Clinical trial NCT01217060
Conditions: Esophageal Cancer
Keywords: Adenocarcinoma Squamous cell carcinoma Thoracic esophagus Gastroesophageal junction Chemoradiotherapy Esophagectomy 5-Fluorouracil Docetaxel Radiation Radiotherapy XRT IMRT Taxotere Adrucil Efudex Dexamethasone Decadron
Sponsor: M.D. Anderson Cancer Center
Start date: 2010-10-01; Completion date: 2020-06-14
Enrollment: 4 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The goal of this clinical research study is to learn if giving chemotherapy and radiation therapy before surgery for early-stage esophageal cancer can help to control the disease and if so, for how long. The safety of this treatment will also be studied.

Detailed description:
The Study Treatment:

5-fluorouracil and docetaxel are designed to stop the growth of cancer cells, which may cause the cells to die. Docetaxel may also damage blood vessels in tumor tissue.

The radiation therapy in this study will be either intensity modulated radiation therapy (IMRT), which is a form of photon-based radiation therapy, or proton beam therapy (PBT). This will be up to your doctor. Both IMRT and PBT are designed to give radiation to the tumor area and limiting radiation exposure to nearby organs such as the lungs, heart, and spinal cord.

The surgery in this study removes part of the esophagus and nearby lymph nodes. The type of surgery will be the doctor's decision based on the location of the tumor in the esophagus. It will either be laparoscopic surgery (a minimally invasive procedure through small holes made in the abdomen) or open surgery (through the chest wall).

Study Treatment Administration:

If you are found to be eligible to take part in this study, you will receive radiation therapy and chemotherapy on the following schedule for up to 5 1/2 weeks. If there are holidays on the scheduled treatment days, the schedule may be slightly different and the study staff will discuss this with you.

* Radiation therapy will be given Monday through Friday. This will take about 30 minutes, including about 10-15 minutes for the radiation treatment.
* 5-fluorouracil will be given by vein, continuously for about 96 hours a week (Monday through Friday).
* Docetaxel will be given by vein over about 1 hour, 1 time a week (on Mondays).

  5-fluorouracil will be given using a portable pump about the size of a personal CD player. You will need to carry this portable pump with you for about 96 hours each week.

Docetaxel will be given through a central venous catheter. A central venous catheter is a sterile flexible tube that will be placed into a large vein while you are under local anesthesia. Your doctor will explain this procedure to you in more detail, and you will be required to sign a separate consent form for this procedure. The catheter will be removed at the end of Week 5.

Before every dose of docetaxel, you will receive dexamethasone to lower the risk of side effects. Dexamethasone will be given by vein over a few seconds.

Your doctor will let you know if and when you are eligible to have surgery. In this study, the surgery must be performed within 8-10 weeks after you finish chemotherapy and radiation therapy. You will be asked to sign a separate consent form that describes the surgery and anesthesia (numbing medicine) and their risks in more detail. The screening tests that will help your doctor decide if you are eligible to have surgery include the scans and endoscopy described below (4-6 weeks after radiation and chemotherapy).

You will no longer be able to receive radiation and chemotherapy if the disease gets worse or intolerable side effects occur. You will not be able to have surgery if the doctor decides surgery is not in your best interest (for example, if the disease or your general health gets worse).

Study Visits:

During Study Therapy:

Blood (about 3 tablespoons) will be drawn for routine tests during Week 3 of radiation and chemotherapy.

Follow-Up:

At 4-6 weeks after your last dose of radiation and chemotherapy, the following tests and procedures will be performed:

* You will have a CT scan of the chest and a whole-body PET/CT scan to check the status of the disease.
* You may have an endoscopy of your esophagus with 1 or more biopsies of the tumor to check the status of the disease. The number of biopsies you have will be the doctor's decision at the time of the procedure, based on the status and location of the disease.
* Blood (about 3 tablespoons) will be drawn for routine tests.
* You will fill out 3 quality-of-life questionnaires. This should take about 10-15 minutes.

About 4 weeks after surgery, you will fill out 3 quality-of-life questionnaires. You will then fill out 2 quality-of-life questionnaires at 6 of your routine follow-up visits after surgery.

Every 3-6 months in the first 3 years after your last dose of radiation and chemotherapy, then every 6 months in the next 2 years, and every year after that from then on, the following tests and procedures will be performed:

* You will have a CT scan of the chest or a whole-body PET/CT scan to check the status of the disease.
* You will have an endoscopy of your esophagus to check the status of the disease during every follow-up visit in Year 1. After that, you will have an endoscopy of your esophagus at follow-up visits anytime the doctor decides it is needed. You will have 1 or more tumor biopsies at these follow-up visits if the doctor decides they are needed, based on the status and location of the disease. This will be decided at the time of the endoscopy.

Biomarker Testing:

If leftover tumor tissue is available from before you joined the study, the leftover tissue will be used for genetic biomarker testing. If you do not have leftover tumor tissue available from before you joined the study, leftover tissue from study procedures will be used for genetic biomarker testing.

This is an investigational study. Docetaxel and 5-fluorouracil are FDA approved and commercially available to treat esophageal cancer. However, it is investigational to give these drugs to patients with early-stage esophageal cancer.

It is investigational to give the combination of chemotherapy, radiation therapy, and surgery to patients with early-stage esophageal cancer.

Up to 30 patients will take part in this study. All will be enrolled at MD Anderson.

