
==== Front
BMC Gastroenterol
BMC Gastroenterol
BMC Gastroenterology
1471-230X
BioMed Central London

39223478
3382
10.1186/s12876-024-03382-w
Research
Evaluation of pembrolizumab plus cisplatin and fluorouracil in radical treatment for patients with T4b esophageal squamous cell carcinoma
Hokamura Nobukazu nhokamur@gmail.com

1
Fukagawa Takeo 1
Fukushima Ryoji 1
Kiyokawa Takashi 1
Horikawa Masahiro 1
Soeda Naruyoshi 1
Suzuki Yusuke 1
Kaneshiro Shinya 1
Abe Koichiro 2
Kodashima Shinya 2
Yamamoto Takatsugu 2
Oshima Yasutoshi 3
Ishida Tsuyoshi 3
Sasajima Yuko 3
Nomoto Akihiro 4
Shiraishi Kenshiro 4
Ito Ai 5
1 https://ror.org/01gaw2478 grid.264706.1 0000 0000 9239 9995 Department of Surgery, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi, Tokyo, 173-8606 Japan
2 https://ror.org/01gaw2478 grid.264706.1 0000 0000 9239 9995 Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
3 https://ror.org/01gaw2478 grid.264706.1 0000 0000 9239 9995 Department of Pathology, Teikyo University School of Medicine, Tokyo, Japan
4 https://ror.org/01gaw2478 grid.264706.1 0000 0000 9239 9995 Department of Radiology, Teikyo University School of Medicine, Tokyo, Japan
5 https://ror.org/01gaw2478 grid.264706.1 0000 0000 9239 9995 Department of Pharmacy, Teikyo University School of Medicine, Tokyo, Japan
2 9 2024
2 9 2024
2024
24 29511 6 2023
23 8 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
Background

Pembrolizumab plus cisplatin and 5-fluorouracil administered as first-line therapy for advanced esophageal cancer patients has shown a better objective response and survival than conventional chemotherapy with less severe hematological adverse events. The safety and efficacy of this regimen were evaluated in patients with T4b esophageal squamous cell carcinoma (ESCC).

Methods

Eight consecutive patients with T4b ESCC received this regimen according to KEYNOTE-590 as induction, and they were evaluated after 1–3 courses. The programmed death-ligand 1 (PD-L1) combined positive score (CPS) was also evaluated before chemotherapy. Efficacy for the primary lesion was evaluated by our original formula for the tumor reduction rate.

Results

The numbers of patients with partial response (PR), stable disease, and progressive disease (PD) were 5, 1, and 2, respectively. The tumor reduction rate ranged from 69 to 87% in PR patients, and all PR patients had relief from T4b. Two patients underwent conversion surgery with R0 resection. PD-L1 CPS was over 90 in 2 PR patients, but under 10 in 2 other PR patients. PD-L1 CPS was under 10 in PD patients. One patient had hyperprogression, resulting in an esophago-pulmonary fistula. Greater than grade 3 adverse events were bleeding gastric ulcer in one patient (12.5%), neutropenia without G-CSF in 3 patients (37.5%), and hypopotassemia in 1 patient (12.5%). No patient had febrile neutropenia.

Conclusions

Marked tumor reduction was confirmed in 62.5% of patients with pembrolizumab plus cisplatin and 5-fluorouracil with less adverse events. This regimen could be administered as induction chemotherapy for patients with T4b ESCC.

Keywords

Pembrolizumab
Induction chemotherapy
Esophageal squamous cell carcinoma
issue-copyright-statement© BioMed Central Ltd., part of Springer Nature 2024
==== Body
pmcBackground

Advanced esophageal cancer can easily invade into adjacent organs due to the lack of serosa in the esophagus. Cancers invading into other adjacent structures such as aorta, vertebral body, or trachea are classified as T4b, according to the TNM staging system of the Union for International Cancer Control (UICC). Patients can develop fatal complications such as fistulas, followed by persistent pneumonia and bleeding. Patients with cancer invading into the airway or the aorta still account for around 10% of esophageal squamous cell carcinoma (ESCC) cases, and they are not candidates for surgery [1]. For these patients, definitive chemoradiotherapy is standard care [2, 3]. However, the primary lesion remains in more than 70% of patients, and this condition makes their prognosis challenging [4]. Some patients can have surgery for residual or recurrent disease after definitive chemoradiotherapy, but they face an increased risk of major perioperative complications [5, 6].

Recent studies have shown that combination chemotherapy using docetaxel/cisplatin/5-fluorouracil (DCF) is effective as preoperative chemotherapy for advanced esophageal cancer. Yokota et al. evaluated the efficacy and feasibility of induction DCF followed by conversion surgery for patients with T4b esophageal squamous cell carcinoma (ESCC), and they reported that nearly 40% of patients could have R0 resection, and estimated 3-year progression-free survival was 61.3% in patients with R0 resection [7]. DCF for advanced ESCC was also evaluated as induction chemotherapy, and estimated 2-year progression-free survival was 74.5% [8, 9]. However, DCF therapy can cause severe adverse events, such as grade 3 or 4 neutropenia (range 66.6–78.2%) and febrile neutropenia (FN) (range 14.5–22.9%) [10, 11]. Akiyama et al. introduced biweekly DCF as an alternative especially for elderly patients and/or patients with comorbidities, and they reported equivalent efficacy with reduced toxicities [12].

