DOI: https://doi.org/10.21203/rs.3.rs-2546903/v1
To explore the efficacy and toxicity of multimodal radical radiotherapy and systematic therapy in refractory recurrent metastatic esophageal cancer.
A 57-year-old man with locally advanced esophageal squamous cell carcinoma (ESCC) presented with supraclavicular lymph nodes and bone metastases six years after radical resection and adjuvant chemotherapy. After multiline systemic therapy, the tumor progressed with involvement of lymph nodes in the left neck, supraclavicular, subclavian, and axillary regions, as well as the C6 vertebral bone. The patient exhibited Horner’s syndrome on the left side as well as brachial plexus nerve injury with serious pain. Adaptive intensity-modulate radiotherapy (IMRT) combined with high-dose brachy radiotherapy (BRT), and stereotactic radiotherapy (SBRT) was applied to control local foci, together with systemic treatment using target and immunotherapy as maintenance.
The patient showed complete remission (CR) of symptoms and signs, including the complete disappearance of the left neck metastatic lymph nodes, CR of the left upper-neck metastatic lymph nodes, and satisfactory local control of bone metastases. The progression-free survival (PFS) was more than 20 months, with CR of pulmonary metastases, satisfactory control of hepatic metastases, and PFS for lung and liver foci of over 17 months. No significant adverse events were observed, and the overall survival (OS) was more than 30 months.
Adaptive IMRT combined with high-dose brachy implantation radiotherapy and maintenance therapy can effectively improve both local control and PFS in patients with refractory recurrent metastatic esophageal cancer.
Esophageal cancer is one of the most common malignancies. Over 600 000 people worldwide are diagnosed with esophageal cancer each year, with approximately 540 000 of these resulting in death[1]. The incidence and death ratio of males to females is 2–3:1[1]. China has a high incidence of esophageal cancer with locally advanced squamous cell carcinoma being the most common. Forty percent of patients still develop metastases after surgery-based multidisciplinary treatment[2], representing an important reason for the failure of esophageal cancer treatment. The most common recommendations are systemic treatment or clinical trials. The present study reports the application of multimodal precision radiotherapy combined with Anlotinib and Camrelizumab in a patient with refractory metastatic esophageal cancer. The value of using multimodal radiotherapy in metastatic esophageal cancer is also discussed to provide a clinical reference for the treatment of refractory metastatic malignant tumors.
A 57-year-old man with moderately differentiated middle-to-lower ESCC was treated with radical partial resection of the esophagus combined with supraesophageal arch anastomosis in November 2013 (pT3N1M0), followed by four cycles of TP regimen (paclitaxel and cisplatin) chemotherapy. The patient received regular follow-up examinations. Unfortunately, he developed 4.1 x 3.2-cm metastasis of the left supraclavicular lymph node, and biopsy confirmed metastatic squamous cell carcinoma in July 2020. This was accompanied by C6 metastasis with no other abnormalities. The patient received two cycles of chemotherapy, resulting in stable disease, followed by two cycles of TP plus Durvalumab, with the disease remaining stable (4.9×3.1 cm). The treatment was modified to S-1 combined with Pembrolizumab with the foci remaining unchanged after two cycles. Antitumor therapy was discontinued for three months due to other inconveniences and the tumor progressed. The patient presented with Horner's syndrome (complete closure of the left eyelid, lack of facial sweating) and damage to the brachial plexus on the left side (severe pain, red and swollen arm, thickening, numbness, weakness, and disturbance of arm-finger shoulder motion), and a massive mass on the left clavicle, 10 cm in diameter, hard as stone with a fixed base, strongly positive for tenderness, with red, swollen, hot, and painful skin; several enlarged lymph nodes were palpable on the upper left neck. PETCT (April 2021) revealed the involvement of multiple lymph nodes in the left cervical region II-V and the supraclavicular and left superior mediastinal regions which were partially fused, and indistinguishable from the left sternocleidomastoid muscle. The largest was 6.9×5.4 cm, with SUVmax=9.5. There was also C6 osteolytic destruction (SUVmax=4.4), edema of the left chest wall and subcutaneous edema in the left arm, and enlarged left axillary lymph nodes. The treatment procedure is shown in Figure 1A.