Arms: arm 1: Docetaxel 20 mg/m2 given by vein (IV) once a week up to 5 1/2 weeks. Dexamethasone 10 mg IV 30 minutes prior to weekly Docetaxel. 5-FU 300 mg/m2 IV, continuously for 96 hours 5 days a week for about 5 1/2 weeks. Radiation 50.4 Gy (1.8G/Fx/day) for about 5 1/2 weeks. Surgery to remove part of esophagus and nearby lymph nodes, approximately 8 to 10 weeks after completing chemoradiation.
Interventions: intervention 1: Docetaxel intervention 2: 5-FU intervention 3: Radiotherapy intervention 4: Esophagectomy intervention 5: Dexamethasone
Intervention descriptions: intervention 1: 20 mg/m2 given by vein (IV) over 1 hour once a week for up to 5 1/2 weeks. intervention 2: 300 mg/m2 given by vein, continuously for 96 hours a week for about 5 1/2 weeks. intervention 3: 50.4 Gy (1.8G/Fx/day) for about 5 1/2 weeks, Monday through Friday. intervention 4: Surgery to remove part of esophagus and nearby lymph nodes, approximately 8 to 10 weeks after completing chemoradiation. intervention 5: 10 mg IV 30 minutes prior to weekly Docetaxel.

Protocol documents:
Prot_SAP_000.pdf: 
Protocol Page
Phase IIB Study of Trimodality Management of clinical T1bN0M0 cancers of the 
esophagus
2010-0333
Core Protocol Information
Short Title 
Trimodality management of T1b esophageal cancers
Study Chair: 
Steven H. Lin
Additional Contact:
Aileen Mapps
Dustin M. Silk
Victoria Cox
Additional Memo Recipients:
Recipients List
OPR Recipients (for OPR use only)
None
Study Staff Recipients
None
Department:
Radiation Oncology
Phone:
713-563-2300
Unit:
97
Study Manager:
Denise M. Erdman
Full Title: 
Phase IIB Study of Trimodality Management of clinical 
T1bN0M0 cancers of the esophagus
Public Description:
N/A
Protocol Type:
Standard Protocol
Protocol Phase:
Phase I/Phase II
Version Status:
Activated -- Closed to new patient entry as of 09/12/2019
Version:
10
Document Status:
Saved as "Final"
Submitted by:
Dustin M. Silk--9/12/2019 3:53:05 PM
OPR Action:
Accepted by:  Amber M. Cumpian -- 9/12/2019 8:13:05 PM
Which Committee will review this protocol?
 The Clinical Research Committee - (CRC)


