Skip to content
How It Works
Explore
Resources Ask a Question
Who It's For
Patients
Decode results, prep for appointments, weigh options.
Caregivers & advocates
Carry the research load for someone you love.
Providers & clinicians
Resources for patients in your practice.
Log In Ask a Question
PubMed This is a summary of 23 peer-reviewed journal articles Updated
Oncology · Esophageal Cancer

Treatment Strategy: Standard of Care and the CROSS Protocol

At a Glance

Standard treatment for locally advanced esophageal cancer often begins with neoadjuvant therapies like the CROSS protocol to shrink the tumor before surgery. The main goal of surgery is an R0 resection, meaning complete removal of the cancer with clear margins.

Treatment for esophageal cancer has transitioned from a “one-size-fits-all” approach to a highly structured sequence of therapies. Depending on your stage and tumor type, your team will likely recommend a combination of radiation, chemotherapy, surgery, and immunotherapy [1][2].

The Neoadjuvant Phase: CROSS and FLOT

For many patients with locally advanced esophageal cancer—meaning the tumor has grown through the wall of the esophagus or into nearby lymph nodes—the most common treatment begins before surgery, known as neoadjuvant therapy.

There are two major regimens:

  • The CROSS Protocol: This is the gold standard for many patients. It involves receiving five weekly treatments of chemotherapy (carboplatin and paclitaxel) while simultaneously receiving daily radiation for about five weeks [3][4]. About 6 to 10 weeks after finishing radiation, you undergo surgery to remove the remaining tumor [4].
  • The FLOT Regimen: While CROSS is heavily used, a regimen called FLOT (a different combination of powerful chemotherapy drugs given before and after surgery, without radiation) is often the preferred choice for adenocarcinomas located at the lower esophagus or gastroesophageal junction (GEJ) [5].

The goal of these neoadjuvant therapies is to “downstage” or shrink the tumor before surgery, which has been shown to significantly improve long-term survival [6][7].

The Goal of Surgery: R0 Resection

When a surgeon removes the esophagus (esophagectomy), you may hear them use specific terms for the procedure, such as Ivor Lewis (approached through the abdomen and chest), McKeown (approached through the neck, chest, and abdomen), or Transhiatal (approached through the abdomen and neck). The best approach depends on your tumor’s exact location [8].

Regardless of the approach, the primary goal is an R0 resection [9].

  • R0 Resection: This means the tumor was removed entirely, and when a pathologist looks at the edges (margins) under a microscope, they find no cancer cells [9][10].
  • Why it matters: Achieving an R0 resection is one of the most important predictors of long-term success, as it means the local cancer has been completely cleared [11][12].

Adjuvant Therapy: The “Safety Net”

Even after a successful surgery, there may be a need for adjuvant therapy (treatment given after surgery) to kill any microscopic cells that might remain.

The most significant advancement in this area is the use of nivolumab (an immunotherapy) [13][14]. If your surgical pathology report shows residual disease (meaning the chemoradiation didn’t kill 100% of the tumor cells before surgery), taking nivolumab for up to a year can significantly reduce the risk of the cancer returning [13][15].

Targeted Therapies and Biomarkers

If your cancer has specific “markers,” your team may add targeted drugs to your regimen:

  • HER2-Targeted Therapy: If your tumor is HER2-positive, drugs like trastuzumab may be used, particularly in the advanced or metastatic setting [16][17].
  • Anti-Angiogenesis: Drugs like ramucirumab work by cutting off the blood supply to the tumor [16].

When Surgery is Not the Path

Not every patient requires or is a candidate for surgery.

  • Definitive Chemoradiation: This is a curative-intent approach using higher doses of radiation and chemotherapy without surgery. It is often used for patients who are not healthy enough for a major operation or for those with specific types of squamous cell carcinoma that respond very well to non-surgical treatment [18][19].
  • Salvage Surgery: If the cancer returns or persists after definitive chemoradiation, salvage esophagectomy may still be an option, though it is a more complex procedure with a higher risk of complications [20][21]. Determining the best path forward often requires a multidisciplinary team at a high-volume cancer center [22][23].

