RAMIE vs OTE for Esophageal Cancer

(RAMIE vs OTE Trial)

Overseen By Yogita S. Patel

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: St. Joseph's Healthcare Hamilton

Disqualifiers: Pregnancy, Stage IV cancer, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

54 Participants Needed

Trial Summary

What is the purpose of this trial?

In Canada, the incidence of esophageal cancer has been increasing over time, while surgical standards for esophageal resections have remained unchanged. Currently, the standard of surgical care for this cancer is Open Transthoracic Esophagectomy (OTE), a highly morbid operation that is associated with a complication rate of 60-80%, and a recovery period of many months. While Minimally Invasive Esophagectomy (MIE) has been developed it has not been adopted because it is highly complex, technically demanding, and has a longer operative time than OTE. With the advent of robotic platforms, Robotic Assisted Minimally Invasive Esophagectomy (RAMIE) has recently emerged as a novel minimally invasive alternative to OTE. RAMIE utilizes the DaVinci Xi robotic surgical platform which offers superior dexterity, 3D-vision, and wristed surgical equipment. To date, case reports and small case series have demonstrated the safety of RAMIE, however it has not been performed yet in Canada, and there has been no randomized trial that has compared RAMIE to OTE. This study proposes to build the infrastructure for introducing RAMIE to Canada, while laying the foundations for a future randomized controlled trial which will compare it to OTE.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications.

What data supports the effectiveness of the treatment RAMIE vs OTE for Esophageal Cancer?

Research shows that robotic-assisted minimally invasive esophagectomy (RAMIE) has similar long-term survival and disease-free survival rates compared to open transthoracic esophagectomy (OTE) for esophageal cancer, with potentially better short-term outcomes like reduced blood loss and shorter ICU stays. ^{1 2 3 4 5}

Is robotic-assisted minimally invasive esophagectomy (RAMIE) safe compared to open esophagectomy (OE) for esophageal cancer?

Research indicates that RAMIE is a safe alternative to OE, with better short-term outcomes and similar long-term survival rates. RAMIE may also lead to reduced blood loss and shorter ICU stays compared to OE. ^{1 2 4 5 6}

How does the RAMIE vs OTE treatment for esophageal cancer differ from other treatments?

The RAMIE (Robotic Assisted Minimally Invasive Esophagectomy) treatment is unique because it uses robotic assistance to perform the surgery, which can potentially offer more precision and less invasiveness compared to traditional open surgery methods like OTE (Open Transthoracic Esophagectomy). This approach may lead to quicker recovery times and fewer complications for patients. ^{7 8 9 10 11}

Eligibility Criteria

This trial is for adults with Stage I, II, or III esophageal cancer who are eligible for surgery. It's not open to pregnant or breastfeeding women, those not using birth control, people allergic to ICG/sodium iodide/iodine, or anyone unsuitable for minimally invasive surgery.

Inclusion Criteria

I am 18 years old or older.

My surgeon has approved me for a less invasive surgery.

My esophageal cancer is in an early stage and I am a candidate for surgery.

Exclusion Criteria

I am not pregnant, breastfeeding, and if able to bear children, I am using effective birth control.

Hypersensitivity or allergy to ICG, sodium iodide, or iodine

My esophageal cancer is in stage IV.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase A: Learning Curve

40 patients undergo NIF-guided RAMIE using ICG dye to gain proficiency

Varies per patient

Phase B: Randomized Controlled Feasibility Trial

54 patients are randomized to either NIF-guided RAMIE using ICG dye or OTE

Varies per patient

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks

Postoperative Day 1, 3-Weeks Postoperative, 12-Weeks Postoperative

Treatment Details

Interventions

• Open Transthoracic Esophagectomy (OTE)
• Robotic Assisted Minimally Invasive Esophagectomy (RAMIE)

Trial Overview The study compares two surgical methods for esophageal cancer: a new robotic-assisted technique (RAMIE) and the standard open surgery (OTE). RAMIE uses advanced robotics aiming to reduce complications and recovery time.

Participant Groups

Group I: NIF-Guided RAMIE using ICG Dye (Experimental Arm) Experimental Treatment 1 Intervention

The patient will undergo NIF-guided RAMIE using ICG dye using the standard Ivor-Lewis approach. This will be a two-stage operation involving a first stage through a 5-port robotic approach through the abdomen to achieve a proximal gastrectomy and D2 nodal dissection. A feeding jejunostomy would not be inserted, as per the enhanced recovery pathway for esophagectomy. In addition, the vascularization of the conduit can be confirmed using the near-infrared camera of the robot with the ICG dye. The second stage of the operation will involve a 4-port robotic approach through the right chest to achieve thoracic nodal dissection, esophagectomy, and a hand-sewn anastomosis between the residual esophagus and the gastric conduit at the level of the azygous vein. During this second stage of the operation, NIF with ICG dye will be used to visualize the vascular supply of the gastric conduit, and assess the gastric conduit for any perfusions to potentially reduce anastomotic leaks.