Protocol Body
1.0 Objectives
Objectives:  To assess the efficacy (pathologic complete response) and safety of Trimodality management 
(chemoradiotherapy followed by esophagectomy) in patients with clinically staged T1bN0M0 cancer of the esophagus or 
gastroesophageal junction.
Primary endpoint:  Pathologic Complete Response (PCR) rate
Secondary Objectives:  
1.  Time to disease progression or death
2.  Evaluation of preoperative toxicity and postoperative morbidity/mortality 
3.  Evaluation of feasibility of pretreatment and posttreatment/preoperative 
deoxyribonucleic acid (DNA) 
methylation biomarkers in tumor and blood as predictor of 
pCR rate 
2.0 Rationale
1.  The Need to Improve the outcomes for T1b esophageal cancer
Esophagectomy or endoscopic mucosal resection is the most standard approach for the management of stage I esophageal 
cancers.  Early stage T1N0 disease can be defined as disease that is confined to the superficial mucosal layer (T1a) or that 
which has invaded to the submucosal layer (T1b).  Multiple single institutional experiences documenting the outcomes of 
patients treated with esophagectomy for stage I esophageal cancers have demonstrated a less than optimal outcomes for 
patients with T1b disease.  From M.D. Anderson, Cen et al. have reported the results of 99 consecutive patients with T1 
adenocarcinoma who have underwent esophagectomy/lymphadenectomy, of which 51 patients have T1b disease (1).  The 
investigators reported a much better 5-year overall survival (OS) for patients with T1a tumors (88%) than those with T1b tumors 
(62%) (p=0.001).  Patients with evidence of lymphovascular invasion (LVI) and/or nodal metastasis (LNM) had a worse 5 year 
OS (≤37%) compared to those without either risk factors (88%, p<0.001).  Also from M.D. Anderson, Liu et al reviewed the 
pathologic correlate of LVI or LNM to the clinical stage of patients (2).  They found that T1b stage is significantly associated with 
LNM (44% versus 12% for T1a, p<0.001), larger tumors (>75% have >1.2 cm tumors versus ~30% for T1a tumors, p<0.001), 
and LVI (73% versus 18% for T1a, p<0.001).  These investigators found that both LNM and LVI were prognostic for tumor 
recurrence, but only LVI was prognostic for overall survival.  Tumor recurrence was more frequent in T1b disease (40% at 5 
years) than T1a disease (0% at 5 years), resulting in 5 year OS of 58% for T1b and 91% for T1a disease (2).  These findings 
have been confirmed in another large cohort study of 100 patients with T1 esophageal cancers receiving primary 
esophagectomy (3).  They also found that LNM was significantly associated with T1b disease (27% vs. 7% for T1a).  Although 
the 5 year OS for the entire cohort was 62%, and the 3 year DFS was 80%, this rate was significantly lower for patients with N1 
disease (5 year OS is 35% N+ vs 70% N-, p=0.0057).  These and other surgical series have demonstrated the poor outcomes 
of surgery alone for T1b disease due to the high propensity of these tumors to exhibit poor prognostic features such as LVI, 
TNM, and larger tumors, which has also been demonstrated to be an independent prognostic factor (4).   
From these surgical series, it is also apparent that neither endoscopic mucosal resection (EMR) nor endoscopic submucosal 
resection (ESR) are adequate treatments for T1b esophageal cancers.  Limited resection is very effective treatment for T1a 
disease, which has been demonstrated by the low risk features of this stage of disease based on these surgical series as well 
as institutional experiences utilizing EMR for management of early esophageal cancers.  However, even in the most 
experienced centers, R0 resection is still only 75%, with high incidence of recurrences (30%) (5, 6).  Even in the most selective 
group of patients (<2cm tumors, T1a, no LVI, histologic grades 1 to 2), as reported by a series of 100 patients in Germany, the 
lateral positive margin was still 34% (6).  During the median 33 month follow-up, recurrence or metachronous disease was 
found in 11% of patients.  All recurrences were salvageable, yielding a 3 year OS of 98%.  However, this treatment approach 
wouldn’t be appropriate for T1b cancers because the unpredictably high rates of LNM and LVI would not be adequately 
addressed by a mucosal or submucosal limited resection.  Recently, Barbour et al (2010) (34) produced a stratification scheme 
based on 85 T1 patients treated with surgical resection alone.  The patients were analyzed based on three risk factors: T1b 
status, tumor grade, and presence of LVI.  While patients with T1a disease or T1b disease with Grades 1 or 2 and negative LVI 
had fairly good survival (5 yr overall survival of 95% and 85%, respectively), patients with T1b disease and grade 3 or any 
patients with LVI had 5 year survival of 50% and 30%, respectively.  
So while esophagectomy is the standard of care for T1b esophageal cancers, multiple surgical series have demonstrated that 
this disease carries high rate of unsuspected lymph nodal metastasis (LNM) (27-45%) (2, 3, 7, 8) and lymphovascular invasion 
(LVI) (1, 2).  The presence of such features portends to a poorer recurrence risk and overall survival as that seen for more 
locally advanced disease (stage II-III), where trimodality management with chemotherapy with radiation followed by surgical 
resection is the standard of care in the United States.  This is based on numerous trials (9-11) and a meta-analysis (12) 
demonstrating survival benefit with preoperative chemoradiation compared to surgery alone.  
2.  Non-surgical management for T1b cancers
The only curative measure for esophageal cancers without a surgical resection is definitive chemoradiation.  Definitive 
chemoradiation has been demonstrated to be curative for around 20-25% locally advanced esophageal cancer patients in a 
large randomized trial of unresectable patients (13).  Whether definitive chemoradiation will yield better outcomes in early stage 
esophageal cancers (exclusively squamous cell cancers) was evaluated by investigators in Japan.  In an earlier experience, 
Yamada and colleagues tested the role of definitive chemoradiation in 63 T1N0M0 squamous cell cancers of the esophagus 
(T1a=23, T1b=40) (14).  The chemoradiation employed a median dose of 59.4 Gy with concurrent cisplatin/5FU, followed by 10-
12 Gy HDR brachytherapy.  They found high rates of control for T1a disease at 84.4%, but the 5 year disease free survival was 
50.5% for T1b disease.  Seven patients developed metastatic disease, all of which were patients with T1b disease.  Local 
failures were seen in 15 patients (11 local only, 4 local + distant metastasis), with salvage therapies successful in saving 5 of 11 
local recurrence only patients.  In a separate phase II study investigating the efficacy of definitive chemoradiation for exclusively 
T1bN0 patients, cisplatin and 5FU were concurrently administered with a split course regimen of 60 Gy of radiotherapy (one 


