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Evaluation of pembrolizumab plus cisplatin and fluorouracil in radical treatment for patients with T4b esophageal squamous cell carcinoma

BMC Gastroenterology volume 24, Article number: 295 (2024) Cite this article

Abstract

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.

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Background

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 [13,14,15]. 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% [16,17,18]. 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 [19,20,21]. 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
Full size table

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
Full size table

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
Full size table

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
figure 1

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

Full size image

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
figure 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

Full size image

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 [28,29,30]. 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.

Data availability

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

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

References

  1. 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. https://doi.org/10.1016/j.radonc.2021.02.031.

    Article  PubMed  Google Scholar 

  2. 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. https://doi.org/10.1200/JCO.1997.15.1.277.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.6004/jnccn.2019.0033

  4. 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. https://doi.org/10.1016/j.radonc.2021.01.007.

    Article  PubMed  Google Scholar 

  5. 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. https://doi.org/10.1200/JCO.2005.00.034.

    Article  PubMed  Google Scholar 

  6. 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. https://doi.org/10.1200/JCO.2005.04.7118.

    Article  CAS  PubMed  Google Scholar 

  7. 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. https://doi.org/10.1245/s10434-019-07654-8.

    Article  Google Scholar 

  8. 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. https://doi.org/10.1111/cas.12274.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. 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. https://doi.org/10.1007/s00280-016-3062-2.

    Article  CAS  Google Scholar 

  10. 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. https://doi.org/10.1245/s10434-014-3684-8.

    Article  PubMed  Google Scholar 

  11. 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. https://doi.org/10.1038/bjc.2016.350.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 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. https://doi.org/10.1186/s12957-018-1420-8.

    Article  PubMed  PubMed Central  Google Scholar 

  13. 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. https://doi.org/10.1056/NEJMoa2032125.

    Article  Google Scholar 

  14. 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. https://doi.org/10.1016/S1470-2045(19)30626-6.

    Article  CAS  PubMed  Google Scholar 

  15. 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. https://doi.org/10.1016/S0140-6736(17)31827-5.

    Article  CAS  PubMed  Google Scholar 

  16. 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. https://doi.org/10.1016/S0140-6736(21)01234-4.

    Article  CAS  PubMed  Google Scholar 

  17. 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. https://doi.org/10.1016/S0140-6736(21)00797-2.

    Article  Google Scholar 

  18. 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. https://doi.org/10.1056/NEJMoa2111380.

    Article  CAS  PubMed  Google Scholar 

  19. 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. https://doi.org/10.1200/JCO.1999.17.9.2915.

    Article  CAS  PubMed  Google Scholar 

  20. Halvorsen RA Jr, Thompson WM. CT of esophageal neoplasms. Radiol Clin North Am. 1989;27:667–85.

    Article  PubMed  Google Scholar 

  21. 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. https://doi.org/10.1016/s1072-7515(00)00757-2.

    Article  CAS  Google Scholar 

  22. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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, et al. Randomized phase III KEYNOTE-181 study of Pembrolizumab versus chemotherapy in advanced esophageal cancer. J Clin Oncl. 2002;38:4138–48. https://doi.org/10.1200/JCO.20.01888.

    Article  Google Scholar 

  25. 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. https://doi.org/10.1038/s41416-020-0811-0.

    Article  CAS  Google Scholar 

  26. 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. https://doi.org/10.1111/cas.15198.

    Article  CAS  PubMed  Google Scholar 

  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, 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. https://doi.org/10.1093/annonc/mdx178.

    Article  CAS  PubMed  Google Scholar 

  29. 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. https://doi.org/10.1007/s10120-018-00922-8.

    Article  CAS  PubMed  Google Scholar 

  30. 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. https://doi.org/10.1080/15384047.2020.1834319.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 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. https://doi.org/10.1158/1078-0432.CCR-16-3133.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 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. https://doi.org/10.1158/1078-0432.CCR-09-1624.

    Article  CAS  PubMed  Google Scholar 

  33. 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. https://doi.org/10.1158/1078-0432.CCR-18-3206.

    Article  CAS  Google Scholar 

  34. 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. https://doi.org/10.1016/S1470-2045(17)30074-8.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

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Acknowledgements

English language editing was performed by Forte.

Funding

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Authors and Affiliations

  1. Department of Surgery, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi, Tokyo, 173-8606, Japan

    Nobukazu Hokamura, Takeo Fukagawa, Ryoji Fukushima, Takashi Kiyokawa, Masahiro Horikawa, Naruyoshi Soeda, Yusuke Suzuki & Shinya Kaneshiro

  2. Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan

    Koichiro Abe, Shinya Kodashima & Takatsugu Yamamoto

  3. Department of Pathology, Teikyo University School of Medicine, Tokyo, Japan

    Yasutoshi Oshima, Tsuyoshi Ishida & Yuko Sasajima

  4. Department of Radiology, Teikyo University School of Medicine, Tokyo, Japan

    Akihiro Nomoto & Kenshiro Shiraishi

  5. Department of Pharmacy, Teikyo University School of Medicine, Tokyo, Japan

    Ai Ito

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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.

Corresponding author

Correspondence to Nobukazu Hokamura.

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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.

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Not applicable.

Competing interests

The authors declare no competing interests.

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Hokamura, N., Fukagawa, T., Fukushima, R. et al. Evaluation of pembrolizumab plus cisplatin and fluorouracil in radical treatment for patients with T4b esophageal squamous cell carcinoma. BMC Gastroenterol 24, 295 (2024). https://doi.org/10.1186/s12876-024-03382-w

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Keywords

BMC Gastroenterology

ISSN: 1471-230X

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