Neoadjuvant and Systemic Therapy for Esophageal Cancer

Author: Jason Muesse, MD
Institution: University of Arkansas
Date Reviewed: December 2024
Learning Domain: General Thoracic
Learning Objective: 
PowerPoint File: Neoadjuvant and Systemic Therapy for Esophageal Cancer

AJCC 8th Edition TNM Staging Changes

• Gastric cancers are treated with different chemotherapy regimen (FLOT) & behave differently
• Radiation is often omitted from gastric cancer therapy 
• Although distal esophagectomy / proximal gastrectomy can be performed for tumors of proximal stomach if there is no esophageal involvement total gastrectomy and esophagojejunostomy is usually recommended
• If any esophageal involvement, usually needs esophagectomy
• If have dysphagia, probably has some esophageal component and will benefit from neoadjuvant radiation  

Rice TW, Ishwaran H, Ferguson MK, Blackstone EH, Goldstraw P. Cancer of the Esophagus and Esophagogastric Junction: An Eighth Edition Staging Primer. J Thorac Oncol. 2017;12(1):36-42. 

The Siewert Classification of GE Tumors: 

• Type I: Center 1–5 cm above GEJ
• Type II: Center 1 cm above to 2 cm below GEJ arises from cardia
• Type III: Center 2–5 cm below GEJ, below cardia

Clinical Staging Guides Therapy

Stage II-III Neoadjuvant Therapy

• 5-6 weeks of chemotherapy with platinum based drug + paclitaxel or 5FU
  • MAGIC trial, NEJM 2006
    • (improves 5 yr survival v surgery alone from 23% to 36%, p<0.001)
  • <10 percent of tumors are Her2 receptor positive, target for trastuzimab/Herceptin (adjuvant)
  • PD-L1 testing for Keytruda (adjuvant)
• Concurrent radiotherapy for 6 weeks (daily treatments for 5 days a week, 30 treatments total) 50.4 Gy of radiation total
  • CROSS trial, NEJM 2012 
  • (improves 5 yr survival v surgery alone from 34% to 47%, p=0.003)
  • Radiation helps you with the radial margins
• Repeat PET or CT scan at the end of treatment, 
  • if no evidence of progression then wait 5-6 week and have esophagectomy
  • If progress, continue to definitive chemoradiotherapy (70 Gy)
• Before starting therapy , determine nutritional needs – esophageal stent versus feeding tube; should see nutritionist
  • Try not to interrupt therapy for feeding access 

Neoadjuvant Chemotherapy 

• Medical Research Council Oesophageal Cancer Working Group OEO2, Lancet 2002
  • 802 previously untreated patients with resectable oesophageal cancer of any cell type were randomly allocated either two 4-day cycles, 3 weeks apart, of cisplatin 80 mg/m(2) by infusion over 4 h plus fluorouracil 1000 mg/m(2) daily by continuous infusion for 4 days followed by surgical resection (CS group, n=400), or resection alone (S group, 402
  • Clinicians could choose to give preoperative radiotherapy to all their patients irrespective of randomisation. Primary outcome measure was survival time. Analysis was by intention to treat.
  •  Median survival was 512 days (16.8 months) in the CS group compared with 405 days (13.3 months) in the S group (difference 107 days; 95% CI 30-196), and 2-year survival rates were 43% and 34% (difference 9%; 3-14). 
  • Keep in mind this was only two cycles !!!

Medical Research Council Oesophageal Cancer Working Group. Surgical resection with or without preoperative chemotherapy in oesophageal cancer: a randomised controlled trial. Lancet. 2002 May 18;359(9319):1727-33
 

Neoadjuvant Chemotherapy 

• MAGIC trial, NEJM 2006
  • Assigned patients with resectable adenocarcinoma of the stomach, esophagogastric junction, or lower esophagus to either perioperative chemotherapy and surgery (250 patients) or surgery alone (253 patients)
  • Chemotherapy consisted of two or three preoperative cycles of intravenous cisplatin (100 mg/m(2)) on day 1, and a continuous intravenous infusion of fluorouracil (800 mg/m(2)/d) for 5 consecutive days (days 1 to 5) every 28 days and three or four postoperative cycles of the same regimen. 
  • As compared with the surgery group, the perioperative-chemotherapy group had a higher likelihood of overall survival (hazard ratio for death, 0.75; 95 percent confidence interval, 0.60 to 0.93; P=0.009; five-year survival rate, 36 percent vs. 23 percent) and of progression-free survival (hazard ratio for progression, 0.66; 95 percent confidence interval, 0.53 to 0.81; P<0.001).
    • improves 5 yr survival v surgery alone from 23% to 36%, p<0.001)

Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, Scarffe JH, Lofts FJ, Falk SJ, Iveson TJ, Smith DB, Langley RE, Verma M, Weeden S, Chua YJ, MAGIC Trial Participants. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006 Jul 6;355(1):11-20.

Neoadjuvant Radiotherapy

• CROSS trial, NEJM 2012
  • 366 patients, 178 were randomly assigned to neoadjuvant chemoradiotherapy followed by surgery, and 188 to surgery alone
  • Weekly administration of carboplatin (dose titrated to achieve an AUC [area under the curve] of 2 mg/mL/minute) and paclitaxel (50 mg/m2 of BSA [body surface area
  • Total radiation dose of 41.4 Gy was given in 23 fractions of 1.8 Gy each, with 5 fractions per week
    • Improves 5 yr survival v surgery alone from 34% to 47%, p=0.003
    • Additionally, preoperative chemoradiation improved the rate of R0 resections (92% vs. 69%, P < .001). R0 is defined as complete resection with no tumor within 1 mm of resection margins.
    • Preoperative chemoradiation therapy reduced locoregional recurrence from 34% to 14% (P < .001) and peritoneal carcinomatosis from 14% to 4% (P < .001). 
    • A complete pathologic response was achieved in 29% of patients who underwent resection after chemoradiation therapy. 
      • A pathologic complete response was observed in 23% of patients with adenocarcinoma compared with 49% of patients with squamous cell carcinoma (P = .008).
• Long-term results from the CROSS trial, published August 5, 2015, in Lancet Oncology, confirmed the overall survival benefit of adding neoadjuvant chemoradiotherapy to surgery 
  • With a median follow-up of 84.1 months, the median overall survival was 48.6 months for patients who received neoadjuvant chemoradiotherapy plus surgery and 24.0 months for patients who received surgery alone. 
  • At the longer follow-up, patients continued to benefit from preoperative therapy, regardless of whether they had adenocarcinoma or squamous cell carcinoma.

CROSS Group. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012 May 31;366(22):2074-84.
CROSS study group. Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial. Lancet Oncol. 2015 Sep;16(9):1090-1098

Dosing for Radiotherapy

• 41 v 50.4 Gy
  • For inoperable tumors, radiation is increased to 50-50.4 Gy
    •  Intergroup Radiation Therapy Oncology Group (RTOG)-8501,
  • Doesn’t seem to affect me much surgically if get 41 or 50.4 Gy.  If marginal surgical candidate, would go with 50.4 Gy.
• 50.4 v 60-70+ Gy, 
  • RTOG study (#90-12) found that escalating the dose to 64.8 Gy did not confer a benefit compared with standard doses and may have contributed to a higher incidence of treatment-related death
  • Seems to be undecided if going to higher doses is helpful but may make sense if you know patient is inoperable due oncological or medical reasons
  • Higher doses for definitive therapy used more commonly in Asian population
• Radiation therapy is an art – technique is important, technology is important.
  • Bad technique can make surgery difficult and risky 
    • Helps with radial margins and benefits are well documented if can get R0 resection
  • Aerodigestive fistula is fatal
  • Aortoenteric fistula is fatal

Adjuvant Therapy?