week break in between 30 Gy radiation) (15).  Since the primary endpoint of the study was clinical complete response (cCR) 
rate, each of the 72 patients enrolled in the study was evaluated for clinical response at 4 weeks after chemoradiation with an 
EGD and biopsy.  A clinical CR was defined as EGD evidence without tumor except for flat erosion, a negative biopsy, and no 
evidence of new lesions.  Although they found a cCR rate of 87.5%, the 4 year recurrence free survival was only 52.8%, similar 
to the previously reported retrospective study.  Of the 36 patients who developed recurrence or achieved less than a CR after 
chemoradiation, 16 had endoscopic resection as salvage therapy, and 6 that failed within the treatment port underwent 
esophagectomy as salvage.  However of the 14 patients who couldn’t be salvaged, 6 patients had distant metastasis and 8 
patients had regional lymph node involvement.  All 14 patients died of disease, resulting in a 4 year OS of 80.5%.  
Although these studies demonstrated the feasibility and relative safety of performing non-surgical management for T1b 
esophageal cancers, the high risk of recurrence from these studies highlights the need for more aggressive therapies.  Also, all 
the patients treated in these two Japanese studies had squamous cell cancers and so the applicability of this to patients treated 
in the United States where adenocarcinomas are prevalent is unknown.  From these two reports, around 10-15% of non-
salvageable recurrence is due to regional LNM.  If upfront esophagectomy and lymphadenectomy clears the residual disease 
left in the primary site or regional lymph nodes after chemoradiation, approximately a 10-15% improvement in survival should be 
expected.  
3.  The importance of pathologic complete response in predicting prognosis in esophageal cancer patients after preoperative 
chemoradiation
Pathologic response rate after preoperative chemoradiation is an important prognostic factor for survival in locally advanced 
patients (16).  This generally ranges from 25-45% in most series of locally advanced cancers managed with the trimodality 
therapy (9-11).  There is currently no experience what the pCR rate is for stage I patients since trimodality therapy has not been 
evaluated for this stage of disease.  Utilizing a treatment regimen where that could be systematically assessed will be important 
to determine the potential of an organ preservation approach for T1b patients in the future.
4.  Preoperative chemoradiation may improve outcomes in T1b patients
Since patients with submucosal disease (T1b) tend to have high risk for nodal metastasis and LVI, with the 5 year survival rates 
for the T1b patients with these features nearly comparable to locally advanced cancers (stage II-III), preoperative or adjuvant 
therapies may be necessary to improve outcomes of these patients.  Adding adjuvant therapies after upfront surgery is an 
option for these patients, but postoperative therapies incorporating radiation or chemotherapy alone have not shown to improve 
outcomes in multiple randomized trials in locally advanced cancers after surgical resection (17).  Although postoperative 
chemoradiation have been shown to improve outcomes of patients with gastric/GE junction tumors based on the U.S. Intergroup 
0116 study (18), which randomized gastric (80%) or GE junction (20%) tumors to surgery alone or postoperative 
chemoradiation, there are several disadvantages of using postoperative chemoradiation.  Radiation fields after surgery tends to 
be larger since it must cover not only the pretreatment surgical bed but also the areas of dissection.  The dose used 
postoperatively is higher and will vary depending on the surgical margin status.  Oxygenation tends to be poorer in a dissected 
area, and therefore may decrease the efficacy of radiotherapy (and the reason for the need of higher doses of radiation).  With 
higher doses of radiation, toxicity is likely to also be higher.  In the area of the upper abdomen where sensitive structures such 
as the stomach, small bowel, and liver reside, doses above 45 to 50 Gy will be very difficult to administer without causing severe 
gastrointestinal side effects (nausea/vomiting, strictures, fistulas, small bowel obstruction).  
Preoperative chemoradiation is an accepted standard in the United States for locally advanced stage II-III esophageal 
cancers.  The basis of this was first established by an Irish study that randomized 113 patients with adenocarcinomas of the 
esophagus to 2 cycles of preoperative cisplatin/5FU and concurrent radiation to 40 Gy in 15 fractions or to surgical resection 
alone (9).  The pCR rate for preoperative chemoradiation is 25%.  There was a significant improvement in the 3 year overall 
survival (32% versus 6%) and median survival (16 months versus 11 months) (p=0.01) for the preoperative chemoradiation 
group.  Many with a pCR (85%) were alive and disease free at 2 to 43 months.  However the surgical resection group had an 
unusually poor 3 year survival rate of 6%, especially when historical surgical series demonstrate a 3 year survival of 20-
25%.  Many would argue that preoperative chemoradiation made up for the poor outcomes of surgery in this series of 
patients.  At around the same time, Arlene Forastiere and colleagues in the United States were also studying the role of 
preoperative chemoradation, first as a phase II study that demonstrated promising results compared to historical controls of 
surgery alone, and later as a prospective randomized study of 100 patients (10, 19).  This latter study randomized patients to 
preoperative chemoradiation with 5FU/Cisplatin/Vinblastine plus radiation (45 Gy) or surgery alone.  The pCR rate was 
28%.  There was an improved local control rate in the chemoradiation group (81% versus 60%, p=0.04), but because of the 
small size of the study, there was only a trend to improved survival for the chemoradiation group (30% versus 16%) 
(10).  Although technically a  negative study, this trial is largely viewed as a positive trial demonstrating the superiority of 
preoperative chemoradiation since the survival rate in the neoadjuvant group is similar to the Walsh et al. study and that the 
surgery alone arm had survival rates that was largely equivalent to historical rates.  These results were further corroborated by 
the recent publication of the results of CALGB 9781, a phase III study that closed to poor accrual with only 56 patients enrolled 
out of the planned 475 patients (11).  Patients were randomized to preoperative cisplatin/5FU and radiation to 50.4 Gy or 
surgery alone.  The pCR rate was 40%, and the median survival was better in the chemoradiation group (4.5 years versus 1.8 
years) as well as the 5 year overall survival (39% versus 16%).  However, trials done through the EORTC (Europe) and the 
TTROG (Australia) testing the role for preoperative chemoradiation have been largely negative studies, with only a benefit of 
disease free survival but not overall survival for patients treated with preoperative chemoradiation (20, 21).  A meta-analysis of 
10 randomized trials comparing preoperative chemoradiation versus surgery (1209 patients) found better hazard-ratio for 
mortality (0.81), corresponding to a 13% absolute 2-year survival benefit.  The benefit was seen for both squamous and 
adenocarcinoma histologies (12).  
Our experience at M.D. Anderson also favors the trimodality approach.  We have analyzed our experience in 132 consecutive 
stage II-III patients treated at M.D. Anderson between 1990 to 1998 (22).  We found that preoperative chemoradiation was 
better than definitive chemoradiation alone for 5 year loco-regional control (67.1% vs 22.1%, p<0.000), disease-free survival 
(40.7% vs 9.9%, p<0.000), and 5-year overall survival (52.6% vs 6.5%, p<0.000).  There was no difference in distant 
metastastic free survival between the two groups, however.  There may been some negative selection bias for the definitive 
chemoradiation group since these patients tended to be older, have more squamous cell carcinoma, located at upper thoracic or 