The patient first saw a doctor in our department in May 2021.MRI and CT examinations showed nodule/lump-shaped soft tissue densities of various sizes in the left neck and mediastinum partially fused into a 7.5 × 7.2-cm mass at the maximum diameter. The contour was unclear, showing heterogeneous signal intensity with a large mass surrounding adjacent vessels, where the walls of the left upper and lower clavicle arteries appeared coarse with narrowing of the vessel lumens and invasion of adjacent muscles (Figure 2A). Multiple lymph nodes in the left axilla showed rough edges with diameters below 1 cm and faint peripheral fat spaces. There were no obvious abnormalities at other sites. The patient did not complete the MRI enhancement scan due to pain.
After multidisciplinary consultation, concurrent radiochemotherapy was performed from May to July 2021. Capecitabine 1650 mg/m2/d was given concomitantly with chemotherapy during radiotherapy. The gross tumor volumes (GTVs) of all metastases were contoured and plan target volumes (PTVs) were generated based on a set-up error of 3 mm. Adaptive radiotherapy (ART) and replan were used during IMRT, as shown in Figure 3A. The complete procedure comprised delivery of PGTVn (left neck, supraclavicular) at 40 Gy/20f +10Gy/5f+2Gy/1f+ 15.4 Gy/7f, PGTVn1 (axillary metastases) of 60 Gy/33f, PTV (axillary drainage area) at 50 Gy/25f, PGTVp (cervical 6 vertebral metastases) at 40 Gy/20f with the dose reaching 50 Gy for the scattering dose contribution of the surround target volume; the prescribed doses for the above target volumes as are provided in Figure3A and 3B.
The CT and ultrasonography image-guide three-dimensional implantation brachy-radiotherapy (BRT) with 10 Gy/1f was delivered after EBRT (Figure 3C).
Unfortunately, the cancer again progressed, with the development of liver oligometastasis (Figure 4A) and multiple lung metastases (Figure 5A) by August 2021, as shown in Figure 1B. The hepatic foci were treated with SBRT at 54 Gy/9f based on 4DCT simulated localization. The patient was then treated with the angiogenesis inhibitor (Anlotinib) plus immunotherapy with Camrelizumab, as shown in Figure 1B.
Informed consent was obtained from the patient and ethical approval from the Ethics Committee of Hainan Cancer Hospital for the treatment, imaging, and pathological information involved in this study.
Treatment efficacy for the left neck, supraclavicular, and axillary lymph node lesions, and bone metastases
The Horner’s symptoms and brachial plexus damage were significantly relieved and the left supraclavicular tumor was reduced after treatment with 40 Gy/20f of IMRT. Complete remission (CR) of the left neck lymph nodes and axillary lymph node was achieved at the end of radiotherapy, and the left supraclavicular lymph node was shrunk to a size of 5 × 5 cm without obvious enhancement after the injection of an enhancement agent (Fig. 2B). The control of the bone metastases was satisfactory, and the above-mentioned efficacy was maintained until the final follow-up (Fig. 2C).
Treatment efficacy for hepatic and pulmonary metastases.
Treatment resulted in the satisfactory control of the liver metastases which showed marked reductions to 5×5 cm with central necrosis and stability, without obvious enhancement after the injection of an enhancement agent (Fig. 4B). CR of the pulmonary nodules was achieved after two cycles of systemic therapy (Fig. 5B). These effects on both the liver and lung foci were maintained until the last follow-up (Figs. 2C, 4C, 5C).
Toxic side effects
The patients showed degree II radiation-related mucositis and grade I leukopenia during ART-IMRT. Mild fatigue was the chief complaint six months after receiving immunotherapy. No other significant toxic side effects were observed.
Survival analysis
Progression-free survival (PFS) after treatment of the neck, supraclavicular, and axillary lymph node metastases with ART-EBRT was over 20 months up to the last follow-up (January 2023). The local control of the liver and lung lesions was satisfactory, and the PFS was 17 months. The free-distant metastases survival was 17 months, and the overall survival time was 30 months.
