)

esophageal cancer

neoadjuvant treatment

immunochemotherapy

Globally, cancer remains a significant health issue for humanity, with esophageal cancer being the sixth leading cause of cancer-related deaths[1]. The five-year overall survival rate of patients with esophageal cancer was between 12% and 20%, and esophageal cancer treatments faced enormous challenges[2, 3]. Patients with esophageal cancer urgently needed better treatment options to increase clinical benefits.

Neoadjuvant chemotherapy (nCT) or neoadjuvant chemoradiotherapy (nCRT) has been recommended as standard treatment in patients with locally advanced esophageal cancer[4]. Although the prognosis of patients was improved to some extent, patients still faced the risk of cancer recurrence[4]. Recently, nICT has shown acceptable safety and high efficacy in patients with locally advanced esophageal cancer[5–7]. However, there was still insufficient clinical evidence to suggest that nICT was superior to nCT in esophageal cancer patients.

Several studies have found that pathological tumor response (PTR), such as tumor regression grade (TRG) and downstaging, was a prognostic factor for patients with esophageal cancer who received neoadjuvant treatment[8–11]. This study compared the differences in pathological complete remission (pCR) rate, major pathological response (MPR) rate, tumor regression grade (TRG), downstaging, and event-free survival (EFS) between nICT and nCT groups to investigate whether neoadjuvant immunochemotherapy was superior to chemotherapy alone in patients with esophageal cancer.

2.1 Patients

This retrospective study enrolled 65 patients with stage II to III esophageal cancer who received esophagectomy after neoadjuvant immunochemotherapy or chemotherapy. All patients were diagnosed with esophageal cancer by gastroscopic biopsy before surgery.

2.2 Study design

The patients were classified as receiving nICT or nCT arm. TRG systems was designed to classify regressive changes after neoadjuvant treatment based on histopathological results to reveal prognostic information. The College of American Pathologists (CAP) grading system was used to assess tumor response. We classified the degree of degeneration of histomorphology into the following four categories: grade 0, no residual cancer cells (pCR); grade 1, single cells or small groups of cancer cells; grade 2, residual cancer with evident tumor regression but more than single cells or rare small groups of cancer cells; and grade 3, extensive residual cancer with no evident tumor regression. Pathological regression was assessed using hematoxylin and eosin (H&E) stained slides of surgical specimens. Two independent radiologists or pathologists reviewed all imaging data and pathological data. Tumors with ≤ 10% residual viable tumor cells were considered as having achieved an MPR, while those showing no viable residual tumor were defined as achieved a pCR. Patients with ≥ 50% residual viable tumor were defined as non-responders. The eighth AJCC criteria were used for esophageal cancer staging. Regular follow-up, including CT scans to monitor for recurrence of the disease.

2.3 Statistical analysis

Statistical analyses were performed using SPSS 17.0 (SPSS Inc, Chicago, IL, USA) software and presented with the GraphPad Prism software (GraphPad Software, San Diego, CA, USA). Continuous data were expressed as median with the range. Classified variables were shown as counts and percentages. The different clinic-pathological features were compared by the Kruskal-Wallis test for continuous variables and the Chi-square (χ2) test for categorical variables. Kaplan-Meier curves were used to estimate EFS from the date of treatment to recurrence or death. A two-sided P value < 0.05 was considered statistically significant.

3.1 Baseline characteristics

This study enrolled 65 patients, including 54(83.1%) males and 11(16.9%) females. The median age was 67 years (rang:44–79). According to endoscopic diagnosis, 2(3.1%) tumors occurred in the proximal esophagus, 24(36.9%) in the middle esophagus, 34(52.3%) in the distal esophagus, and 5(7.7%) in the gastroesophageal junction. By pathological biopsy, 57(87.7%) patients were diagnosed with esophageal squamous carcinoma, 5(7.7%) with esophageal adenocarcinoma, and 3(4.6%) with other pathological types. 33(50.8%) and 32(49.2%) were TNM stages II and III before treatment of esophageal carcinoma. The median cycle of treatment was 2 (range, 1–6). Fifteen patients (23.1%) received sintilimab in combination with platinum and paclitaxel chemotherapy. Seven patients (10.8%) received camrelizumab combined with platinum and paclitaxel chemotherapy. Three patients (4.6%) received tislelizumab combined with platinum and paclitaxel chemotherapy. And one patient (1.5%) received pembrolizumab combined with platinum and paclitaxel chemotherapy. Thirty-nine patients (60%) received platinum combined with paclitaxel chemotherapy. Patients’ characteristics were summarized in Table 1.