cervical locations, and have more T4 tumors, but on both univariate and multivariate analysis, surgical resection remained a 
significant independent predictor of outcomes.  
The importance of adding surgical resection after chemoradiation remains controversial since two European randomized trials 
demonstrated only an improvement in local control but not overall survival (23, 24).  One major caveat of these studies is that 
the potential survival benefit of surgery was offset by the high rates of postoperative morbidity/mortality.  We expect that the 
benefits of surgery should be seen at high volume centers where the morbidity and mortality rates are expected to be lower 
(25).  Since surgical resection is the expected standard for T1b esophageal cancers where the postoperative complication rates 
are low (3), it is therefore important to assess the toxicity of trimodality treatment of T1b patients before adopting it for 
widespread use.  
5.  Biomarker predictors for pathologic response
It is a fact that definitive chemoradiation can cure select patients (26), particularly those who achieves a pCR after 
treatment.  Clinical predictors for pCR using PET response or EDG biopsy results posttreatment are correlative, but are not 
sensitive enough to predict pCR (27).  Tumor biomarkers may be a more sensitive way to determine which tumors are likely to 
respond to treatment.  Ajani and colleagues have utilized expression microarray to identify three markers (PERP, S100A2, and 
SPRR3) that have allowed discrimination of pCR from <pCR with high sensitivity and specificity (28).  This is currently being 
validated in larger clinical sets.  
Promoter CpG island DNA methylation is a cancer-specific mechanism to turn-off tumor-suppressor genes.  Since DNA is a 
stable molecule that is easily amplifiable from small amounts of materials, detection of residual cancer specific DNA methylation 
changes in small amounts of tissue or body fluids may be a promising approach to assess treatment response after 
chemoradiation (29, 30).  
3.0 Patient Eligibility
Inclusion criteria:
1)  Histologically documented adenocarcinoma or squamous cell carcinoma of the thoracic esophagus or gastroesophageal 
junction that are staged as T1b using endoscopic ultrasound (EUS) or from a large biopsy (either criteria # 1 or #2 can be 
met for eligibility). 
2)  Patients who undergo a diagnostic Endoscopic Mucosal Resection (EMR) and have a diagnosis of T1b stage 
established.   
3)  Performance score Karnofsky Performance Scale (KPS) 80-100.
4)  Patients should be surgical candidates for esophagectomy and should have no contraindications for chemotherapy or 
radiation.
5)  Negative pregnancy test for women of child bearing potential.  They must agree to adequate contraception.
6)  Complete blood count (CBC) and complete metabolic panel (chemo-14: Glucose, Calcium, Albumin, Total Protein, 
Sodium, Potassium, CO2, Chloride, Blood Urea Nitrogen (BUN), Creatinine, Alkaline Phosphatase, ALT (SGPT), AST 
(SGOT), and Bilirubin) to assess adequate hematologic, renal and hepatic functioning will be obtained.  The values are as 
follows: Adequate hematologic (White Blood Count (WBC) >2,500/uL, platelets > 75,000/uL), renal (creatinine clearance > 
50 mL/min), and liver function (bilirubin <=1.5 fold the upper limit of normal and liver enzymes < 3 fold the upper limit of 
normal).  
7)
Based on the risk factors and propensity of 
LNM and poorer survivals seen in retrospective studies as discussed in the introduction, only patients with any one (1) of high risk 
features such as LVI, tumors >1.2 cm, and high grade will be enrolled (Grade is the pathologic term defining the degree of 
differentiation. Grade 1 is well differentiated, Grade 2 is moderately differentiated, and Grade 3 is poorly differentiated).
Exclusion criteria:
1)  Prior radiation to the chest
2)  Previous or concomitant cancers other than 1) curatively treated carcinoma in situ of cervix, basal cell of the skin, curative 
treatment for transitional cell carcinoma of the bladder, and early stage cancers at another non-overlapping site that was treated 
more than 3 years ago for cure.  
3)  Pregnant or breast-feeding females
4)  Clinically significant uncontrolled major cardiac, respiratory, renal, hepatic, gastrointestinal or hematologic disease but not 
limited to:
a) active uncontrolled infection
b) Symptomatic congestive heart failure, unstable angina, or cardiac dysarrhythmia not controlled by pacer device
c) no myocardial infarction within 3 months of registration 
5) Known hypersensitivity to docetaxel, 5-fluorouracil, polysorbate-80, or any component of the formulation.
4.0 Pretreatment evaluation
4.1.  Pretreatment evaluation:
A complete history and physical to include performance status, recent weight loss, percent of weight loss, usual weight, and 
concurrent non-malignant disease and its therapy must be recorded.  Laboratory studies will included CBC with differential, 
platelet count, Liver function tests (LFTs), electrolytes, and creatinine within 3 weeks.  
Computed tomography (CT) of chest with contrast and Positron emission tomography/ computed tomography (PET/CT) scans 
are required workup components that should be done within 3 months prior to starting chemoradiation.  Pulmonary function 
tests (PFTs) should be updated within 3 months prior to starting treatment. Esophagogastroduodenoscopy (EGD) with EUS +/- 
biopsy at M.D. Anderson are required to confirm staging.  
Patients are evaluated independently by the thoracic surgeon, the medical oncologist, and the radiation oncologist.  
Quality of life (QOL) during treatment will be assessed at baseline, during treatment, and at followup.  The QOL scale used are 
the FACT E (Appendix A), the FACT TS-G (Appendix B), and the Mayo (Appendix C).  These will be administered at various 