Esophageal cancer is a disease with a specific geographical distribution, with a high incidence in Asia, Europe, and Africa[1]. Squamous cell carcinoma and adenocarcinoma are the most common pathological types[3]. Esophageal cancer accounts for about 50% of cancer patients throughout the world, with ESCC accounting for about 90% of esophageal cancer cases[3]. The pathogenic factors associated with esophageal cancer include alcohol and tobacco intake, HPV infection, preserved food, vitamin deficiency, and the consumption of high-temperature foods[1,4–7]. More than 80% of ESCC tumors are located in the middle and lower thoracic segments and are characterized by moderately and poorly differentiated squamous cell carcinoma[8]. The supraclavicular lymph node metastasis rate is about 15%, which is regarded as distant involvement, and the five-year survival rate for patients is about 24%[9]. Esophageal cancer is always locally advanced at the time of consultation due to atypical symptoms. Surgery, radiotherapy, and chemotherapy are the main treatment methods for locally advanced esophageal cancer[7]. The patient described here had middle and lower thoracic ESCC staged as T3N1M0 at the time of initial treatment using radical resection and adjuvant chemotherapy. The patient presented left supraclavicular lymph node and bone metastases after six years of follow-up. It has been found that the five-year survival rate of locally advanced esophageal cancer is about 15–40%[4], and long-term survivors subject to continuous exposure to genetic and behavioral risk factors can develop second primary cancers[10]. Analysis by the SEER database showed that the overall incidence of second primary cancer is about 2.4–17% while being as high as 30% in patients with esophageal cancer[10,11]. The case described here was potentially a metachronous second primary cancer with the diagnosis involving metastatic squamous cell carcinoma of the supraclavicular lymph nodes. The possible primary anatomical location could have been head-and-neck squamous cell carcinoma, cancer of the urinary system or skin, and even head-and-neck cancer of unknown primary origin. On the other hand, it has been confirmed that about 80% of patients with esophageal cancer develop metastasis at different times after the initial treatment[8,12]. Combined with related examinations, the present case was preferentially diagnosed as esophageal squamous cell carcinoma with metastasis of the left supraclavicular lymph node and bone. Chemotherapy or chemotherapy plus immunotherapy represent alternative options for metastatic ESCC with positive PD-L1 expression[7]. The combined use of docetaxel and cisplatin has been found to have a response rate of 25-34.2% in metastatic esophageal carcinoma after failure of PF first-line therapy[13–16]. Sintilimab is reported to be superior to chemotherapy alone for the second-line treatment of metastatic esophageal squamous cell carcinoma[17,18]. Multicenter randomized studies have demonstrated the benefit of immunotherapy in patients with squamous cell carcinoma with high PD-L1 expression[17–27], and the updated results are summarized in Table 1. Unfortunately, the patient described here did not achieve CR after chemotherapy and chemotherapy plus immunotherapy. Furthermore, the cancer progressed to refractory relapsed metastatic esophageal cancer after multiple lines of systemic therapy, while the optimum recommendation remained clinical trials or systemic treatment[3,7].