Common questions in this guide

What is the CROSS protocol for esophageal cancer?
The CROSS protocol is a standard treatment that combines five weeks of chemotherapy with daily radiation. It is used before surgery to shrink locally advanced esophageal tumors, making them easier to completely remove.
What is the difference between the CROSS and FLOT regimens?
The CROSS protocol uses both chemotherapy and radiation before surgery, while the FLOT regimen involves powerful chemotherapy given both before and after surgery, without radiation. FLOT is often preferred for tumors located where the esophagus meets the stomach.
What does an R0 resection mean?
An R0 resection means the surgeon completely removed the tumor, and a pathologist found no cancer cells at the edges of the removed tissue. Achieving an R0 resection is one of the most important predictors of long-term success.
Why might I need to take nivolumab after my surgery?
If your post-surgery pathology report shows that some cancer cells survived your initial chemotherapy and radiation, you may be prescribed an immunotherapy called nivolumab. Taking this medication after surgery can significantly reduce the risk of the cancer returning.
What are my options if I cannot have surgery for esophageal cancer?
Patients who cannot or choose not to have surgery may receive definitive chemoradiation, which uses higher, curative doses of radiation and chemotherapy. If the cancer persists or returns after this treatment, salvage surgery might still be an option.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Am I a candidate for the CROSS protocol or the FLOT regimen, and how will my body be monitored for toxicities during treatment?
  2. 2.What is the target surgical approach for me (Ivor Lewis, McKeown, etc.), and is an R0 resection achievable given the tumor's location?
  3. 3.If my post-surgery pathology shows residual cancer cells (ypT+ or ypN+), will we start adjuvant nivolumab?
  4. 4.How does my tumor’s HER2 or PD-L1 status change the standard treatment plan?
  5. 5.In my case, is there a benefit to definitive chemoradiation instead of surgery, and what are the trade-offs for my long-term quality of life?

Questions For You

Tap a prompt to share your answer — we'll use it plus this page's context to start a tailored conversation.

References

References (23)
  1. 1

    A Canadian single institution real-world experience using the CROSS trial regimen in the treatment of oesophageal and gastroesophageal junction carcinoma.

    Khalid S, Hopman WM, Virik K

    Internal medicine journal 2022; (52(9)):1587-1595 doi:10.1111/imj.15427.

    PMID: 34139041
  2. 2

    Comparison of esophageal cancer survival after neoadjuvant chemoradiotherapy plus surgery versus definitive chemoradiotherapy: A systematic review and meta-analysis.

    Ke J, Xie Y, Huang S, et al.

    Asian journal of surgery 2024; (47(9)):3827-3840 doi:10.1016/j.asjsur.2024.02.099.

    PMID: 38448293
  3. 3

    CROSS and beyond: a clinical perspective on the results of the randomized ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study.

    van der Woude SO, Hulshof MC, van Laarhoven HW

    Chinese clinical oncology 2016; (5(1)):13 doi:10.3978/j.issn.2304-3865.2016.02.04.

    PMID: 26932437
  4. 4

    Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial.

    Shapiro J, van Lanschot JJB, Hulshof MCCM, et al.

    The Lancet. Oncology 2015; (16(9)):1090-1098 doi:10.1016/S1470-2045(15)00040-6.

    PMID: 26254683
  5. 5

    Racial Disparities in Esophageal Cancer.

    Pickens A

    Thoracic surgery clinics 2022; (32(1)):57-65 doi:10.1016/j.thorsurg.2021.09.004.

    PMID: 34801196
  6. 6

    Effect of Neoadjuvant Chemoradiotherapy on Health-Related Quality of Life in Esophageal or Junctional Cancer: Results From the Randomized CROSS Trial.

    Noordman BJ, Verdam MGE, Lagarde SM, et al.

    Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2018; (36(3)):268-275 doi:10.1200/JCO.2017.73.7718.

    PMID: 29161204
  7. 7

    Long-term Efficacy of Neoadjuvant Chemoradiotherapy Plus Surgery for the Treatment of Locally Advanced Esophageal Squamous Cell Carcinoma: The NEOCRTEC5010 Randomized Clinical Trial.

    Yang H, Liu H, Chen Y, et al.

    JAMA surgery 2021; (156(8)):721-729 doi:10.1001/jamasurg.2021.2373.

    PMID: 34160577
  8. 8

    What's the Best Way to Treat GE Junction Tumors? Approach Like Gastric Cancer.

    Mullen JT, Kwak EL, Hong TS

    Annals of surgical oncology 2016; (23(12)):3780-3785 doi:10.1245/s10434-016-5426-6.

    PMID: 27459983
  9. 9

    Resectability and survival outcome in real world practice of 720 cholangiocarcinoma patients: intrahepatic, perihilar and distal cholangiocarcinoma.

    Sarkhampee P, Ouransatien W, Lertsawatvicha N, et al.

    World journal of surgical oncology 2024; (22(1)):314 doi:10.1186/s12957-024-03596-y.

    PMID: 39605039
  10. 10

    The impact of R1 resection for colorectal liver metastases on local recurrence and overall survival in the era of modern chemotherapy: An analysis of 1,428 resection areas.

