PET Scan Imaging in Assessing Response in Patients With Esophageal Cancer Receiving Combination Chemotherapy

Randomized Phase II Trial of PET Scan-Directed Combined Modality Therapy in Esophageal Cancer

RATIONALE: PET scans done during chemotherapy may help doctors assess a patient's response to treatment and help plan the best treatment.

PURPOSE: This randomized phase II trial is studying PET scan imaging in assessing response in patients with esophageal cancer receiving combination chemotherapy.

Study Overview

• Status: Completed
• Conditions: Esophageal Cancer; Adenocarcinoma of the Gastroesophageal Junction
• Intervention / Treatment: Drug: Carboplatin; Radiation: Radiation Therapy; Drug: Paclitaxel; Procedure: Computed Tomography; Procedure: Positron Emission Tomography; Drug: Fluorouracil; Drug: Oxaliplatin; Drug: Leucovorin Calcium

Detailed Description

OBJECTIVES:

Primary

• To induce a complete pathologic response (pCR) rate of 20% in positron emission tomography (PET) scan non-responders treated with either induction FOLFOX or carboplatin/paclitaxel, who then crossover to the other regimen during radiotherapy.

Secondary

• To compare PET/CT response between induction treatment arms.
• To compare pCR between induction treatment arms among PET/CT scan responders.
• To directly compare pCR between induction treatment arms among non-responders if both treatment regimens are found to be efficacious.
• To determine 8-month progression-free survival (PFS) in PET/CT scan responders, and in non-responders treated with alternative crossover chemoradiotherapy.
• Estimate the PFS and overall survival (OS) curves, overall and among PET responders and PET/CT non-responders by induction treatment.
• To determine the rate of postoperative anastomotic leak after neoadjuvant chemotherapy followed by chemoradiation.
• To evaluate immunohistochemistry and RT-PCR of ERCC1, and genetic polymorphisms of ERCC1, XPD, and XRCC1.
• To evaluate status and levels of methylation of nine candidate biomarker genes as well as expression levels of selected specific microRNAs, which will be correlated with chemoradiation response.
• To compare the quality of life (QOL) of responders and nonresponders (as determined by PET/CT scanning) to presurgical treatment for esophageal cancer, in terms of global QOL, physical symptoms, physical functioning, and emotional well-being.
• To examine the association between OS and QOL in esophageal cancer patients treated with chemotherapy, chemoradiation therapy, and surgery.

OUTLINE: This is a multicenter study. Patients are stratified according to T-stage (T1-2 vs T3-4) and nodal status (N0 vs N+). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive modified FOLFOX-6 therapy comprising oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours on day 1 and fluorouracil IV continuously on days 1-5. Treatment repeats every 14 days for 3 courses. Patients then undergo PET/CT scan. Patients with responsive disease (tumor metabolic activity decreased by ≥ 35%) receive 3 additional courses of FOLFOX-6 therapy and undergo concurrent radiotherapy (RT) (3D-conformal or intensity-modulated) once daily, 5 days a week, for approximately 6 weeks. Patients without responsive disease (tumor metabolic activity did not decrease by 35%) cross over to arm II during RT.
• Arm II: Patients receive carboplatin IV over 30 minutes and paclitaxel IV over 1 hour on days 1 and 8. Treatment repeats every 21 days for 2 courses. Patients then undergo PET/CT scan. Patients with responsive disease (tumor metabolic activity decreases ≥ 35%) continue to receive carboplatin IV over 30 minutes and paclitaxel IV over 1 hour once weekly for 5 weeks and undergo RT (3D-conformal or intensity-modulated) once a day, 5 days a week, for approximately 6 weeks. Patients without responsive disease (metabolic activity did not decrease by 35%) cross over to arm I during RT.

Within 4-10 weeks after completion of neoadjuvant chemoradiotherapy, patients undergo surgery at the discretion of the treating team.

Patients may undergo blood sample collection at baseline and periodically during study for correlative studies. Patients may also complete quality-of-life questionnaires at baseline and periodically during study.