Table 1

Clinical characteristics of the 65 patients in this study.
Characteristic	Category	All Patients (n = 65)	nICT (n = 26)	nCT (n = 39)	P
Age (years)	Median (range)	67 (44–79)	67 (44–79)	67 (48–73)
sex					1.000
	Male	54 (83.1%)	22 (40.7%)	32 (59.3%)
	Female	11 (16.9%)	4 (36.4%)	7 (63.6%)
Location					0.199
	Proximal	2 (3.1%)	1 (50.0%)	1 (50.0%)
	Middle	24 (36.9%)	9 (37.5%)	15 (62.5%)
	Distal	34 (52.3%)	16 (47.1%)	18 (52.9%)
Gastroesophageal junction		5 (7.7%)	0 (0.0%)	5 (100.0%)
Histology					0.167
Squamous cell carcinoma		57 (87.7%)	25 (43.9%)	32 (56.1%)
Adenocarcinoma		5 (7.7%)	0 (0.0%)	5 (100.0%)
Others		3 (4.6%)	1 (33.3%)	2 (66.7%)
c-TNM					0.685
	II	33 (50.8%)	14(42.4%)	19(57.6%)
	III	32 (49.2%)	12 (37.5%)	20 (62.5%)
nICT, neoadjuvant immunochemotherapy; nCT, neoadjuvant chemotherapy.

3.2 Pathological tumor response (PTR)

TRG grading was performed on postoperative specimens from 65 patients, including 26 in the nICT group (grade 0, n = 3, 11.5%; grade 1, n = 3, 11.5%; grade 2, n = 8, 30.8%; grade3, n = 12, 46.2%) and 39 in the nCT group (grade 0, n = 4, 10.3%; grade 1, n = 7, 17.9%; grade 2, n = 3, 7.7%; grade3, n = 25, 64.1%) (P = 0.101). Among the 65 patients, 7 (10.2%) achieved pCR, and 17 (26.2%) achieved MPR. Three (11.5%) of the 26 patients achieved pathological complete remission (pCR) in the nICT group, and four (10.3%) of the 39 patients achieved pCR in the nCT group (P = 1.0). Six (23.1%) of the 26 patients achieved major pathological response (MPR) in the nICT group, and eleven (28.2%) of the 39 patients achieved MPR in the nCT group (P = 0.645) (Table 2).

Table 2

Pathological response in patients who underwent resection.
	Category		All Patients (n = 65)	nICT (n = 26)	nCT (n = 39)	P
ypTNM						0.746
	I		26 (40.0%)	12 (46.2%)	14 (53.8%)
	II		7 (10.8%)	3 (42.9%)	4 (57.1%)
	IIIA		8 (12.3%)	4 (50.0%)	4 (50.0%)
	IIIB		17 (26.2%)	5 (29.4%)	12 (70.6%)
	IVA		7 (10.8%)	2 (28.6%)	5 (71.4%)
TRG						0.108
	0		7 (10.8%)	3 (42.9%)	4 (57.1%)
	1		10 (15.4%)	3 (30.0%)	7 (70.0%)
	2		11 (16.9%)	8 (72.7%)	3 (27.3%)
	3		37 (56.9%)	12 (32.4%)	25 (67.6%)
Pathological response
	pCR					1.000
		YES	7 (10.8%)	3 (42.9%)	4 (57.1%)
		NO	58 (89.2%)	23 (39.7%)	35 (60.3%)
	MPR					0.645
		YES	17 (26.2%)	6 (35.3%)	11 (64.7%)
		NO	48 (73.8%)	20 (41.7%)	28 (58.3%)
TNM stage of tumor						0.732
	Down		29 (44.6%)	13 (44.8%)	16(55.2%)
	Up		18 (27.7%)	7 (38.9%)	11 (61.1%)
	Stable		18 (27.7%)	6 (33.3%)	12 (66.7%)
nICT, neoadjuvant immunochemotherapy; nCT, neoadjuvant chemotherapy; pCR, pathological complete remission; MPR, major pathological response; TRG, tumor regression grade.