Inhibitors of immune checkpoint protein programmed death (PD-1) were initially introduced for patients with unresectable and metastatic ESCC as a second-line treatment and showed significant survival benefit compared with conservative chemotherapy [13–15]. Immune checkpoint inhibitors (ICIs) combined with chemotherapy were administered as induction therapy in recent phase III studies, and an apparent survival benefit was shown in these studies. In these studies, the objective response rate was over 40%, and grade 3 or 4 neutropenia was seen in less than 25% [16–18]. In the study of KEYNOTE-590, the highest survival benefit was observed in patients with ESCC and PD-L1 CPS over 10 [16].

For patients with T4b ESCC, control of the primary lesion is important to prevent fatal complications and improve survival. Patients’ general conditions sometimes deteriorate with advanced cancer and poor oral intake, and they do not tolerate potent chemotherapy such as DCF. In the present study, pembrolizumab, an anti-PD-1 monoclonal antibody, combined with chemotherapy was administered to patients with T4b ESCC as induction therapy to evaluate its efficacy and safety, focusing especially on control of the primary lesion. This is the first study to evaluate the efficacy and safety of an ICI plus chemotherapy as induction therapy for patients with T4b ESCC.

Materials and methods

Patients

Eight consecutive patients with T4b ESCC who received pembrolizumab plus cisplatin and 5-fluorouracil as induction therapy at the Department of Surgery at the Teikyo University School of Medicine (Tokyo, Japan), from April 2022 to September 2022 were retrospectively reviewed. The diagnostic criteria for T4b tumors were described previously [19–21]. Briefly, patients were diagnosed with tracheobronchial invasion when tumor extended into the lumen or caused airway deformities at the tracheobronchial tree. Aortic invasion was diagnosed in cases with: obliteration of the fat plane in the triangular space between the esophagus, aorta, and spine; a tumor mass shadow between the aorta and spine; or > 90° of direct contact between the tumor and aorta on CT. One patient with T4b cancer in the cervical esophagus refused to continue this treatment, so was excluded from the analysis. Three of them already had distant metastasis (one in the liver, one in the lung, and one in the pleura).

No patients were older than 80 years of age. One patient had liver cirrhosis (LC) from alcoholism and was diagnosed as having Child Pugh classification Grade B. The remaining 7 patients had adequate cardiac, hepatic, renal, and bone marrow reserve.

Treatment protocol

Pembrolizumab 200 mg and cisplatin (80 mg/m2) were administered by rapid infusion on day 1, and 5-FU (800 mg/m2) was administered by continuous intravenous infusion on days 1 through 5. The next course was given 3 weeks later if laboratory data and patient condition were acceptable.

Evaluation of clinical response

Tumor responses were assessed according to the Response Evaluation Criteria in Solid Tumor version 1.1 (RECIST version 1.1). The first patient was evaluated by endoscopy and contrast-enhanced CT 1 week after 3 courses were completed according to Keynote-590. In this case, clinical symptoms improved dramatically after 1 course. Therefore, from the next case, all patients were basically evaluated after 2 courses were completed. One patient had prolonged renal damage after the 1st course and so was evaluated only by plain CT after 1 course. The other patient had abdominal pain after the 1st course and was evaluated by contrast-enhanced CT. This patient was evaluated again after 3 courses. In the RECIST, tumor response is evaluated by calculation from the sum of one-dimensional diameters of target lesions. In general, production of two axes can represent a volume of a primary lesion better than one axis. To evaluate control of the primary lesion more precisely, the tumor reduction rate (TRR) was calculated by the following formula: tumor size (S) was calculated as the product of the maximum long axis and the maximum short axis, and TRR (%) was defined by (SPOST - SPRE) * 100/SPRE. Adverse events were graded according to the Common Terminology Criteria for Adverse Events v 4.0.

PD-L1 CPS is defined as the number of PD-L1-positive cells (tumor cells, macrophages, and lymphocytes) divided by the total number of viable tumor cells. CPS was evaluated in biopsy specimens before chemotherapy in 7 patients.

Survival

The overall survival was experimentally estimated using the Kalpan-Meier method.

Results

Patients’ characteristics

From April to October 2022, 8 consecutive patients were given this chemotherapy regimen (age range: 57–75 years). The primary lesion invaded into the aorta in 4, into the trachea in 4, into a vertebral body in 3, and into a bronchus in 1 (overlapping in some cases). Three patients had distant organ metastasis (one in the liver, one in the lung, one in the pleura). Three patients had metastasis to cervical lymph nodes (Table 1). One patient with LC had prolonged renal damage after 1 course, and it seemed difficult to continue this regimen. His plain CT showed marked tumor shrinkage suggesting the possibility of R0 resection from the bronchus, so he underwent conversion surgery after 1 course. One patient underwent percutaneous endoscopic gastrostomy before chemotherapy due to severe dysphagia.