The ESWN01 study compared irinotecan plus S-1 with S-1 alone for the treatment of recurrent and metastatic esophageal cancer. It was found that while the combination chemotherapy was superior to monotherapy in terms of median OS and PFS, the overall prognosis remained poor[28]. Both the CHECKMATE648 and ATTRACTION3 studies demonstrated that Nivolumab plus chemotherapy was significantly better than chemotherapy alone in patients with recurrent and metastatic esophageal cancer, with a median OS of 10.5–15.4 months[22,25]. However, we observe that patients who received radiotherapy or resection were included in the above study. In the current study of a patient with lymph node recurrence and metastasis, treatment with chemotherapy and chemotherapy plus immunotherapy did not lead to CR, and even after adjustment of the treatment regimen, the cancer progressed, as seen in the development of Horner’s syndrome and brachial plexus injury-related symptoms and signs, seriously affecting the quality of life of the patient. The use of palliative local therapeutic interventions might be an optimal alternative treatment for symptom relief. It has been found concurrent chemoradiotherapy improved the prognosis of patients with metastatic esophageal cancer compared with radiotherapy alone[29–36]. In addition, the radiotherapy dose is a factor affecting the prognosis of patients with metastatic esophageal cancer[31]. It was confirmed that patients with metastatic esophageal cancer benefited from higher-dose (> 50.4 Gy) irradiation of primary foci[31,32,37]. In the current study, the patient was treated with ART-IMRT followed by Doppler ultrasound/CT dual-image guided three-dimensional implantation brachy radiotherapy due to the massive tumor burden and involvement of the vasculature and nerves. After aggressive multimodal radiotherapy, the control of the local tumors was satisfactory without obvious injury. Unexpectedly, the patient developed liver and lung metastases shortly afterward. It has been demonstrated that chemotherapy plus immunotherapy significantly improves the prognosis of patients with metastatic esophageal cancer[17,19,20,22,25,26,38,39]. The current patient received multi-line systemic therapy, including immunotherapy, before the concurrent radiochemotherapy, and did not achieve effective objective remission. In an analysis of the SEER database, the median OS of patients with and without liver-bone metastatic esophageal cancer was six months and nine months, respectively, and the patients were observed to benefit from local treatment[40]. In the current case, SBRT was performed on liver oligometastasis, resulting in reliable local control. The pulmonary metastases were not suitable for SIRT due to their multiplicity and small size, and alternative novel systemic therapy was considered. It has been found that the combination of the anti-angiogenic agent (Anlotinib) with immune checkpoint inhibitors had a synergistic effect and was recommended as an alternative for advanced esophageal cancer[39]. Furthermore, the first ESCORT study confirmed that Camrelizumab treatment led to 20% objective remission in patients with metastatic esophageal cancer[20]. The present patient achieved complete remission of all lung metastases after treatment with Anlotinib plus Camrelizumab, with the PFS for the liver and lung metastases maintained for 17 months and the left neck /supraclavicular metastases for 20 months. The long-term prognosis is still under follow-up. The outcome of this patient was better than any of the results in the studies described above, demonstrating the benefit of aggressive radiotherapy. Importantly, the patient showed excellent tolerance to the treatment with no adverse events. The optimal duration of maintenance therapy is unclear.
In the current study, aggressive multimodal radiotherapy resulted in an obvious improvement in both the quality of life and prognosis for a patient with metastatic disease, suggesting the value of aggressive radiotherapy combined maintenance systemic therapy as an alternative treatment for refractory recurrent metastatic esophageal cancer.
A limitation of this study was that treatment-related molecular detection was not conducted timeously, resulting in an absence of effective molecular markers for the guidance of treatment and prognosis prediction.
The aggressively optimized and personalized regimen of concurrent radiochemotherapy contributed to the improvement of local disease and quality of life in a patient with refractory relapsed and metastatic esophageal cancer. Radical radiotherapy also offers significant benefits to patients as palliative therapy. The combination of an anti-angiogenic agent (Anlotinib) and immune checkpoint inhibitors (Camrelizumab) was safe, and this regimen represents a novel alternative for patients with refractory relapsed and metastatic esophageal cancer who have previously received immunotherapy. As the current patient is still being followed up, the long-term prognosis and optimal duration of maintenance therapy remain unclear.
ESCC, esophageal squamous cell carcinoma; S, surgery; CT, chemotherapy; M, metastasis; C6, six cervical vertebras; ScLN, supraclavicular lymph node;
TP, taxol and cisplatin; Nivo, nivolumab; Perbm, pembrolizumab; PD, disease progression; AxLN, axillary lymph node; ART, adaptive radiotherapy; IMRT, intensity modulated radiation therapy;3D-BRT, three dimensional brachy radiotherapy;
4DCT, four-dimensional computed tomography; SBRT, stereotactic body radiotherapy;
CR complete remission.
Disclosure statement
The authors have no conflict of interest.
Ethnic Approval
The study had been approved by Ethnic Committee of Hainan Cancer Hospital and patients informed consent.
Consent to participate
Written informed consent was obtained from individual participants. Informed consent was obtained from the patient for publication the imaging in this study.
Funding
Not applicable.
Conflicts of interest
The authors declare no conflicts of interest.
Availability of data and material
Not applicable.
Code availability
Not applicable.
Authors' contributions
Luo draft and analyze the manuscript.