TNM staging was performed again after radical resection of esophageal cancer; 40.0% of the patients were stage I, 10.8% were stage II, 12.3% were stage IIIA, 26.2% were Stage IIIB, and 10.8% were stage IVA, respectively. Downstaging was achieved in 13 (44.8%) patients in nICT group and 16 (55.2%) patients in nCT group, respectively (P = 0.732) (Table 2).

To verify the TRG results, we compared them with MPR and pCR, which showed a significant dependency (P < 0.001) (Table 3). 17 patients achieved MPR (TRG grade 0, n = 7, 41.2%; TRG grade 1, n = 10, 58.8%) (P < 0.001) and 7 patients achieved pCR (TRG grade 0, n = 7, 100%) (P < 0.001) after induction of nICT or nCT. In addition, among 17 patients who achieved MPR, 15 (88.2%) achieved tumor downgrading (P༜0.001). Among 7 patients who achieved pCR, 7 (100%) achieved downgrading (P = 0.010). This indicated that patients who achieved downstaging showed higher MPR and pCR rates (Table 3).

Table 3

Subgroup analyses of MPR and pCR
	MPR (n = 65)			pCR (n = 65)
	YES (n = 17)	NO (n = 48)	P value	YES (n = 7)	NO (n = 58)	P value
TRG (grade)			< 0.001			< 0.001
0	7 (100.0%)	0 (0.0%)		7 (100.0%)	0 (0.0%)
1	10 (100.0%)	0 (0.0%)		0 (0.0%)	10 (100.0%)
2	0 (0.0%)	11 (100.0%)		0 (0.0%)	11 (100.0%)
3	0 (0.0%)	37 (100.0%)		0 (0.0%)	37 (100.0%)
TNM stage of tumor			< 0.001			0.010
Down	15 (51.7%)	14 (48.3%)		7 (24.1%)	22 (75.9%)
UP	2 (11.1%)	16 (88.9%)		0 (0.0%)	18 (100.0%)
Stable	0 (0.0%)	18 (100.0%)		0 (0.0%)	18 (100.0%)
nICT, neoadjuvant immunochemotherapy; nCT, neoadjuvant chemotherapy; pCR, pathological complete remission; MPR, major pathological response; TRG, tumor regression grade.

3.3 Event-free survival (EFS)

The median follow-up was 15 months. Postoperative recurrence occurred in 8 patients who received nICT and 14 patients who received nCT alone. The estimated 12-month EFS was 84.6% in both nICT and nCT groups. The estimated 24-month EFS was 62.1% in the nICT group and 55.9% in the nCT group, respectively. There was no significant difference in EFS between nICT group and nCT group (HR = 1.011, 95%CI: 0.421–2.425, P = 0.981) (Fig. 1).

3.4 Treatment-related adverse events

In this study, none of the 65 patients who received nICT or nCT occurred grade 3 or higher treatment-related adverse events, and no surgery was postponed due to neoadjuvant treatment-related adverse events. Commonly observed treatment-related adverse effects included Grade 1 or 2 pruritus (n = 3, 5.0%), reactive cutaneous capillary endothelial proliferation (RCCEP) (n = 1, 2.0%), diarrhea (n = 2, 3.0%), and anemia (n = 20, 30.8%).

In this retrospective study, patients with esophageal cancer who received nICT showed higher pCR and downstaging rates compared with nCT arm; however, the differences were not statistically significant. Patients who achieved downgrading showed better MPR and pCR rates. Finally, the nICT group did not show significantly better EFS than the nCT group. This suggested that neoadjuvant immunochemotherapy was not superior to chemotherapy alone in esophageal cancer treated with neoadjuvant therapy.