Table 1 Patients’ characteristics

Case	Age (y)	T4b organ	N	M	
No. 1	73	Aorta / Vertebral body	1	0	
No. 2	66	Aorta / Trachea / Vertebral body	3	1 (Liver)	
No. 3	64	Bronchus	2	0	
No. 4	69	Trachea	2	1 (Lung, Cervical Lymph node)	
No. 5	75	Trachea	1	0	
No. 6	71	Trachea	3	1 (Cervical lymph node)	
No. 7	57	Aorta / Vertebral body	0	1 (Pleura)	
No. 8	69	Aorta	2	1 (Cervical lymph node)	

Evaluation of efficacy

Cases 1 and 6 were evaluated after 3 courses. The case 3 patient was evaluated after 1 course. In 5 cases (62.5%), the tumor shrank markedly, and they were evaluated as PR. In these 5 cases, the minimum TRR was 69%, and the maximum was 87%. One patient was evaluated as SD, and PD developed in 2 cases (Table 2). In all PR cases, relief from T4b was confirmed. Two of 4 cases without distant organ metastasis underwent conversion surgery with R0 resection, and one patient (Case 1) received definitive chemoradiotherapy with curative intent. Case 6 underwent CT for abdominal pain after 1 course, and it showed slight progression of the primary lesion. However, dysphagia was much improved after 2 courses, and so Case 6 had one more course (total of 3 courses) and was evaluated as PR. The primary lesion shrank dramatically on CT after 2 more courses. The SD patient underwent definitive chemoradiotherapy. One PD case (Case 4) received radiotherapy followed by chemotherapy, and another PD case (Case 6) with pleural metastasis underwent palliative treatment because an esophago-pulmonary fistula developed.

Comparison between good and poor responders

Two of 5 responders were female. All poor responders were male. The average age of good and poor responders was 68.6 and 67.0, respectively. PD-L1 CPS was over 95 in 2 of 5 good responders (Case 1 and 8). It was less than 5 in all poor responders. In all responders, the primary lesion became less than T3. Two responders underwent conversion surgery and 2 had definitive chemoradiotherapy according to their choice. T4b condition remained in all poor responders.

Table 2 Evaluation, tumor reduction rate, CPS, and treatment after pembrolizumab + CF

Case	No. of cycles	Efficacy	TRR (%)	TRR*
(%)	PD-L1 CPS	Treatment after pembrolizumab + CF	
No. 1	3	PR	-78	-59	98–100	Definitive chemoradiotherapy	
No. 2	2	PR	-87	-64	NA	Nivolumab infusion	
No. 3	1	PR	-77	-62	1	Conversion surgery	
No. 4	2	PD	-14	-1	< 1	Radiotherapy followed by chemotherapy	
No. 5	2	SD	+ 6	+ 6	3–5	Definitive chemoradiotherapy	
No. 6	3	PR	-81	-70	1–2	Continue Pembrolizumab + CF	
No. 7	2	PD	+ 22	+ 15	2–3	Palliation	
No. 8	2	PR	-69	-65	95–100	Conversion surgery	
CF, cisplatin and 5-fluorouracil; NA, not assessed

TRR*, tumor reduction rate calculated according to RECIST.

Adverse events

A grade 4 bleeding gastric ulcer with anemia developed in 1 case after 3 courses (12.5%). Grade 3 neutropenia developed in 3 cases (37.5%), and grade 3 leukopenia developed in 2 cases (25%), but they recovered without G-CSF. There were no cases of febrile neutropenia. Grade 3 hypopotassemia developed in 1 case (12.5%). As already mentioned, grade 2 prolonged renal damage developed in Case 3, and he underwent conversion surgery after 1 course (Table 3).

Table 3 Adverse events

	Grade 1, 2	Grade ≥ 3	
Leukopenia	3	(37.5%)	2	(25%)	
Neutropenia	1	(12.5%)	3	(37.5%)	
Hyponatremia	2	(25%)	0		
Hypopotassemia	2	(25%)	1	(12.5%)	
Hyperpotassemia	3	(37.5%)	0		
Anemia	5	(62.5%)	1	(12.5%)	
Renal damage	3	(37.5%)	0		
Bleeding gastric ulcer	0		1	(12.5%)	
Hypoalbuminemia	4	(50%)	0		
Anorexia	4	(50%)	0		

Survival

With a median follow-up period of 14.6 months (range 5–26 months), the median survival 8.6 months (95% CI 0–29.4). Four of 8 patients died of primary disease. Two patients died of other diseases. Residual 2 patients, one had definitive chemoradiotherapy and the other had conversion surgery, were alive without recurrence.