After completion of study therapy, patients are followed up periodically for 5 years.

• Study Type: Interventional
• Enrollment (Actual): 257
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Mountain View, California, United States, 94040
      • Camino Medical Group - Treatment Center
    • Palo Alto, California, United States, 94301
      • Palo Alto Medical Foundation
    • San Francisco, California, United States, 94115
      • UCSF Helen Diller Family Comprehensive Cancer Center
  • Connecticut
    • New Haven, Connecticut, United States, 06520-8028
      • Yale Cancer Center
  • Delaware
    • Lewes, Delaware, United States, 19958
      • Tunnell Cancer Center at Beebe Medical Center
    • Newark, Delaware, United States, 19713
      • CCOP - Christiana Care Health Services
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Lombardi Comprehensive Cancer Center at Georgetown University Medical Center
  • Hawaii
    • 'Aiea, Hawaii, United States, 96701
      • Kapiolani Medical Center at Pali Momi
    • 'Aiea, Hawaii, United States, 96701
      • Oncare Hawaii, Incorporated - Pali Momi
    • Honolulu, Hawaii, United States, 96817
      • Kuakini Medical Center
    • Honolulu, Hawaii, United States, 96826
      • Kapiolani Medical Center for Women and Children
    • Honolulu, Hawaii, United States, 96813
      • OnCare Hawaii, Incorporated - Lusitana
    • Honolulu, Hawaii, United States, 96813
      • Queen's Cancer Institute at Queen's Medical Center
    • Honolulu, Hawaii, United States, 96813
      • Straub Clinic and Hospital, Incorporated
    • Honolulu, Hawaii, United States, 96817-3169
      • OnCare Hawaii, Incorporated - Kuakini
    • Kailua, Hawaii, United States, 96734
      • Castle Medical Center
    • Lihue, Hawaii, United States, 96766
      • Kauai Medical Clinic
  • Illinois
    • Chicago, Illinois, United States, 60637-1470
      • University of Chicago Cancer Research Center
    • Chicago, Illinois, United States, 60611-3013
      • Robert H. Lurie Comprehensive Cancer Center at Northwestern University
    • Chicago, Illinois, United States, 60612-3785
      • John H. Stroger, Jr. Hospital of Cook County
    • Peoria, Illinois, United States, 61615
      • CCOP - Illinois Oncology Research Association
    • Peoria, Illinois, United States, 61615
      • Oncology Hematology Associates of Central Illinois, PC - Peoria
    • Urbana, Illinois, United States, 61801
      • CCOP - Carle Cancer Center
  • Iowa
    • Ames, Iowa, United States, 50010
      • McFarland Clinic, PC
    • Sioux City, Iowa, United States, 51101
      • Siouxland Hematology-Oncology Associates, LLP
  • Maryland
    • Elkton, Maryland, United States, 21921
      • Union Hospital of Cecil County
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Michigan
    • Ann Arbor, Michigan, United States, 48106-0995
      • Saint Joseph Mercy Cancer Center
  • Minnesota
    • Saint Paul, Minnesota, United States, 55102
      • United Hospital
    • Saint Paul, Minnesota, United States, 55101
      • Regions Hospital Cancer Care Center
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi Cancer Clinic
    • Pascagoula, Mississippi, United States, 39581
      • Regional Cancer Center at Singing River Hospital
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis
  • Montana
    • Billings, Montana, United States, 59107-7000
      • Billings Clinic - Downtown
  • Nebraska
    • Omaha, Nebraska, United States, 68114
      • Methodist Estabrook Cancer Center
  • New Jersey
    • New Brunswick, New Jersey, United States, 08903
      • Cancer Institute of New Jersey at UMDNJ - Robert Wood Johnson Medical School
    • Voorhees, New Jersey, United States, 08043
      • Cancer Institute of New Jersey at Cooper - Voorhees
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan-Kettering Cancer Center
    • New York, New York, United States, 10016
      • NYU Cancer Institute at New York University Medical Center
    • New York, New York, United States, 10029
      • Mount Sinai Medical Center
    • Syracuse, New York, United States, 13210
      • SUNY Upstate Medical University Hospital
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599-7295
      • Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill
    • Charlotte, North Carolina, United States, 28232-2861
      • Blumenthal Cancer Center at Carolinas Medical Center
    • Charlotte, North Carolina, United States, 28233-3549
      • Presbyterian Cancer Center at Presbyterian Hospital
    • Statesville, North Carolina, United States, 28677
      • Iredell Memorial Hospital
  • North Dakota
    • Fargo, North Dakota, United States, 58122
      • CCOP - MeritCare Hospital
    • Fargo, North Dakota, United States, 58102
      • MeritCare Broadway
  • Ohio
    • Columbus, Ohio, United States, 43210-1240
      • Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer Center
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Oklahoma University Cancer Institute
  • Pennsylvania
    • Monroeville, Pennsylvania, United States, 15146
      • Forbes Regional Hospital
    • Natrona Heights, Pennsylvania, United States, 15065
      • Alle-Kiski Medical Center
    • Philadelphia, Pennsylvania, United States, 19107-5541
      • Kimmel Cancer Center at Thomas Jefferson University - Philadelphia
    • Philadelphia, Pennsylvania, United States, 19140
      • Fox Chase Cancer Center CCOP Research Base
    • Pittsburgh, Pennsylvania, United States, 15232
      • UPMC Cancer Centers
    • Pittsburgh, Pennsylvania, United States, 15212
      • Allegheny Cancer Center at Allegheny General Hospital
  • South Carolina
    • Spartanburg, South Carolina, United States, 29303
      • Gibbs Regional Cancer Center at Spartanburg Regional Medical Center
  • Vermont
    • Berlin, Vermont, United States, 05602
      • Mountainview Medical
    • Burlington, Vermont, United States, 05401
      • Fletcher Allen Health Care - University Health Center Campus
  • Wisconsin
    • Eau Claire, Wisconsin, United States, 54701
      • Center for Cancer Treatment & Prevention at Sacred Heart Hospital
    • Marshfield, Wisconsin, United States, 54449
      • Saint Joseph's Hospital
    • Marshfield, Wisconsin, United States, 54449
      • Marshfield Clinic - Marshfield Center
    • Minocqua, Wisconsin, United States, 54548
      • Marshfield Clinic - Lakeland Center
    • Rhinelander, Wisconsin, United States, 54501
      • Ministry Medical Group at Saint Mary's Hospital
    • Rice Lake, Wisconsin, United States, 54868
      • Marshfield Clinic - Indianhead Center
    • Stevens Point, Wisconsin, United States, 54481
      • Marshfield Clinic at Saint Michael's Hospital
    • Stevens Point, Wisconsin, United States, 54481
      • Saint Michael's Hospital Cancer Center
    • Weston, Wisconsin, United States, 54476
      • Diagnostic and Treatment Center
    • Weston, Wisconsin, United States, 54476
      • Marshfield Clinic - Weston Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