Recently, immunotherapy has become a popular field for treating solid tumors, including esophageal cancer[12]. In multiple Phase II clinical studies, neoadjuvant immunochemotherapy demonstrated safety and efficacy in treating esophageal cancer[5, 7, 13]. And in Phase III clinical study by Sun et al., objective response rates (ORR) were significantly higher in the group treated with pembrolizumab combined with chemotherapy than in the group treated with chemotherapy alone (45.0% vs. 29.3%, P༜0.001)[14]. At first sight, these observations seemed to be contradictory to our results. However, there were several reasons that can explain why the EFS of the nICT group was not significantly better than the nCT group. Firstly, EFS has been influenced by postoperative adjuvant therapy. Over time, the selection of appropriate postoperative adjuvant therapy may shorten the difference in tumor recurrence or progression time between nICT and nCT groups. It was worth mentioning that further studies were needed to determine whether patients with esophageal cancer needed further adjuvant therapy after surgery. Evidence showed that esophageal cancer patients with residual lymphatic invasion after surgery needed adjuvant therapy[15]. Secondly, some patients with esophageal cancer receiving neoadjuvant therapy may not be sensitive to immunotherapy. It was essential to look for biomarkers that predicted a high response to immunotherapy in patients with esophageal cancer. Unfortunately, this study did not include relevant predictive indicators, including PD-L1. Liu et al. confirmed that esophageal squamous cell carcinoma (ESCC) patients with up-regulation of ABCC3, CBR1, and TALDO1 were not sensitive to immunotherapy[16].

In contrast, ESCC patients with enriched immune-related functional pathways (such as NK cells and B cell activity) were sensitive to immunotherapy and had a better prognosis[16]. In addition, the absence of subgroup analysis of the pathological types of esophageal cancer in this study may also be the reason why the EFS of the nICT group was not better than the nCT group. A study showed that ESCC (PD-L1 positive rate of about 44%) had a better response to immunotherapy than esophageal adenocarcinoma (PD-L1 positive rate of about 18%)[12]. This may also be related to the biological characteristics of ESCC, including the high frequency of tumor antigens[17]

The prognostic analysis of esophageal cancer patients receiving neoadjuvant therapy in this study was based on histopathology, and post-operative specimens achieved the grading of pathological reactions. Pathological reactions have been used to predict the efficacy of neoadjuvant therapy[9]. Among patients receiving neoadjuvant therapy, those who achieved pCR or MPR had a better prognosis[18, 19]. In this study, 17 patients achieved MPR and 7 pCR. These results suggested that TRG was a prognostic factor for esophageal cancer.

On the other hand, patients who achieved downgrading had higher MPR and PCR rates, suggesting that downgrading can also be used as a prognostic indicator for esophageal cancer patients receiving neoadjuvant therapy. Computed tomography (CT), positron emission tomography/computed tomography (PET-CT), and endoscopic ultrasound (EUS) cannot be adequate to accurately assess pCR in patients with esophageal cancer after neoadjuvant therapy[20]. To a certain extent, the combination of endoscopy and biopsy determined the pathological response of esophageal cancer patients receiving neoadjuvant treatment [21]. Other methods have also been found to predict the prognosis of esophageal cancer patients treated with neoadjuvant therapy. It was worth mentioning that metabolic response was superior to histopathology in assessing the prognosis of patients receiving neoadjuvant therapy[22]. A study by Buck et al. proved that using the binary classifier trained on spatial tumor metabolite data for stratification of esophageal adenocarcinoma patients receiving neoadjuvant therapy had an accuracy of 89.7% was better than 70.5% using histopathology[22]. In addition, another study demonstrated that the quantitative response evaluation criteria in solid tumors with multiparametric MRI can assess the prognosis of ESCC patients receiving neoadjuvant therapy[23].