Fig. 1 Kaplan-Meier estimates of overall survival (n = 8)

Discussion

Several trials have already shown that induction chemotherapy followed by conversion surgery can improve survival, especially in R0 resection cases [7, 11]. Besides the long survival benefit, controlling the primary lesion in T4b ESCC is important to prevent fatal complications, such as esophageal fistula and massive bleeding, and to maintain oral intake. Although DCF is one of the strong candidates for induction chemotherapy for T4b ESCC, severe hematological adverse events make us hesitate to administer DCF to patients with T4b ESCC, because many of them are in generally poor condition from reduced oral intake and the effects of tumor progression.

ICI combined with chemotherapy has opened a new era of treatment for unresectable and metastatic ESCC, with not only better survival than conventional chemotherapy, but also good objective response [16, 17]. In our preliminary study, pembrolizumab plus cisplatin and 5-fluorouracil caused marked shrinkage of the primary lesion in 5 cases with reduced adverse events. Objective response rate was 62.5% (5 of 8 patients). The average TRR in responders within 3 cycles was 78% and a primary lesion came to resectable in all responders. This suggested this chemotherapy can provide a chance of conversion surgery and 2 responders underwent it with R0 resection. Early tumor shrinkage over 20% seemed associated with excellent outcome in colo-rectal cancer [22]. TRR in our study was over 75% in a primary lesion. Consequently, this chemotherapy seemed to have a potential to improve survival of patients with T4b ESCC. Figure 2 demonstrated a remarkable tumor reduction effect in two cases. Recent data exhibited in the ACSO 2024 showed long-term survival benefit of this chemotherapy in patients with unresectable and/or recurred ESCC. This suggests good responders can have not only the chance of curative treatment but also the possibility of long-term survival [23].

All females were a good responder and all poor responders were male. PD-L1 CPS was over 95 in 2 of 5 good responders, however, it was less than 5 in all poor responders. There was no apparent difference between good and poor responders in T, N and M categories. Although the patient number was very small, gender and PD-L1 CPS could be a predictive factor in the tumor shrinkage response.

Only 8 patients were enrolled, but none of them had febrile neutropenia or G-CSF injection. Hematological adverse events and renal damage mainly came from cisplatin and 5-fluorouracil because there was no increase in the number of eosinophil and no patient needed steroid therapy. No apparent irAE developed in our cases. Pembrolizumab plus cisplatin and 5-fluorouracil seems to be one alternative to DCF for patients with T4b ESCC.

Fig. 2 Tumor reduction effect in a primary lesion in case 1 and case 2

a) Case 1 primary lesion invading into the aorta, the lung and the vertebral body

b) Case 2 primary lesion invading into the aorta, the trachea and the vertebral body

a') Case 1 primary lesion after 3 cycles of chemotherapy

b’) Case 2 primary lesion after 2 cycles of chemotherapy

Previous studies suggested that pembrolizumab was more effective in patients with high PD-L1 CPS (> 10) [16, 24]. In the present study, 2 of 5 good responders had high PD-L1 CPS (> 90), but 2 of them had low PD-L1 CPS (< 10). There was no apparent relationship between efficacy and the PD-L1 CPS. Both these biomarkers were evaluated in biopsy specimens. Okadome et al. showed heterogeneity in biopsy specimens [25]. In some specimens, PD-L1 was expressed inside the tumor, not the surface, PD-L1 CPS of the biopsy specimen was low in this case. They also showed that chemotherapy with cisplatin and 5-fluorouracil can induce expression of PD-L1 in ESCC [26]. That means that PD-L1 could be induced during chemotherapy in patients with low biopsy specimen PD-L1 CPS, and pembrolizumab can work more effectively. Depending on these results, this regimen could be indicated for patients with T4b ESCC even if their biopsy specimen PD-L1 CPS is low. The FDA approved pembrolizumab in combination with fluoropyrimidine- and platinum-based chemotherapy, for patients with metastatic or locally advanced esophageal and gastroesophageal junction cancers who are not candidates for curative treatment, independent of their PD-L1 expression [27].

Immunotherapy is a completely new treatment pattern that is distinct from conventional chemotherapies, thus bringing quite unique clinical responses. One is hyperprogression disease (HPD), accelerated tumor growth after immunotherapy [28–30]. Although there are still no consistent definitions, Kato et al. defined HPD as a short time to term treatment failure of less than 2 months or a greater than 50% increase in tumor size [31]. According to the latest reports, HPD rates for some types of cancers have been observed to range from 7 to 29%, and HPD is associated with a poor prognosis [29, 31]. Another response is quite the opposite one, pseudoprogression. Pseudoprogression is defined as an increase in the size of the primary tumor or the appearance of a new lesion followed by tumor regression. This has led to the development of immune-related response-evaluation criteria, such as irRC [32], irRECIST [33], and iRECIST [34] to continue immunotherapy beyond this progression [35]. To distinguish HPD from pseudoprogression is crucial, especially in patients with T4b ESCC. If the patient is incorrectly evaluated, patients with pseudoprogression will miss a chance to continue effective immunotherapy, and, on the other hand, patients with HPD will miss a chance for other curative therapies including radiotherapy and face fatal complications.