• Surgically resectable, histologically confirmed esophageal adenocarcinoma, including Siewert gastroesophageal (GE) junction adenocarcinomas types 1 and 2
• T1N1-3M0 or T2-4NanyM0 as determined by endoscopic ultrasound (EUS) and PET/CT (histologic confirmation of lymph involvement is not required); all disease (tumor and nodes) must be both surgically resectable and capable of containment in a radiotherapy field; no T4 tumor with clear evidence of invasion of the vertebral column, heart, great vessels, or tracheobronchial tree
• All patients must have locoregional staging determined by endoscopic ultrasound (EUS) if technically feasible; endoscopy reports or subsequent gastrointestinal (GI) clinic note should clearly state both the T and N stage
• No evidence of distant metastases (as determined by EUS or PET/CT)
• Patients with cervical, supraclavicular, or other nodal disease that is either not included in the radiation field or is not able to be resected at the time of esophagectomy are not eligible
• Patient must have pre-resection tissue available for central pathology review, in case that the patient has a pCR at the time of surgical resection to confirm diagnosis
• Patients must have an fludeoxyglucose F 18 (FDG)-avid tumor with a maximum standard uptake value (SUVmax) of >= 5.0 on baseline PET/CT scan of primary tumor; baseline PET/CT scan should be performed; if it is necessary to repeat baseline PET/CT scan, reimbursement information is available
• No prior malignancy within 5 years of registration, with the exception of basal or squamous cell skin cancers, or in situ bladder or cervical cancer; patients with prior malignancy treated with surgery only and disease free for more than 5 years are eligible; however, no prior thoracic radiation therapy (RT) or abdominal RT or chemotherapy allowed
• No known contraindication to the use of fluorouracil, taxanes, or platinum compounds
• No history of severe hypersensitivity reaction to Cremophor EL
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Patient must be non-pregnant and non-nursing; women of child bearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 72 hours prior to randomization; women of child-bearing potential include any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea >= 12 consecutive months; or women on hormone replacement therapy [HRT] with documented serum follicle stimulating hormone [FSH] level > 35mIU/mL); even women who are using oral, implanted or injectable contraceptive hormones or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy or practicing abstinence or where partner is sterile (e.g., vasectomy), should be considered to be of child bearing potential
• Absolute neutrophil count (ANC) >= 1,500/μL
• Platelet count >= 100,000/μL
• Bilirubin =< 1.5 times upper limit of normal (ULN)
• Calculated creatinine clearance >= 60 mL/min
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 times ULN