times pretreatment and throughout the course of treatment and at followup.  The questionnaire to be administered and the time 
line of when these will be administered is detailed in the Appendix D.  
5.0 Evaluation During Study
5.1  Treatment Schematic
The following demonstrates the treatment schematic for each week of therapy until radiotherapy is complete (approximately 5.5 
weeks).
Table 1: Phase 2 Treatment Schematic
Docetaxel and Fluorouracil (5-FU)
Docetaxel and 5-FU should be prepared and administered in accordance with the prescribing information approved by the Food 
and Drug Administration (FDA) or other regulatory agencies where docetaxel and 5-FU are commercially available.  
See Table 2: Therapy Dose and Schedule below for additional information regarding the dose and schedules for docetaxel, and 
5-FU.
Table 2: Therapy Dose and Schedule
*We will premedicate with 
dexamethasone 10 mg IV 30 minutes prior to weekly docetaxel administration.
Docetaxel and 5-FU
Although commercial supplies of 5-FU and docetaxel will be utilized, records should, when possible, document manufacturer, 
supplier, and lot numbers for each vial administered to each patient.  Any remaining or unused 5-FU or docetaxel should be 
handled according to the institution’s guidelines for handling and disposing of antineoplastic agents.
5.2  Study Drug Handling and Disposal
Docetaxel and 5-FU
Docetaxel and 5-FU should be disposed of in accordance with the prescribing information approved by the Food and Drug 
Administration (FDA) or other regulatory agencies where docetaxel and 5-FU are commercially available.  See the docetaxel 
and 5-FU Product Information Sheets for details regarding handling and disposal.  
5.3  Radiation Therapy 
Participating institutions must utilize 3-D CT based planning and must be able to comply with the criteria described below.
5.3.1  Dose Specifications
The daily prescription dose will be 1.8 Gy to be delivered to the periphery of the planning target volume (PTV).  The isodose line 
(generally 93-98%) chosen will encompass at least 95% of the PTV.  
The maximum point dose, minimum point dose, and mean dose to PTV will be reported.
The total dose will be 50.4 Gy (1.8G/Fx/day) prescribed to the periphery of the PTV.
5.3.2  External Beam Equipment
For Photons, megavoltage equipment is required with effective photon energies >6 MV.  Proton beam therapy (PBT) will also be 
allowed for this trial.
5.3.3  Treatment Planning Imaging and Localization Requirements
A volumetric treatment planning CT study will be required to define gross tumor volumes (GTV) and planning target volume 
(PTV).  For this study, the local regional nodes (whether clinically positive or negative) will be included in the clinical target 
volume (CTV).  Each patient will be positioned in an individualized immobilization device in the treatment position on a flat 
table.  Contiguous CT slices, 3-5 mm thickness of the regions, harboring gross tumor and 8-10 mm thickness of the remaining 
regions, are to be obtained starting from the level of the cricoid cartilage and extending inferiorly through the liver.  The GTV and 
PTV and normal organs will be outlined on all appropriate CT slices and displayed using beam’s eye view.  Normal tissues to be 
contoured include lungs, skin, heart, spinal cord, esophagus, and liver.  A measurement scale for the CT image shall be 
included.
For cervical primaries (defined as tumors above the carina), the bilateral supraclavicular nodes need to be included.  For mid-
esophageal primaries (at or below the carina), the paresophageal nodes need to be included—not the supraclavicular or 
celiac.  For distal/gastroesophageal primaries, the field should include the celiac nodes and left gastric nodes. 