The number of patients were very small, and 5 of 8 patients had distant metastasis besides T4b lesion. Therefore, it was difficult to evaluate the therapeutic effect of this therapy on their survival. Type of curative therapy combined with this induction and its timing seemed important.

Conclusion

ICI combined with chemotherapy can provide marked tumor shrinkage and relief from tumor invasion in patients with T4b ESCC, with reduced severe adverse events. To distinguish HPD from pseudoprogression is crucial in patients with T4b ESCC on immunotherapy. We plan to evaluate more T4b ESCC patients treated with this regimen and examine its value as induction therapy for T4b ESCC.

Acknowledgements

English language editing was performed by Forte.

Author contributions

NH was responsible for the conception of the work, data curation, formal analysis, supervision, validation, and visualization. TF, RF, TK, MH, NS, and YS supported data curation. SK, KA, SK, TY, and YS supported the diagnosis. YO, TI, AN, KS, AI supported treatment. NH wrote the original draft, reviewed and edited the manuscript. All authors read and approved the final manuscript.

Funding

Not applicable.

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

The current study was approved by the Ethics Committee of Teikyo University School of Medicine and performed in accordance with the guidelines approved by The Japan Esophageal Society. All patients provided their written informed consent to participate.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Abbreviations

ESCC Esophageal squamous cell carcinoma

PD-L1 Programmed death-ligand 1

CPS Combined positive score

PR Partial response

PD Progressive disease

DCF Docetaxel / cisplatin / 5-fluorouracil

FN Febrile neutropenia

PD-1 Programmed death-1

ICIs Immune checkpoint inhibitors

LC Liver cirrhosis

RECIST Response evaluation criteria in solid tumor

TRR Tumor reduction rate

CF Cisplatin / 5-fluorouracil

NA Not assessed

HPD Hyperprogression disease

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
==== Refs
References

1. Chen B Deng M Yang C High incidence of esophageal fistula on patients with T4b clinical esophageal squamous cell carcinoma who received chemoradiotherapy: a retrospective analysis Radiother Oncol 2021 158 191 99 10.1016/j.radonc.2021.02.031 33667583
Chen B, Deng M, Yang C, et al. High incidence of esophageal fistula on patients with T4b clinical esophageal squamous cell carcinoma who received chemoradiotherapy: a retrospective analysis. Radiother Oncol. 2021;158:191–99. 10.1016/j.radonc.2021.02.031.33667583 10.1016/j.radonc.2021.02.031
2. Al-Sarraf M Marts K Herkovic A Progress report of combined chemoradiotherapy versus radiotherapy alone in patients with esophageal cancer: an itergroup study J Clin Oncol 1997 15 277 84 10.1200/JCO.1997.15.1.277 8996153
Al-Sarraf M, Marts K, Herkovic A, et al. Progress report of combined chemoradiotherapy versus radiotherapy alone in patients with esophageal cancer: an itergroup study. J Clin Oncol. 1997;15:277–84. 10.1200/JCO.1997.15.1.277.8996153 10.1200/JCO.1997.15.1.277
3. Ajani JA, D’Amico TA, Bentrem DJ et al. Esophageal and esophagogastric junction cancers. Version 2. 2019, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw 2019: 855–83. 10.6004/jnccn.2019.0033
4. Huang TT Li SH Chen YH Definitive chemoradiotherapy for clinical T4b esophageal cancer – treatment outcomes, failure patterns, and prognostic factors Radiother Oncol 2021 157 56 62 10.1016/j.radonc.2021.01.007 33482233
Huang TT, Li SH, Chen YH, et al. Definitive chemoradiotherapy for clinical T4b esophageal cancer – treatment outcomes, failure patterns, and prognostic factors. Radiother Oncol. 2021;157:56–62. 10.1016/j.radonc.2021.01.007.33482233 10.1016/j.radonc.2021.01.007
5. Stahl M Stuschke M Lehmann N Chemoradiation with and without surgery in patients with locally advanced squamous cell carcinoma of the esophagus J Clin Oncol 2005 23 2310 17 10.1200/JCO.2005.00.034 15800321
Stahl M, Stuschke M, Lehmann N, et al. Chemoradiation with and without surgery in patients with locally advanced squamous cell carcinoma of the esophagus. J Clin Oncol. 2005;23:2310–17. 10.1200/JCO.2005.00.034.15800321 10.1200/JCO.2005.00.034