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I (FOLFOX regimen); Patients receive modified FOLFOX-6 therapy comprising oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours on day 1 and fluorouracil IV continuously on days 1-5. Treatment repeats every 14 days for 3 courses. Patients then undergo PET/CT scan. Patients with responsive disease (tumor metabolic activity decreased by >= 35%) receive 3 additional courses of FOLFOX-6 therapy and undergo concurrent RT (3D-conformal or intensity-modulated) once daily, 5 days a week, for approximately 6 weeks. Patients without responsive disease (tumor metabolic activity did not decrease by 35%) cross over to Arm II during RT.	Drug: Carboplatin; Given IV; Radiation: Radiation Therapy; Undergo RT; Drug: Paclitaxel; Given IV; Procedure: Computed Tomography; Undergo PET/CT scan; Procedure: Positron Emission Tomography; Undergo PET/CT scan; Drug: Fluorouracil; Given IV; Drug: Oxaliplatin; Given IV; Drug: Leucovorin Calcium; Given IV
Experimental: Arm II (carboplatin + paclitaxel + radiation); Patients receive carboplatin IV over 30 minutes and paclitaxel IV over 1 hour on days 1 and 8. Treatment repeats every 21 days for 2 courses. Patients then undergo PET/CT scan. Patients with responsive disease (tumor metabolic activity decreases >= 35%) continue to receive carboplatin IV over 30 minutes and paclitaxel IV over 1 hour once weekly for 5 weeks and undergo RT (3D-conformal or intensity-modulated) once a day, 5 days a week, for approximately 6 weeks. Patients without responsive disease (metabolic activity did not decrease by 35%) cross over to Arm I during RT	Drug: Carboplatin; Given IV; Radiation: Radiation Therapy; Undergo RT; Drug: Paclitaxel; Given IV