Barium swallow during the planning CT is optional provided a diagnostic chest CT was done with contrast to delineate the 
outline of the esophagus.  
Optimal immobilization is critical for this protocol.  Alpha cradle or approved alternative immobilization system is 
required.  Patients may be placed on the supine or prone position.  In general, supine is recommended for proximal and distal 
primaries whereas prone is recommended for mid-esophageal.
5.3.4  Volume and ICRU Reference Point Definitions
The definition of volumes will be in accordance with the 1993 ICRU Report #50: Prescribing, Recording and Reporting Photon 
Beam Therapy.
Gross Tumor Volume (GTV) is defined as all known gross disease as defined by the planning CT and clinical 
information.  Gross tumor includes the primary (GTV-P) only.  Note:  ICRU Report #50 also defines a clinical target volume 
(CTV) that includes the area of subclinical involvement around the GTV.  For this protocol, we have chosen to define the CTV a 
minimum of 4 cm proximal and distal and 1 cm lateral beyond the GTV delineated by CT scan and /or endoscopy (endoscopy is 
preferable).  The final CTV may be larger since for cervical primaries, the supraclavicular nodes need to be included, and for 
distal primaries, the celiac nodes need to be included in the treatment fields.  CTV must be determined by the treating physician, 
and with CT based planning, must respect anatomic boundaries of potential microscopic disease spread.  
Planning Target Volume (PTV) will provide margin around the CTV to compensate for variability in treatment set up, breathing, 
or motion during treatment.  A margin around the CTV will define the PTV.  The PTV volume must include a minimum of 1 cm 
and a maximum of 2 cm around the CTV.  Therefore, the superior and inferior margins will be approximately 5 cm beyond the 
GTV, and the lateral margins will be approximately 2 cm beyond the GTV.  Once again, the final PTV may be larger since for 
cervical primaries, the supraclavicular nodes need to be included, and for distal primaries, the celiac nodes need to be included 
in the treatment fields.  If daily verification imaging is done, a 0.5cm expansion for the PTV is allowed.
5.3.5  3D Planning
For photon based radiation, both 3D conformal and Intensity Modulated Radiation Therapy (IMRT) techniques can be used.  For 
PBT, either passive scattering PBT or Intensity Modulated Proton Therapy (IMPT) can be used.  The techniques and modality 
utilized will be at the discretion of the treating physician.
Normal Tissue Volume and Tolerance.  The normal tissues in the table below are to be contoured in their entirety.
The following organs and doses are guidelines for the treatment plan (see Table 3: Normal Tissue Volume and 
Tolerance).  Physician/ Dosimetrist should make every effort not to exceed these tolerance levels.  All normal tissues assume 
treatment at 1.8 Gy/Fx (uncorrected).
Table 3: Normal Tissue Volume and Tolerance


It is expected that the dose to the lungs, heart, spinal cord, and liver will be the primary dose-limiting structures.  Every effort 
should be made to keep the total lung dose to a minimum.
When planning the beam arrangement to the PTV, the lungs, heart, spinal cord, and liver should be out of the field to the 
greatest extent possible.  The dose per fraction to the lungs, heart, and spinal cord should be maintained at 2 Gy or less per 
fraction to the greatest extent possible.  If tolerance dose to any of the normal organs is exceeded, alternate beam arrangement 
should be used.
5.3.6  Treatment Verification
At least twice weekly (at least 48 hours apart) verification films or images of the orthogonal views (anterior to 
posterior and lateral projection) must be reviewed by the treating physician.  If daily orthogonal films are taken, the 
PTV margin can be reduced to 0.5 cm expansion from the CTV.  The required accuracy of patient positioning and 
the use of multi-leaf collimator apertures suggest the daily use of on-line imaging may be desirable.
5.3.7  Therapy Interruptions
If interruption of therapy (up to 2 weeks) becomes necessary, radiation therapy should be completed to the prescribed 
doses.  Total number of fractions and elapsed days should be carefully reported.  
If the patient develops >Grade 3 RT-related toxicity, RT, and chemotherapy (docetaxel and 5-FU) should be 
withheld.  Treatment can resume once RT-related toxicity is <Grade 3 (e.g. Grade 1 or 2 or pre-therapy baseline).  
5.3.8 
Criteria for Toxicity
Toxicities related to radiation therapy include: fatigue, myleosuppression, skin erythema, subcutaneous fibrosis, esophagitis, 
carditis, myelits, acute radiation pneumonitis and late pulmonary fibrosis, and esophageal stricture.
Acute toxicity monitoring:  Acute (< 90 days from RT start) side effects of radiation therapy will be documented and graded 
according to the NCI-CTCAE version 4.0.  
Late toxicity monitoring:  Late (> 90 days since start or persisting beyond 90 days) post-treatment complications will be 
evaluated and graded according to the RTOG Late Effects Radiation Morbidity Criteria.
5.3.9  Dose Delays and Dose Modifications for Toxicity
Treatment with docetaxel, 5-FU, and radiation therapy may be delayed, up to 2 weeks (14 days), to allow for resolution of 
toxicity.  
Treatment must be delayed and/or modified if any of the following apply:
Table 4: Dose Delays and Modifications for Toxicity


5.4
Post-treatment evaluation:
Four to six weeks after chemoradiation patient will be brought back for restaging studies using contrast enhance CT of chest 
and PET-CT, as well as repeat EGD with biopsy to assess for clinical response to therapy.  Once patients are deemed eligible 
for surgical resection, surgery should begin no later than 8 to 10 weeks after completing chemoradiation.  
5.5  Surgery
Transhiatal or transthoracic approaches (left thoractomy or Ivor Lewis) will be left to the discretion of the surgeon.  
5.6.  Biomarker study
One of the secondary objectives is evaluation of feasibility of pretreatment and posttreatment/preoperative DNA 
methylation biomarkers in tumor and blood as predictor of pCR rate.  Patient will be consented for blood draw for 
assessing DNA methylation biomarkers on protocol LAB09-0307, an approved protocol that consents patients being 
treated with radiation for blood draws at various times before, during, and after treatment.  Tumor biomarkers will be 
assessed using tissue collected at the time of diagnosis either as fresh frozen or paraffin-embedded samples.  The 
protocol to allow for use of this tissue is LAB09-0856.  
6.0 Statistical Considerations
6.1  Preliminaries.  This is a single-arm phase IIB trial of chemo-radiation followed by surgery for patients with early stage 
grade T1b esophageal cancer. This trial is motivated by the idea that adding chemo-radiation to surgery in this patient subgroup 
will improve their clinical outcome. The primary endpoint will be pathologic CR (PCR).  Secondary endpoints will include T = 
disease-free survival (DFS) time, defined as the time to disease progression or death, pre-surgery toxicity (PreTox), defined as 
any NCI grade 4 non-hematologic toxicity observed during the 10-week period beginning at the start of chemo-radiation and 
ending at the time of surgery, and post-surgery mortality (PostDeath), defined as death due to any cause during the 30-day 
period following surgery. 
6.2. Outcomes and Stopping Rules. The design will include three early stopping rules: (a) A futility rule based on PCR that 
stops the trial if it is unlikely that an improvement in 
Prob(PCR), from the historical rate of .25 to a targeted rate of at least .45, will be achieved; (b) A safety rule based on PreTox 
that stops the trial if it is likely that a probability of this event higher than the historical probability of .30 will occur (c) A safety 
rule based on PostDeath that stops the trial if it is likely that a probability of this event higher than the historical probability of 
.026 will occur. A maximum of 30 patients will be treated with a follow up of 1 year after the last patient is accrued. An accrual 
rate of 6 patients per year will be assumed.