6. Bedenne L Michel P Bouche O Chemoradiation followed by surgery compared with chemoradiation alone in squamous cancer of the esophagus: FFCD 9102 J Clin Oncol 2007 25 1160 68 10.1200/JCO.2005.04.7118 17401004
Bedenne L, Michel P, Bouche O, et al. Chemoradiation followed by surgery compared with chemoradiation alone in squamous cancer of the esophagus: FFCD 9102. J Clin Oncol. 2007;25:1160–68. 10.1200/JCO.2005.04.7118.17401004 10.1200/JCO.2005.04.7118
7. Yokota T Kato K Hamamoto Y A 3-year overall survival update from a phase 2 study of chemoselection with DCF and subsequent conversion surgery for local advanced unresectable esophageal cancer Ann Surg Onclo 2020 27 460 67 10.1245/s10434-019-07654-8
Yokota T, Kato K, Hamamoto Y, et al. A 3-year overall survival update from a phase 2 study of chemoselection with DCF and subsequent conversion surgery for local advanced unresectable esophageal cancer. Ann Surg Onclo. 2020;27:460–67. 10.1245/s10434-019-07654-8.10.1245/s10434-019-07654-8
8. Hara H Tahara M Daiko H Phase II feasibility study of preoperative chemotherapy with docetaxel, cisplatin, and fluorouracil for esophageal squamous cell carcinoma Cancer Sci 2013 104 1455 60 10.1111/cas.12274 23991649
Hara H, Tahara M, Daiko H, et al. Phase II feasibility study of preoperative chemotherapy with docetaxel, cisplatin, and fluorouracil for esophageal squamous cell carcinoma. Cancer Sci. 2013;104:1455–60. 10.1111/cas.12274.23991649 10.1111/cas.12274
9. Satake H Tahara M Mochizuki S A prospective, multicenter phase I/II study of induction chemotherapy with docetaxel, cisplatin and fluorouracil (DCF) followed by chemotherapy in patients with unresectable locally advanced esophageal carcinoma Cancer Chemother Pharmacil 2016 78 91 9 10.1007/s00280-016-3062-2
Satake H, Tahara M, Mochizuki S, et al. A prospective, multicenter phase I/II study of induction chemotherapy with docetaxel, cisplatin and fluorouracil (DCF) followed by chemotherapy in patients with unresectable locally advanced esophageal carcinoma. Cancer Chemother Pharmacil. 2016;78:91–9. 10.1007/s00280-016-3062-2.10.1007/s00280-016-3062-2
10. Watanabe M Baba Y Yoshida N Outcomes of preoperative chemotherapy with docetaxel, cisplatin, and 5-fluorouracil followed by esophagectomy in patients with resectable node-positive esophageal cancer Ann Surg Oncol 2014 21 2838 44 10.1245/s10434-014-3684-8 24715216
Watanabe M, Baba Y, Yoshida N, et al. Outcomes of preoperative chemotherapy with docetaxel, cisplatin, and 5-fluorouracil followed by esophagectomy in patients with resectable node-positive esophageal cancer. Ann Surg Oncol. 2014;21:2838–44. 10.1245/s10434-014-3684-8.24715216 10.1245/s10434-014-3684-8
11. Yokota T Kato K Hamamoto Y Phase II studi of chemoselection with docetaxel plus cisplatin and 5-fluorouracil induction chemotherapy and subsequent conversion surgery for locally advanced unresectable oesophageal cancer Br J Cancer 2016 115 1328 34 10.1038/bjc.2016.350 27811857
Yokota T, Kato K, Hamamoto Y, et al. Phase II studi of chemoselection with docetaxel plus cisplatin and 5-fluorouracil induction chemotherapy and subsequent conversion surgery for locally advanced unresectable oesophageal cancer. Br J Cancer. 2016;115:1328–34. 10.1038/bjc.2016.350.27811857 10.1038/bjc.2016.350
12. Akiyama Y Sasaki A Endo F Outcomes of esophagectomy after chemotherapy with biweekly docetaxel cisplatin and fluorouracil for advanced esophageal cancer: a retrospective cohort analysis World J Surg Oncol 2018 16 122 29 10.1186/s12957-018-1420-8 29966526
Akiyama Y, Sasaki A, Endo F, et al. Outcomes of esophagectomy after chemotherapy with biweekly docetaxel cisplatin and fluorouracil for advanced esophageal cancer: a retrospective cohort analysis. World J Surg Oncol. 2018;16:122–29. 10.1186/s12957-018-1420-8.29966526 10.1186/s12957-018-1420-8
13. Kelly RJ Ajani JA Kuzdzal J Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer N Engl J Med 2021 354 1191 203 10.1056/NEJMoa2032125
Kelly RJ, Ajani JA, Kuzdzal J, et al. Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer. N Engl J Med. 2021;354:1191–203. 10.1056/NEJMoa2032125.10.1056/NEJMoa2032125
14. Kato K Cho BC Takahashi M Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): a multicentre, randomized, open-label, phase 3 trial Lancet Oncol 2019 20 1506 17 10.1016/S1470-2045(19)30626-6 31582355