    Ardito F, Panettieri E, Vellone M, et al.

    Surgery 2019; (165(4)):712-720 doi:10.1016/j.surg.2018.09.005.

    PMID: 30482518
  11. 11

    Thoracoscopic salvage esophagectomy with prophylactic mediastinal lymph node dissection after definitive chemoradiotherapy for patients with esophageal cancer.

    Abe T, Fujieda H, Higaki E, et al.

    Surgical endoscopy 2024; (38(8)):4695-4703 doi:10.1007/s00464-024-10986-6.

    PMID: 38886226
  12. 12

    Microscopic resection margins adversely influence survival rates after surgery for colorectal liver metastases: An open ambidirectional Cohort Study.

    Lee KS, Suchett-Kaye I, Abbadi R, et al.

    International journal of surgery (London, England) 2020; (83()):8-14 doi:10.1016/j.ijsu.2020.09.007.

    PMID: 32927149
  13. 13

    Adjuvant Nivolumab in Resected Esophageal or Gastroesophageal Junction Cancer.

    Kelly RJ, Ajani JA, Kuzdzal J, et al.

    The New England journal of medicine 2021; (384(13)):1191-1203 doi:10.1056/NEJMoa2032125.

    PMID: 33789008
  14. 14

    Immunotherapy for Resectable Locally Advanced Esophageal Carcinoma.

    Fick CN, Dunne EG, Sihag S, et al.

    The Annals of thoracic surgery 2024; (118(1)):130-140 doi:10.1016/j.athoracsur.2024.02.021.

    PMID: 38408631
  15. 15

    Nivolumab for the treatment of esophageal cancer.

    Mikuni H, Yamamoto S, Kato K

    Expert opinion on biological therapy 2021; (21(6)):697-703 doi:10.1080/14712598.2021.1904887.

    PMID: 33736560
  16. 16

    Targeted Molecular Therapies in the Treatment of Esophageal Adenocarcinoma, Are We There Yet?

    Khalafi S, Lockhart AC, Livingstone AS, El-Rifai W

    Cancers 2020; (12(11)) doi:10.3390/cancers12113077.

    PMID: 33105560
  17. 17

    Advances in the treatment of human epidermal growth factor receptor 2-positive gastric cancer.

    Kudo T

    International journal of clinical oncology 2024; (29(9)):1220-1227 doi:10.1007/s10147-024-02587-z.

    PMID: 39083154
  18. 18

    Definitive chemoradiotherapy.

    Stahl M, Budach W

    Journal of thoracic disease 2017; (9(Suppl 8)):S792-S798 doi:10.21037/jtd.2017.05.05.

    PMID: 28815076
  19. 19

    Can definitive chemoradiotherapy be an alternative to surgery for early-stage oesophageal cancer?

    Deng HY, Li G, Luo J, Alai G

    Interactive cardiovascular and thoracic surgery 2019; (28(1)):37-40 doi:10.1093/icvts/ivy220.

    PMID: 30007292
  20. 20

    A meta-analysis on salvage surgery as a potentially curative procedure in patients with isolated local recurrent or persistent esophageal cancer after chemoradiotherapy.

    Faiz Z, Dijksterhuis WPM, Burgerhof JGM, et al.

    European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 2019; (45(6)):931-940 doi:10.1016/j.ejso.2018.11.002.

    PMID: 30447937
  21. 21

    Outcomes of Salvage Surgery for Esophageal Carcinoma: A Nationwide Cohort Study from the Dutch Upper GI Cancer Audit.

    Visser MR, Voeten DM, Gisbertz SS, et al.

    Annals of surgical oncology 2025; (32(4)):2687-2697 doi:10.1245/s10434-024-16490-4.

    PMID: 39627639
  22. 22

    Salvage esophagectomy: safe therapeutic strategy?

    Jamel S, Markar SR

    Journal of thoracic disease 2017; (9(Suppl 8)):S799-S808 doi:10.21037/jtd.2017.05.09.

    PMID: 28815077
  23. 23

    Salvage esophagectomy for persistent or recurrent disease after definitive chemoradiation.

    Swisher SG, Marks J, Rice D

    Annals of cardiothoracic surgery 2017; (6(2)):144-151 doi:10.21037/acs.2017.03.02.

    PMID: 28447003

This page explains standard esophageal cancer treatment protocols for educational purposes. Always consult your oncology team to determine the best treatment plan for your specific diagnosis and health status.

Get notified when new evidence is published on Carcinoma of esophagus.

We monitor PubMed for new peer-reviewed studies on this topic and email a short summary when something meaningful changes.