Group II: Open Transthoracic Esophagectomy (OTE) Active Control 1 Intervention

The patient will undergo OTE using the standard Ivor-Lewis approach. This is a two-stage operation involving a first stage through laparotomy, proximal gastrectomy, D2 nodal dissection, and insertion of feeding jejunostomy. The second stage of the operation will involve a right thoracotomy, thoracic nodal dissection, esophagectomy, and a stapled anastomosis between the residual esophagus and the gastric conduit at the level of the azygous vein.

Open Transthoracic Esophagectomy (OTE) is already approved in Canada, European Union, United States for the following indications:

Approved in Canada as Open Transthoracic Esophagectomy for:

• Esophageal cancer

Approved in European Union as Open Transthoracic Esophagectomy for:

• Esophageal cancer

Approved in United States as Open Transthoracic Esophagectomy for:

• Esophageal cancer

Who Is Running the Clinical Trial?

St. Joseph's Healthcare Hamilton

Lead Sponsor

Trials

203

Recruited

26,900+

McMaster University

Collaborator

Trials

936

Recruited

2,630,000+

Findings from Research

In a study of 170 patients with esophageal cancer, those who underwent robotic-assisted minimally invasive esophagectomy (RAMIE) reported better quality of life (QOL) scores compared to those who had open esophagectomy (OE) after 2 years, particularly in esophageal symptoms and emotional well-being.

Patients in the RAMIE group experienced significantly lower pain severity compared to the OE group, indicating that RAMIE may offer a safer and more comfortable recovery experience for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Two-Year Quality of Life Outcomes After Robotic-Assisted Minimally Invasive and Open Esophagectomy. Vimolratana, M., Sarkaria, IS., Goldman, DA., et al.[2022]

Robot-assisted minimally invasive thoraco-laparoscopic esophagectomy (RAMIE) for esophageal cancer resulted in a high rate of successful radical resections (95%) and adequate lymph node removal, indicating its oncological effectiveness.

With a median follow-up of 58 months, RAMIE demonstrated a 5-year overall survival rate of 42% and a low local recurrence rate, suggesting it provides good long-term control of the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oncologic Long-Term Results of Robot-Assisted Minimally Invasive Thoraco-Laparoscopic Esophagectomy with Two-Field Lymphadenectomy for Esophageal Cancer. van der Sluis, PC., Ruurda, JP., Verhage, RJ., et al.[2022]

Minimally invasive esophagectomy (MIE) and robotic-assisted minimally invasive esophagectomy (RAMIE) show comparable overall survival rates to open esophagectomy (OE), with no significant differences in mortality rates at 30 and 90 days, indicating their safety and efficacy as surgical options for esophageal cancer.

Both MIE and RAMIE resulted in shorter hospital stays and higher lymph node yields compared to OE, suggesting that these minimally invasive techniques may enhance postoperative recovery and provide better staging information.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Does the Approach Matter? Comparing Survival in Robotic, Minimally Invasive, and Open Esophagectomies. Espinoza-Mercado, F., Imai, TA., Borgella, JD., et al.[2019]

In a study of 9,217 patients with esophageal cancer, robotic-assisted minimally invasive esophagectomy (RAMIE) showed a trend toward higher 30-day mortality compared to open esophagectomy (OE) and minimally invasive esophagectomy (MIE), although this was not statistically significant in matched cohorts.

There were no significant differences in long-term survival among patients undergoing RAMIE, MIE, or OE, suggesting that the surgeon's experience may play a more critical role in patient outcomes than the type of surgical approach used.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Survival After Esophagectomy: A Propensity-Matched Study of Different Surgical Approaches. Weksler, B., Sullivan, JL.[2022]

In a follow-up study of the ROBOT trial involving 112 patients with esophageal cancer, robotic-assisted minimally invasive esophagectomy (RAMIE) showed comparable 5-year overall survival rates (41%) and disease-free survival rates (42%) to open transthoracic esophagectomy (OTE) (40% overall survival, 43% disease-free survival).

The study found no significant differences in recurrence rates or patterns between the two surgical methods, suggesting that RAMIE is a viable alternative to OTE for long-term outcomes in esophageal cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Robot-assisted minimally invasive thoracolaparoscopic esophagectomy versus open esophagectomy: long-term follow-up of a randomized clinical trial. de Groot, EM., van der Horst, S., Kingma, BF., et al.[2021]

In a study of 5170 patients with esophageal cancer, those who underwent robotic-assisted minimally invasive esophagectomy (RAMIE) had significantly better overall survival compared to those who had minimally invasive esophagectomy (MIE) or open esophagectomy (OE), with a median survival of 42 months.