6.3. Futility Monitoring. The following futility monitoring rule, as described in Thall and Sung (31) will be used.  We assume 
that the historical PCR probability qPCR,0 ~ beta (50, 150), reflecting an historical rate of 25% based on approximately 200 
patients, and that for the corresponding probability using the experimental treatment modality in the trial, qPCR,E ~  beta(.25, 
.75), reflecting the same prior mean of 25% but with an effective sample size of 1 patient.  That is, the prior qPCR,E on is non-
informative. Since the binary PCR outcomes will be obtained based on tissue samples taken at surgery, PCR will be monitored 
continuously and the trial will be stopped  for futility if  Pr(qPCR,0 + .20 < qPCR,E | data) < .025. This translates into the 
following decision boundaries: The trial will be stopped for futility if [# patients with PCR]/[# patients evaluated] is less than or 
equal to 0/5, 1/10, 3/15, 4/20, or 6/25.
6.4. Safety Monitoring. Since neoadjuvant chemo-radiation is used as conventional treatment for esophageal cancer patients 
with more advanced disease but surgery alone is standard therapy for T1b stage esophageal cancer patients, the following 
adverse events (AEs) will be monitored to ensure a safe trial.  The method of Thall, Simon and Estey (32) will be used.  The 
historical rates of PreTox and PostDeath that will be used to construct monitoring rules are .30 for q1 = Prob(PreTox) and .026 
for q2 = Prob(PostDeath), where the latter is computed as the weighted average .02*.70 + .04*.30 = .026 to reflect the prior 
experience using chemo-radiation that the PostDeath rates are 2% in patients who do not experience PreTox and 4% in 
patients who do experience PreTox. Indexing the four possible elementary AE outcomes by 1 = (No PreTox, No PostDeath), 2 = 
(PreTox, No PostDeath), 3 = (No PreTox, PostDeath), 4 = (PreTox, PostDeath), and their respective probabilities by w1, w2, 
w3, w4, it follows that q1 = w2 + w4 and q2 = w3 + w4.  Indexing the experimental regimen (neoadjuvant chemo-radiation + 
surgery) by E and the historical standard experience by S, we assume a non-informative Dirichlet prior with parameters (.6818, 
.2922, .0182, .0078) for wE = (wE1, wE2, wE3, wE4) under E and corresponding informative Dirichlet standard historical prior 
with parameters (681.8, 292.2, 18.2, 7.8) for the corresponding historical probability vector wH.  The marginal AE probabilities 
are qE1 = wE2 + wE4  and qE2 = wE3 + wE4 for E and similarly qS1 = wS2 + wS4  and qS,2 = wS3 + wS4 for S. The two early 
stopping rules are as follows. The trial will be stopped early 
6.4.1 due to an excessively high PreTox rate if Prob(q1S < q1E | data) > .97, or
6.4.2  due to an excessively high PostDeath rate if Prob(q2S < q2E | data) > .95
These rules will be applied after each cohort of 5 patients has been treated and evaluated. The early stopping bounds 
determined by these probability criteria are as follows: Stop the trial due to an excessive PreTox rate if [# patients with 
PreTox]/[# patients scored] is greater than or equal to the upper bound 4/5, 7/10, 9/15, 11/20, 13/25.  Stop the trial due to an 
excessive PostDeath rate if [# patients with PostDeath]/[# patients scored] is greater than or equal to the upper bound 2/5, 2/10, 
3/15, 3/20, 3/25.
6.5 Simulation Study. Each case was simulated 1000 times, assuming an accrual rate of 6 patients per year (0.5 per month). 
The overall stopping probability under each scenario was computed as pSTOP = 1 – (1- pSTOP, T)*(1- pSTOP, TOX-DEATH) where pSTOP, T = 
stopping probability due to  the futility rule and pSTOP, TOX-DEATH = stopping probability due to  the two safety rules, assuming 
independence.  Note that the only desirable scenario among the six scenarios considered is that where the true event 
probabilities are Pr(T >2 yrs) = .92, Prob(PreTox) = .30 and Prob(PostDeath) = .026.
6.6  Data Analyses.  
The rates of pathologic CR, PreTox and Postdeath will be tabulated and their possible relationships to baseline covariates 
assessed by logistic regression (32).  Unadjusted progression free survival time will be estimated by the method of Kaplan and 
Meier (33) and its possible relationship to baseline covariates assessed by survival regression modeling (32).
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