Consent for publication
All authors agree to publish.
Acknowledgments
This research was supported by grants from the Science Foundation of Hainan Cancer Hospital (grant #2022BS02).
1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021;71:209–49. doi: 10.3322/caac.21660.
2. van Hagen P, Hulshof MCCM, van Lanschot JJB, Steyerberg EW, van Berge Henegouwen MI, Wijnhoven BPL, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med 2012;366:2074–84. doi: 10.1056/NEJMoa1112088.
3. Lagergren J, Smyth E, Cunningham D, Lagergren P. Oesophageal cancer. The Lancet 2017;390:2383–96. doi: 10.1016/S0140-6736(17)31462-9.
4. Shang Q-X, Yang Y-S, Hu W-P, Yuan Y, Ji A-F, Chen L-Q. Prognostic significance and role of thoracic lymph node metastasis based on Chinese expert consensus in esophageal cancer. Ann Transl Med 2019;7:381. doi: 10.21037/atm.2019.07.63.
5. 杨欢, 孙宛怡, 王建炳, 王晓坤, 张锦雨, 范金虎, et al. 中国食管癌病因学、筛查及早期诊断研究进展. 肿瘤防治研究
YANG H , SUN WY , WANG JB,et al.Research Progress of Etiology, Screening and Early Diagnosis of Esophageal Cancer in China, Cancer Research on Prevention and Teatment. 2022;49 (3):169–75.
6. Jiang Z, Wang J, Shen Z, Zhang Z, Wang S. Characterization of Esophageal Microbiota in Patients With Esophagitis and Esophageal Squamous Cell Carcinoma. Front Cell Infect Microbiol 2021;11:774330. doi: 10.3389/fcimb.2021.774330.
7. Fernández-Montes A, Alcaide J, Alsina M, Custodio AB, Franco LF, Gallego Plazas J, et al. SEOM-GEMCAD-TTD Clinical Guideline for the diagnosis and treatment of esophageal cancer (2021). Clin Transl Oncol 2022;24:658–69. doi: 10.1007/s12094-022-02801-2.
8. Wu S-G, Zhang W-W, Sun J-Y, Li F-Y, Lin Q, He Z-Y. Patterns of Distant Metastasis Between Histological Types in Esophageal Cancer. Front Oncol 2018;8:302. doi: 10.3389/fonc.2018.00302.
9. Wang Z, Mao Y, Gao S, Li Y, Tan L, Daiko H, et al. Lymph node dissection and recurrent laryngeal nerve protection in minimally invasive esophagectomy. Ann N Y Acad Sci 2020;1481:20–9. doi: 10.1111/nyas.14427.
10. Copur MS, Manapuram S. Multiple Primary Tumors Over a Lifetime. Oncology (Williston Park) 2019;33:629384.
11. Baba Y, Yoshida N, Kinoshita K, Iwatsuki M, Yamashita Y-I, Chikamoto A, et al. Clinical and Prognostic Features of Patients With Esophageal Cancer and Multiple Primary Cancers: A Retrospective Single-institution Study. Ann Surg 2018;267:478–83. doi: 10.1097/SLA.0000000000002118.
12. Liu J, Liu Q, Wang Y, Xia Z, Zhao G. Nodal skip metastasis is associated with a relatively poor prognosis in thoracic esophageal squamous cell carcinoma. Eur J Surg Oncol 2016;42:1202–5. doi: 10.1016/j.ejso.2016.05.025.
13. Müller M, Posch F, Kiem D, Barth D, Horvath L, Stotz M, et al. Benefit of second-line therapy for advanced esophageal squamous cell carcinoma: a tri-center propensity score analysis. Ther Adv Med Oncol 2021;13:17588359211039930. doi: 10.1177/17588359211039930.
14. Shim H-J, Cho S-H, Hwang J-E, Bae W-K, Song S-Y, Cho S-B, et al. Phase II study of docetaxel and cisplatin chemotherapy in 5-fluorouracil/cisplatin pretreated esophageal cancer. Am J Clin Oncol 2010;33:624–8. doi: 10.1097/COC.0b013e3181bead92.