Kato K, Cho BC, Takahashi M, et al. Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): a multicentre, randomized, open-label, phase 3 trial. Lancet Oncol. 2019;20:1506–17. 10.1016/S1470-2045(19)30626-6.31582355 10.1016/S1470-2045(19)30626-6
15. Kang YK Boku N Satoh T Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomized, double-blind, placebo-controlled, phase 3 trial Lancet 2017 390 2461 71 10.1016/S0140-6736(17)31827-5 28993052
Kang YK, Boku N, Satoh T, et al. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomized, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;390:2461–71. 10.1016/S0140-6736(17)31827-5.28993052 10.1016/S0140-6736(17)31827-5
16. Sun JM Shen L Shah MA Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomized, placebo-controlled, phase 3 study Lancet 2021 398 759 71 10.1016/S0140-6736(21)01234-4 34454674
Sun JM, Shen L, Shah MA, et al. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomized, placebo-controlled, phase 3 study. Lancet. 2021;398:759–71. 10.1016/S0140-6736(21)01234-4.34454674 10.1016/S0140-6736(21)01234-4
17. Janjigain YY Shitara K Moehler M First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oeophageal adenocarcinoma (CheckMate 649): a randomized, opne-label, phase 3 trial Lancet 2021 398 27 40 10.1016/S0140-6736(21)00797-2 34102137
Janjigain YY, Shitara K, Moehler M, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oeophageal adenocarcinoma (CheckMate 649): a randomized, opne-label, phase 3 trial. Lancet. 2021;398:27–40. 10.1016/S0140-6736(21)00797-2.34102137 10.1016/S0140-6736(21)00797-2
18. Doki Y Ajani JA Kato K Nivolumab combination therapy in advanced esophageal squamous-cell carcinoma N Engl J Med 2022 386 449 62 10.1056/NEJMoa2111380 35108470
Doki Y, Ajani JA, Kato K, et al. Nivolumab combination therapy in advanced esophageal squamous-cell carcinoma. N Engl J Med. 2022;386:449–62. 10.1056/NEJMoa2111380.35108470 10.1056/NEJMoa2111380
19. Ohtsu A Boku N Muro K Definitive chemoradiotherapy for T4 and/or M1 lymph node squamous cell carcinoma of the esophagus J Clin Oncol 1999 17 2915 21 10.1200/JCO.1999.17.9.2915 10561371
Ohtsu A, Boku N, Muro K, et al. Definitive chemoradiotherapy for T4 and/or M1 lymph node squamous cell carcinoma of the esophagus. J Clin Oncol. 1999;17:2915–21. 10.1200/JCO.1999.17.9.2915.10561371 10.1200/JCO.1999.17.9.2915
20. Halvorsen RA Jr Thompson WM CT of esophageal neoplasms Radiol Clin North Am 1989 27 667 85 10.1016/S0033-8389(22)02153-4 2657847
Halvorsen RA Jr, Thompson WM. CT of esophageal neoplasms. Radiol Clin North Am. 1989;27:667–85.2657847 10.1016/S0033-8389(22)02153-4
21. Yano M Shozaki H Tsujinaka T Squamous cell carcinoma of the eosphagus infiltrating the respiratory tract is less sensitive to preoperative concurrent radiation and chemotherapy J Am Cpll Surg 2000 191 626 34 10.1016/s1072-7515(00)00757-2
Yano M, Shozaki H, Tsujinaka T, et al. Squamous cell carcinoma of the eosphagus infiltrating the respiratory tract is less sensitive to preoperative concurrent radiation and chemotherapy. J Am Cpll Surg. 2000;191:626–34. 10.1016/s1072-7515(00)00757-2.10.1016/s1072-7515(00)00757-2
22. Giessen C Laubender RP von Weikersthal LF Early tumor shrinkage in metastatic colo-rectal cancer: retrospective analysis from an irrinotecan-based randomized first-line trial Cancer Sci 2013 104 6 718 24 10.1111/cas.12148 23480146
Giessen C, Laubender RP, von Weikersthal LF, et al. Early tumor shrinkage in metastatic colo-rectal cancer: retrospective analysis from an irrinotecan-based randomized first-line trial. Cancer Sci. 2013;104(6):718–24. /cas.12148.23480146 10.1111/cas.12148
23. Shah MA, Sun JM, Shen L et al. First-line pembrolizumab (pembro) plus chemotherapy (chemo) for advanced esophageal cancer: 5-year outcomes from the phase 3 KEYNOTE-590 study. 2024 ASCO Gastrointestinal Cancers Symposium. January 18, 2024. https://meetings.asco.org/2024-asco-gastrointestinal-cancers-symposium/15565?presentation=229133
24. Kojima T Shar MA Muro K Randomized phase III KEYNOTE-181 study of Pembrolizumab versus chemotherapy in advanced esophageal cancer J Clin Oncl 2002 38 4138 48 10.1200/JCO.20.01888
Kojima T, Shar MA, Muro K, et al. Randomized phase III KEYNOTE-181 study of Pembrolizumab versus chemotherapy in advanced esophageal cancer. J Clin Oncl. 2002;38:4138–48. 10.1200/JCO.20.01888.10.1200/JCO.20.01888