• Adjuvant chemo administered to 208 of 1082 node positive patents who received neoajuvant treatment
• Kaplan-Meier analysis showed patients receiving adjuvant therapy had a longer median survival of 2.6 years vs 2.3 years (P = .02)
• Cox modeling identified adjuvant treatment as independently associated with improved survival, with a 24% reduction in mortality (hazard ratio, 0.76; P [ .005).
• Need to get adjuvant within 4 months of surgery for benefit 

Argument for Neoadjuvant Therapy

• Numerous well designed studies
• Due to the morbidity of the operation and recovery time, not all patients would receive systemic therapy if it were not given in a neoadjuvant fashion 
• Assess the biology of the tumor and of the patient. 
  • If cancer progresses on neoadjuvant therapy they will not benefit from surgery
  • If patient cannot tolerate the neoadjuvant therapy, they may not be able to tolerate the operation
• Radiation makes the operation harder and radiation technique makes a huge difference in safety of operation (especially around airway) but it’s worth it for the improved survival 

Definitive Therapy

• Treatment strategy and duration seem to be individualized and goals of patient must be kept in mind
• Consider feeding access early before obstruction occurs 
• FOLFOX has been used in place of platinum and 5FU to reduce toxicty
• Hercept if Her2 expressed
• PDL1 has shown promising results if have appropriate expression
  • FDA previously approved pembrolizumab for patients with advanced gastric or gastroesophageal junction (adenocarcinoma) cancer that has progressed despite two or more lines of standard treatment, and that approval was in conjunction with the same PD-L1 test. In that approval, patients were required to have tumors that expressed relatively modest levels of PD-L1 (a combined positive score of 1 or greater).
  • For the approval for esophageal cancer, patients must have tumors with much higher PD-L1 expression (a score of 10 or greater). 
    • KEYNOTE-181, a phase 3 trial, 628 patients whose advanced esophageal cancer had progressed on or after one line of treatment were randomly assigned to receive either pembrolizumab or the treating clinician’s choice of three different chemotherapy regimens. 
    • For patients in the trial with esophageal squamous cell tumors with PD-L1 expression of 10 or greater, the median overall survival was 10.3 months for those receiving pembrolizumab, versus 6.3 months for patients receiving chemotherapy. The overall response rate was 22% in patients who received pembrolizumab, compared with 7% in patients who received chemotherapy.

Extra info 

• Survival is worse overall for squamous cell carcinoma for early and intermediate stages, necessitating a separate staging system for adenocarcinoma and squamous cell carcinoma of esophagus
• Chance of complete pathological response is higher with squamous cell tumors with neoadjuvant therapy (up to 32 percent) compared to adenocarcinoma (23 percent) 
  • Very difficult to confirm complete response (absence of disease) without surgery (need the cross sections of the esohagus and the lymph nodes)
  • Only a gamble worth taking if you a high risk but not prohibitive surgical candidate
• Low-grade (G1) and moderately differentiated cancers (G2) are likely subject to substantial interobserver variability. However, poor differentiation or signet-ring cell morphology (G3) are associated with poor outcome and thus must be documented in the biopsy pathology report\
  • Good to know if have signet ring morphology up front, especially if marginal surgical candidate
• Because of variability in clinical staging (imaging, EUS etc), pathological staging remains the best prognostic tool 
  • Complete pathological response ypT0N0M0 does not guarantee 100 percent survival
• 9th Edition of Staging will likely incorporate tumor genetics

Blum  et al. Pathological complete response in patients with esophageal cancer after the trimodality approach: The association with baseline variables and survival-The University of Texas MD Anderson Cancer Center experience. Cancer. 2017 Nov 1;123(21):4106-4113

de Gouw et al. Detecting Pathological Complete Response in Esophageal Cancer after Neoadjuvant Therapy Based on Imaging Techniques: A Diagnostic Systematic Review and Meta-Analysis. J Thorac Oncol. 2019 Jul;14(7):1156-1171

Surgeon’s Role before Esophagectomy

• Set expectations. 
• Assess if patient will ever be a surgical candidate
• Feeding gastrostomy or jejunostomy may be required preoperatively
• Laparoscopic placement is ideal
  •  Along fundus well away from right gastroepiploic artery
  • PEG is ok, but ideal placement can be confirmed with laparoscopy
  • Laparoscopy can help staging but not required
  • IR placed gastrostomy tube is probably the most problematic for conduit
• Document distance of tumor from incisors preoperatively 
  • May be difficult to locate after neoadjuvant treatment
• Bronchoscopy for mid thoracic tumors, especially squamous cell
  • To rule out invasion into membranous portion of airway