15. Thallinger CMR, Raderer M, Hejna M. Esophageal cancer: a critical evaluation of systemic second-line therapy. J Clin Oncol 2011;29:4709–14. doi: 10.1200/JCO.2011.36.7599.
16. Yoshioka T, Sakayori M, Kato S, Chiba N, Miyazaki S, Nemoto K, et al. Dose escalation study of docetaxel and nedaplatin in patients with relapsed or refractory squamous cell carcinoma of the esophagus pretreated using cisplatin, 5-fluorouracil, and radiation. Int J Clin Oncol 2006;11:454–60. doi: 10.1007/s10147-006-0610-5.
17. Lu Z, Wang J, Shu Y, Liu L, Kong L, Yang L, et al. Sintilimab versus placebo in combination with chemotherapy as first line treatment for locally advanced or metastatic oesophageal squamous cell carcinoma (ORIENT-15): multicentre, randomised, double blind, phase 3 trial. BMJ 2022;377:e068714. doi: 10.1136/bmj-2021-068714.
18. Xu J, Li Y, Fan Q, Shu Y, Yang L, Cui T, et al. Clinical and biomarker analyses of sintilimab versus chemotherapy as second-line therapy for advanced or metastatic esophageal squamous cell carcinoma: a randomized, open-label phase 2 study (ORIENT-2). Nat Commun 2022;13:857. doi: 10.1038/s41467-022-28408-3.
19. Janjigian YY, Bendell J, Calvo E, Kim JW, Ascierto PA, Sharma P, et al. CheckMate-032 Study: Efficacy and Safety of Nivolumab and Nivolumab Plus Ipilimumab in Patients With Metastatic Esophagogastric Cancer. J Clin Oncol 2018;36:2836–44. doi: 10.1200/JCO.2017.76.6212.
20. Effect of Camrelizumab vs Placebo Added to Chemotherapy on Survival and Progression-Free Survival in Patients With Advanced or Metastatic Esophageal Squamous Cell Carcinoma: The ESCORT-1st Randomized Clinical Trial - PubMed. (May 17, 2022). Retrieved from https://pubmed.ncbi.nlm.nih.gov/34519801/.
21. Janjigian YY, Shitara K, Moehler M, Garrido M, Salman P, Shen L, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet 2021;398:27–40. doi: 10.1016/S0140-6736(21)00797-2.
22. Doki Y, Ajani JA, Kato K, Xu J, Wyrwicz L, Motoyama S, et al. Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma. N Engl J Med 2022;386:449–62. doi: 10.1056/NEJMoa2111380.
23. Smyth EC, Lordick F. Nivolumab for previously treated squamous oesophageal carcinoma. Lancet Oncol 2019;20:1468–9. doi: 10.1016/S1470-2045(19)30621-7.
24. Nivolumab versus chemotherapy in Japanese patients with advanced esophageal squamous cell carcinoma: a subgroup analysis of a multicenter, randomized, open-label, phase 3 trial (ATTRACTION-3) - PubMed. (May 12, 2022). Retrieved from https://pubmed.ncbi.nlm.nih.gov/33170461/.
25. Kato K, Cho BC, Takahashi M, Okada M, Lin C-Y, Chin K, et al. Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 2019;20:1506–17. doi: 10.1016/S1470-2045(19)30626-6.
26. Sun J-M, Shen L, Shah MA, Enzinger P, Adenis A, Doi T, et al. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study. Lancet 2021;398:759–71. doi: 10.1016/S0140-6736(21)01234-4.
27. Wang Z-X, Cui C, Yao J, Zhang Y, Li M, Feng J, et al. Toripalimab plus chemotherapy in treatment-naïve, advanced esophageal squamous cell carcinoma (JUPITER-06): A multi-center phase 3 trial. Cancer Cell 2022;40:277-288.e3. doi: 10.1016/j.ccell.2022.02.007.
28. Huang J, Xu B, Liu Y, Huang J, Lu P, Ba Y, et al. Irinotecan plus S-1 versus S-1 in patients with previously treated recurrent or metastatic esophageal cancer (ESWN 01): a prospective randomized, multicenter, open-labeled phase 3 trial. Cancer Commun (Lond) 2019;39:16. doi: 10.1186/s40880-019-0359-7.