25. Okadome K Baba Y Nomoto D Prognostic and clinical impact of PD-L2 and PD-L1 expression in a chohort of 437 oesophageal cancers Br J Caner 2020 122 1535 43 10.1038/s41416-020-0811-0
Okadome K, Baba Y, Nomoto D, et al. Prognostic and clinical impact of PD-L2 and PD-L1 expression in a chohort of 437 oesophageal cancers. Br J Caner. 2020;122:1535–43. 10.1038/s41416-020-0811-0.10.1038/s41416-020-0811-0
26. Okadome K Baba Y Yasuda-Yoshihara N PD-L1 and PD-l2 expression status in relation to chemotherapy in primary and metastatic esophageal squamous cell carcinoma Cancer Sci 2022 113 399 410 10.1111/cas.15198 34773342
Okadome K, Baba Y, Yasuda-Yoshihara N, et al. PD-L1 and PD-l2 expression status in relation to chemotherapy in primary and metastatic esophageal squamous cell carcinoma. Cancer Sci. 2022;113:399–410. 10.1111/cas.15198.34773342 10.1111/cas.15198
27. U.S. Food and Drug Administration. FDA approves pembrolizumab for esophageal or GEJ carcinoma. Published March 22, 2021. Accessed January 5, 2022. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-esophageal-or-gej-carcinoma
28. Saada-Bouzid E Defaucheux C Karabajakian A Hyperprogression during anti-PD-1/PD-L1 therapy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma Ann Oncol 2017 28 1605 11 10.1093/annonc/mdx178 28419181
Saada-Bouzid E, Defaucheux C, Karabajakian A, et al. Hyperprogression during anti-PD-1/PD-L1 therapy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma. Ann Oncol. 2017;28:1605–11. 10.1093/annonc/mdx178.28419181 10.1093/annonc/mdx178
29. Sasaki A Nakamura Y Mishima S Predictive factors for hyperprogressive disease during nivolumab as anti-PD1 treatment in patients with advanced gastric cancer Gastric Cancer 2019 22 793 802 10.1007/s10120-018-00922-8 30627987
Sasaki A, Nakamura Y, Mishima S, et al. Predictive factors for hyperprogressive disease during nivolumab as anti-PD1 treatment in patients with advanced gastric cancer. Gastric Cancer. 2019;22:793–802. 10.1007/s10120-018-00922-8.30627987 10.1007/s10120-018-00922-8
30. Sun D Liu D Liu Q Nivolumab induced hyperprogressive disease in advanced esophageal squamous cell carcinoma Cancer Biol Ther 2020 21 1097 104 10.1080/15384047.2020.1834319 33151119
Sun D, Liu D, Liu Q, et al. Nivolumab induced hyperprogressive disease in advanced esophageal squamous cell carcinoma. Cancer Biol Ther. 2020;21:1097–104. 10.1080/15384047.2020.1834319.33151119 10.1080/15384047.2020.1834319
31. Kato S Goodman A Walavalkar V Hyperprogression after immunotherapy: analysis of genomic alterations associated with accelerated growth rate Clin Cancer Res 2017 23 4242 50 10.1158/1078-0432.CCR-16-3133 28351930
Kato S, Goodman A, Walavalkar V, et al. Hyperprogression after immunotherapy: analysis of genomic alterations associated with accelerated growth rate. Clin Cancer Res. 2017;23:4242–50. 10.1158/1078-0432.CCR-16-3133.28351930 10.1158/1078-0432.CCR-16-3133
32. Wolchok JD Hoos A O’Day S Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria Clin Cancer Res 2009 15 7412 20 10.1158/1078-0432.CCR-09-1624 19934295
Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009;15:7412–20. 10.1158/1078-0432.CCR-09-1624.19934295 10.1158/1078-0432.CCR-09-1624
33. Pignon JC Jegede O Shukla SA irRECIST fir the evaluation of candidate biomarkers of response to Nivolumab in metastatic clear cell renal carcinoma: analysis of a phase II prospective clinical trial Cin Cancer Res 2019 25 2174 84 10.1158/1078-0432.CCR-18-3206
Pignon JC, Jegede O, Shukla SA, et al. irRECIST fir the evaluation of candidate biomarkers of response to Nivolumab in metastatic clear cell renal carcinoma: analysis of a phase II prospective clinical trial. Cin Cancer Res. 2019;25:2174–84. 10.1158/1078-0432.CCR-18-3206.10.1158/1078-0432.CCR-18-3206
34. Seymour L Bogaerts J Perrone A iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics Lancet Oncol 2017 18 e143 52 10.1016/S1470-2045(17)30074-8 28271869
Seymour L, Bogaerts J, Perrone A, et al. iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol. 2017;18:e143–52. 10.1016/S1470-2045(17)30074-8.28271869 10.1016/S1470-2045(17)30074-8
35. Ma Y, Wang Q, Dong Q et al. How to differentiate pseudoprogression from true progression in cancer patients with immunotherapy. Am J Cancer Res. 2019;1;9(8): 1546-53. PMCID: PMC6726978.