In the future, more clinical trials are needed to confirm our conclusions. ECOG conducted a phase II/III trial to evaluate the efficacy of nivolumab and ipilimumab in perioperative patients (n = 278) with esophageal adenocarcinoma and gastroesophageal junction adenocarcinoma[3]. The primary endpoints included pCR rates and EFS, which were expected to be completed in 2023[3]. Yan et al. proposed a Phase III clinical trial to further evaluate the role of toripalimab plus chemotherapy in the neoadjuvant setting for patients with resectable ESCC[24]. In addition, improving the efficacy of immunotherapy in patients with esophageal cancer was also the direction of future research. The animal experiment showed that the expression of PD-L1 increased from 45.16–77.42% in a dose-dependent manner in a mouse model of esophageal adenocarcinoma induced by chemoradiotherapy (P = 0.001)[25]. Another study found that trastuzumab can increase tumor PD-L1 expression, and the combination of anti-PD-1 antibodies and trastuzumab can play a synergistic antitumor effect[26]. These suggested that immunotherapy combined with chemoradiotherapy or targeted therapy may bring a higher pathological response rate to patients with esophageal adenocarcinoma.

This study lacked an adequate sample size, and our findings were not statistically significant. The follow-up time was not long enough to see more considerable relapsed events between the nICT and the nCT groups. The retrospective study lacked analyses of markers that predicted the efficacy of neoadjuvant immunotherapy. This study included esophageal squamous cell carcinoma, adenocarcinoma, and other pathological types, without analysis of subgroups. Our study was based on the Chinese population, and the results may not apply to populations in other countries.

Neoadjuvant PD-1 blockade combined with chemotherapy was not superior to chemotherapy alone for resectable locally advanced esophageal carcinoma patients. More prospective clinical studies were needed to validate our conclusions.

nICT

Neoadjuvant immunochemotherapy

nCT

Neoadjuvant chemotherapy

PTR

Pathological tumor response

EFS

Event-free survival

pCR

Pathological complete remission

MPR

Major pathological response

PD-1

Programmed death-1

PTR

Pathological tumor response

TRG

Tumor regression grade

CAP

College of American Pathologists

RCCEP

Reactive cutaneous capillary endothelial proliferation

ESCC

Esophageal squamous cell carcinoma

ORR

Objective response rates

PET-CT

Positron emission tomography/computed tomography

EUS

Endoscopic ultrasound

Ethics approval and consent to participate

The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). This study was approved by the Ethics Committee of the First People’s Hospital of Changzhou. The data are anonymous, and the requirement for informed consent was therefore waived.

Consent for publication

Not applicable.

Availability of data and materials

All data generated or analyzed during this study are included in the article. The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

This study was supported by the Science and Technology Project for Youth Talent of Changzhou Health Commission (QN201703), Young Talent Development Plan of Changzhou Health Commission (CZQM2020024), Major Science and Technology Project of Changzhou Health Commission (ZD202004, ZD202007), and China Postdoctoral Science Foundation (2020M670064ZX).

Authors' contributions

DC collected and analyzed data from patients with esophageal cancer who received neoadjuvant therapy, and was a major contributor in writing the manuscript. WZ and RC reviewed and analyzed the data and participated in the writing of the manuscript. DL and CF participated in collecting the data and edited the tables. CF and MJ revised the final version of the manuscript. All authors read and approved the final manuscript.

Acknowledgments

Not applicable.

Authors' information

Departments of Oncology, the Third Affiliated Hospital of Soochow University, No.185, Jue Qian Road, Changzhou 213004, China

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No competing interests reported.

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Neoadjuvant PD-1 blockade combined with chemotherapy or chemotherapy alone for patients with resectable locally advanced esophageal carcinoma: A real-world data analysis

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Abstract

Background

Methods

Results

Conclusions

Figures

1. Background

2. Materials And Methods

2.1 Patients

2.2 Study design

2.3 Statistical analysis

3. Results

3.1 Baseline characteristics

3.2 Pathological tumor response (PTR)

3.3 Event-free survival (EFS)

3.4 Treatment-related adverse events

4. Discussion

5. Conclusion

Abbreviations

Declarations

References

Additional Declarations

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