29. Li L-Q, Fu Q-G, Zhao W-D, Wang Y-D, Meng W-W, Su T-S. Chemoradiotherapy Versus Chemotherapy Alone for Advanced Esophageal Squamous Cell Carcinoma: The Role of Definitive Radiotherapy for Primary Tumor in the Metastatic Setting. Front Oncol 2022;12:824206. doi: 10.3389/fonc.2022.824206.
30. Li C, Wang X, Wang L, Chen J, Zhang W, Pang Q, et al. Clinical practice and outcome of radiotherapy for advanced esophageal squamous cell carcinoma between 2002 and 2018 in China: the multi-center 3JECROG Survey. Acta Oncol 2021;60:627–34. doi: 10.1080/0284186X.2021.1902564.
31. Guttmann DM, Mitra N, Bekelman J, Metz JM, Plastaras J, Feng W, et al. Improved Overall Survival with Aggressive Primary Tumor Radiotherapy for Patients with Metastatic Esophageal Cancer. J Thorac Oncol 2017;12:1131–42. doi: 10.1016/j.jtho.2017.03.026.
32. Minsky BD, Pajak TF, Ginsberg RJ, Pisansky TM, Martenson J, Komaki R, et al. INT 0123 (Radiation Therapy Oncology Group 94-05) phase III trial of combined-modality therapy for esophageal cancer: high-dose versus standard-dose radiation therapy. J Clin Oncol 2002;20:1167–74. doi: 10.1200/JCO.2002.20.5.1167.
33. Willett CG. Radiation dose escalation in combined-modality therapy for esophageal cancer. J Clin Oncol 2002;20:1151–3. doi: 10.1200/JCO.2002.20.5.1151.
34. Sakanaka K, Ishida Y, Fujii K, Ishihara Y, Nakamura M, Hiraoka M, et al. Radiation Dose-escalated Chemoradiotherapy Using Simultaneous Integrated Boost Intensity-Modulated Radiotherapy for Locally Advanced Unresectable Thoracic Oesophageal Squamous Cell Carcinoma: A Single-institution Phase I Study. Clin Oncol (R Coll Radiol) 2021;33:191–201. doi: 10.1016/j.clon.2020.07.012.
35. Bradley JD, Paulus R, Komaki R, Masters G, Blumenschein G, Schild S, et al. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol 2015;16:187–99. doi: 10.1016/S1470-2045(14)71207-0.
36. Ren XJ, Wang L, Han C, Liu LL. [The efficacy and safety of high dose versus standard dose radiotherapy in concurrent chemoradiotherapy for patients with esophageal squamous cell carcinoma]. Zhonghua Zhong Liu Za Zhi 2019;41:135–9. doi: 10.3760/cma.j.issn.0253-3766.2019.02.011.
37. Gao L-R, Wang X, Han W, Deng W, Li C, Wang X, et al. A multicenter prospective phase III clinical randomized study of simultaneous integrated boost intensity-modulated radiotherapy with or without concurrent chemotherapy in patients with esophageal cancer: 3JECROG P-02 study protocol. BMC Cancer 2020;20:901. doi: 10.1186/s12885-020-07387-y.
38. Kojima T, Shah MA, Muro K, Francois E, Adenis A, Hsu C-H, et al. Randomized Phase III KEYNOTE-181 Study of Pembrolizumab Versus Chemotherapy in Advanced Esophageal Cancer. J Clin Oncol 2020;38:4138–48. doi: 10.1200/JCO.20.01888.
39. Hong Y, Wu T, Lu P, Chang Z, Liang W, Zhang G, et al. Real-world effectiveness of anlotinib in combination with PD-1 inhibitors as second-line or later therapy for advanced or metastatic esophageal squamous cell carcinoma. JCO 2022;40:320–320. doi: 10.1200/JCO.2022.40.4_suppl.320.
40. Yang H, Wang K, Li Y, Li S, Yuan L, Ge H. Local Ablative Treatment Improves Survival in ESCC Patients With Specific Metastases, 2010-2016: A Population-Based SEER Analysis. Front Oncol 2022;12:783752. doi: 10.3389/fonc.2022.783752.