Esophageal Cancer and Nutrition

• Esophageal cancer affects the proximal portion of foregut – if patients have an obstruction, they often present malnourished
  • Common during COVID – pt’s don’t go to the doctor unless can’t eat
• Every esophageal cancer patient seen in our clinic is assessed by a registered nutritionist and an individualized nutritional plan is made
  • Reassessed post neoadjuvant therapy at every post operative visit
  • If a feeding tube is needed preoperatively or esophageal stent, dedicated teaching is provided about that
  • Most patients will not need a feeding tube preoperatively, but if needed placement of the tube should be discussed with surgeon before placement
  • Teaching about jejunostomy tube usage post operatively is provided at first visit and reiterated at each subsequent visit
• During neoadjuvant radiation, about a third of patient’s dysphagia will get worse or not improve
  • Don’t want to interrupt therapy due to nutritional issues

Nutritional Devices

• Gastrostomy tube can be placed open, laparoscopically, endoscopically (PEG tube), or by IR 
  • If the right gastroepiploic artery (which will power the reconstructed esophagus) is damaged during  placement of the G/PEG tube, patient can be inoperable 
    • I think laparoscopic assisted PEG or lap G tube is safest if patient is likely a surgical candidate and needs feeding tube support during neoadjuvant treatment
    • Stent is also a good option that does not jeopardize future surgery
  • Gastrostomy tube was previously felt to be a contraindication to esophagectomy, but we can usually take it down safely and use the stomach if properly placed
  • Gastrostomy tubes are much easier for patients to use, clog less and have less admissions to ER for complications related to them than jejunostomy tubes 
  • Good for patients without poor support – can any liquid into and most crush meds, acts just like normal stomach
• Jejunostomy tube
  • Gold standard, will not affect the conduit  
  • Laparoscopic versus open
  • Clog more, more ER visits
  • Patients have to use a pump (cannot bolus feed)
  • Cannot use Ensure / Boost or get terrible diarrhea
  • Cannot use for meds easily 
• Esophageal Stent

Esophageal Stents

• Can be partially covered (designed to never be removed) or Fully Covered (removable any time)
• Can be placed during treatment if needed without risk of chemotherapy related complications and healing (leukopenia or thrombocytopenia)
  • Usually will need to re-simulate the patient if placed in middle of radiation
• Not always tolerated by patients (get chest pressure)
• Can perforate tumors, takes some experience to know what size is right and when can be used safely
• Great option for palliation 

Esophageal Surgery Referral

• Esophagectomy should be done in a high volume center
  • Most community general surgeons perform < 4 per year
    • Proven survival benefit at high volume centers (>10 per year)
    • Improvement in “failure to rescue”
    • Nationwide, the mortality rates from esophagectomy range from 8% in high-volume centers to as high as 23% in low-volume centers
• Refer early!
  • Surgeons can assess nutritional needs, set expectations
  • Helps medical and radiation oncologists know how to guide therapy if patient is non operative
• No proven mortality or oncologic benefit to minimally invasive approaches (robotic or laparoscopic) at this time
  • Surgeon should use whatever technique they have the best results with
• These are usually unhealthy patients who have a lot of complications
  • Pneumonia is #1 (>30 percent), atrial arrhythmias, recurrent laryngeal nerve injury, aspiration, chylothorax, anastomotic leaks
  • Only about 1/3 have absolutely no complications
• Average hospital stay if do perfect is 10 days
• 2.5-3 month for full recovery

Birkmeyer JD, Siewers AE, Finlayson EV, et al: Hospital volume and surgical mortality in the United States. N Engl J Med 346:1128-1137, 2002.

Resources:

• American Cancer Society  
  • www.cancer.org
  • Excellent resource for esophageal cancer patients, easy to read and understand
• National Cancer Institute
  • www.cancer.gov
  • Health Profession Version has great summaries on previous trials 
• Esophageal Cancer Education Foundation
  • www.fightec.org
  • Weekly group phone calls moderated by a well organized survivor and 1-2 surgeons
  • Help with questions related to surgery and life after surgery 
  • Esophagectomy Post-Surgical Guide: Questions and Answers: Second Edition