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete Pathological Response (pCR) of PET/CT Non-responders	The primary endpoint of this study is the percentage of PET/CT non-responders within each induction treatment group reporting a pCR. A pCR is defined as having no tumor found on pathology review at surgery in all resected lymph nodes and tissue. All tissues sampled must have NO viable tumor.	Up to 5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PET/CT Response Between Treatment Arms	A PET/CT response to induction therapy is defined as metabolic activity of the tumor decreasing by >=35%, as measured by maximum standardized uptake value (SUVmax).	Up to 5 years
pCR Compared Between Induction Treatment Arms Among PET/CT Responders	A PET/CT response to induction therapy is defined as metabolic activity of the tumor decreasing by >=35%, as> >> >> >> measured by maximum standardized uptake value (SUVmax). A pCR is defined as having no tumor found on pathology review at surgery in all resected lymph nodes and tissue. All tissues sampled must have NO viable tumor.	Up to 5 years
pCR Compared Among Non-responders Between Induction Treatment Arms if Treatment Regimens Are Found to be Efficacious	A Complete Pathological Response (pCR) is defined as having no tumor found on pathology review at surgery in all resected lymph nodes and tissue. All tissues sampled must have NO viable tumor. A non-responder was defined as having a PET/CT SUV (standard uptake value) decrease of less than 35% after induction.> >>> > >>> Among the patients who completed induction therapy and did not respond, the percentage of patients reporting a pCR in each arm were compared.	Up to 5 years
Progression Free Survival (PFS) Among PET/CT Non-responders Within Each Induction Treatment Group	A non-responder was defined as having a PET/CT SUV (standard uptake value) decrease of less than 35% after induction. Among the patients who completed induction therapy and did not respond, the progression free survival in each arm were compared. PFS will be measured from study entry until documented progression or death from any cause. PFS will be estimated using the method of Kaplan and Meier.	Up to 5 years

Collaborators and Investigators

• Sponsor: Alliance for Clinical Trials in Oncology
• Collaborators: National Cancer Institute (NCI)

Publications and helpful links

General Publications

• Goodman KA, Ou FS, Hall NC, Bekaii-Saab T, Fruth B, Twohy E, Meyers MO, Boffa DJ, Mitchell K, Frankel WL, Niedzwiecki D, Noonan A, Janjigian YY, Thurmes PJ, Venook AP, Meyerhardt JA, O'Reilly EM, Ilson DH. Randomized Phase II Study of PET Response-Adapted Combined Modality Therapy for Esophageal Cancer: Mature Results of the CALGB 80803 (Alliance) Trial. J Clin Oncol. 2021 Sep 1;39(25):2803-2815. doi: 10.1200/JCO.20.03611. Epub 2021 Jun 2.
• Ku GY, Bains MS, Park DJ, Janjigian YY, Rusch VW, Rizk NP, Yoon SS, Millang B, Capanu M, Goodman KA, Ilson DH. Phase II study of bevacizumab and preoperative chemoradiation for esophageal adenocarcinoma. J Gastrointest Oncol. 2016 Dec;7(6):828-837. doi: 10.21037/jgo.2016.08.09.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2011
• Primary Completion (Actual): November 1, 2015
• Study Completion (Actual): April 1, 2023

Study Registration Dates

• First Submitted: April 7, 2011
• First Submitted That Met QC Criteria: April 7, 2011
• First Posted (Estimate): April 11, 2011

Study Record Updates

• Last Update Posted (Actual): April 13, 2023
• Last Update Submitted That Met QC Criteria: April 10, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: adenocarcinoma of the esophagus; stage IIB esophageal cancer; adenocarcinoma of the gastroesophageal junction; stage IIIA esophageal cancer; stage IIIB esophageal cancer; stage IIIC esophageal cancer; stage IIA esophageal cancer; stage IB esophageal cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Head and Neck Neoplasms; Esophageal Diseases; Adenocarcinoma; Esophageal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Protective Agents; Antineoplastic Agents, Phytogenic; Micronutrients; Vitamins; Calcium-Regulating Hormones and Agents; Antidotes; Vitamin B Complex; Carboplatin; Paclitaxel; Fluorouracil; Oxaliplatin; Leucovorin; Calcium; Levoleucovorin
• Other Study ID Numbers: CALGB-80803; U10CA180821 (U.S. NIH Grant/Contract); CDR0000698428 (Registry Identifier: NCI Physician Data Query); NCI-2011-02642 (Registry Identifier: NCI Clinical Trial Reporting Program)