Patients undergoing RAMIE had a lower risk of death, with hazard ratios indicating a 19% increased risk for MIE and a 22% increased risk for OE, suggesting that RAMIE may be a more effective surgical option for improving long-term outcomes in esophageal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term survival outcomes associated with robotic-assisted minimally invasive esophagectomy (RAMIE) for esophageal cancer. Byiringiro, I., Aurit, SJ., Nandipati, KC.[2023]

Inhibition of 12-lipoxygenase (12-LOX) in esophageal squamous cell carcinoma (ESCC) cells reduced the levels of epithelial-mesenchymal transition (EMT) and decreased the cells' ability to migrate and invade, suggesting that 12-LOX plays a critical role in tumor progression.

The study found that higher levels of 12-LOX expression were associated with poorer overall survival in ESCC patients, indicating that 12-LOX could serve as a valuable biomarker for predicting patient prognosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

12-lipoxygenase promotes tumor progress by TGF-β1-mediated epithelial to mesenchymal transition and predicts poor prognosis in esophageal squamous cell carcinoma. Qu, Y., Wen, Z., Mi, S., et al.[2022]

In a study of 226 patients with esophageal squamous cell carcinoma (ESCC), overexpression of the EP2 receptor was found in 43.4% of cases and was linked to deeper tumor invasion and worse overall survival rates.

For patients with early-stage ESCC (T1-3N0M0), EP2 overexpression was identified as an independent prognostic factor for poor survival, highlighting its potential role in assessing patient risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prognostic role of PGE2 receptor EP2 in esophageal squamous cell carcinoma. Kuo, KT., Wang, HW., Chou, TY., et al.[2022]

In a study of 85 patients, it was found that the expression of COX-2 and the EP2 receptor increased significantly in the progression from Barrett's metaplasia to oesophageal adenocarcinoma, indicating their potential role in cancer development.

The EP4 receptor was also found to be elevated in oesophageal adenocarcinoma, suggesting that both EP2 and EP4 could be targeted for prevention or treatment of Barrett's-associated adenocarcinoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prostaglandin EP2 receptor expression is increased in Barrett's oesophagus and oesophageal adenocarcinoma. Jiménez, P., Piazuelo, E., Cebrian, C., et al.[2010]

In a study using the OE33 esophageal adenocarcinoma cell line, COX-2 was found to be the main source of PGE(2) production, and inhibiting COX-2 significantly reduced cell proliferation, indicating its potential as a therapeutic target.

The research identified that blocking specific PGE(2) receptors (EP(1) and EP(4)) inhibited cell migration and reduced the effects of PGE(2) on cell behavior, suggesting that EP receptor antagonists could be a promising strategy for treating esophageal adenocarcinoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of selective PGE2 receptor antagonists in esophageal adenocarcinoma cells derived from Barrett's esophagus. Piazuelo, E., Jiménez, P., Strunk, M., et al.[2013]

In a study using Wistar rats, the COX-2/PGE2 pathway was found to be significantly involved in the development of esophageal adenocarcinoma (EAC), with 90% of rats showing intestinal metaplasia and 40% progressing to cancer after inducing gastroduodenal reflux.

Selective inhibition of COX-2 and the EP2 receptor reduced cell proliferation in esophageal tissues, suggesting that targeting the EP2 receptor could be a promising strategy for preventing Barrett's associated adenocarcinoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization of the prostaglandin E2 pathway in a rat model of esophageal adenocarcinoma. Piazuelo, E., Santander, S., Cebrián, C., et al.[2019]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Two-Year Quality of Life Outcomes After Robotic-Assisted Minimally Invasive and Open Esophagectomy. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Oncologic Long-Term Results of Robot-Assisted Minimally Invasive Thoraco-Laparoscopic Esophagectomy with Two-Field Lymphadenectomy for Esophageal Cancer. [2022]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Does the Approach Matter? Comparing Survival in Robotic, Minimally Invasive, and Open Esophagectomies. [2019]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Survival After Esophagectomy: A Propensity-Matched Study of Different Surgical Approaches. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Robot-assisted minimally invasive thoracolaparoscopic esophagectomy versus open esophagectomy: long-term follow-up of a randomized clinical trial. [2021]

6. Germany pubmed.ncbi.nlm.nih.gov

Long-term survival outcomes associated with robotic-assisted minimally invasive esophagectomy (RAMIE) for esophageal cancer. [2023]

7. New Zealand pubmed.ncbi.nlm.nih.gov

12-lipoxygenase promotes tumor progress by TGF-β1-mediated epithelial to mesenchymal transition and predicts poor prognosis in esophageal squamous cell carcinoma. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Prognostic role of PGE2 receptor EP2 in esophageal squamous cell carcinoma. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Prostaglandin EP2 receptor expression is increased in Barrett's oesophagus and oesophageal adenocarcinoma. [2010]

10. United States pubmed.ncbi.nlm.nih.gov

Effects of selective PGE2 receptor antagonists in esophageal adenocarcinoma cells derived from Barrett's esophagus. [2013]

11. Netherlands pubmed.ncbi.nlm.nih.gov

Characterization of the prostaglandin E2 pathway in a rat model of esophageal adenocarcinoma. [2019]