ABSTRACT

1
Randomized Phase II Trial of Extended versus
Standard Neoadjvant Therapy for Esophageal
Cancer NCCTG (Alliance) Trial N0849 SR
Alberts1, GS Soori2, Q Shi1,3, DA Wigle1, RP
Sticca4, RC Miller1, JL Leenstra5, PJ Peller1,
T-T Wu1, HH Yoon1, TF Drevyanko6, SJ Ko7, BI
Mattar8, DA Nikcevich9, RJ Behrens10, MF
Khalil11, GP Kim7 1Mayo Clinic, Rochester, MN
2Missouri Valley Cancer Consortium, Omaha, NE
3Alliance Statistics and Data Center, Rochester,
MN 4Meritcare Hospital CCOP, Fargo, ND 5St.
Vincent Regional Cancer Center CCOP, Green Bay,
WI 6Iowa Oncology Research Association CCOP, Des
Moines, IA 7Mayo Clinic, Jacksonville, FL
8Wichita Community Clinical Oncology Program,
Wichita, KS 9Essentia Health Duluth Clinic CCOP,
Duluth, MN 10Iowa Oncology Research Association,
Des Moines, IA 11Geisinger Medical Center,
Danville, PA

• ABSTRACT

• METHODS

• KEY FINDINGS

• RESULTS

Background  Patients (pts) with locally advanced
esophageal or gastroesophageal junction (GEJ)
adenocarcinoma commonly receive neoadjuvant
chemoradiotherapy (chemo-RT). Despite this
approach the rate of recurrence remains high.
Given the difficulties of postoperative therapy,
the efficacy of extended neoadjuvant therapy was
assessed.  Methods  Eligibility criteria
included T3-4,N0 Tany,N() disease amenable to
radiation and surgery. Pts were randomized to
either arm A (docetaxel 60 mg/m2 day 1 ,
oxaliplatin Oxal 85 mg/m2 day 1, and
capecitabine 1250 mg/m2/day days 1-14 x 2 cycles
DOC followed by 5-FU 180 mg/m2/day continuous
IV through radiation Oxal 85 mg/m2 days 1,15,29
50.4 Gy radiation (chemo-RT)) or arm B
(chemo-RT alone). Randomization was stratified by
ECOG PS (0/1 vs 2) and stage (II vs III/IVA).
Primary endpoint was pathologic complete response
(PCR) rate, defined as no gross or microscopic
tumor identified in the surgical specimen. 
Interim analysis assessed efficacy and futility
of the experimental intervention. Wilcoxon rank
sum and Fishers exact tests were used to compare
clinical/pathologic factors between
arms.  Results  Baseline and stratification
factors were well balanced between arms. Of 42
pts included in the interim analysis (86 male
age median 63, range 38-88, 100 PS 0/1 71
stage III 55 esophagus, 40 GEJ 36 measurable
disease), 4 and 1 pts in arms A and B,
respectively, did not have surgery due to death
(A, 2), progressive disease (A, 1), alternative
treatment (A, 1) or adverse event (B, 1). Among
21 arm A pts, 21, 20, and 19 pts started
1st cycle of DOC, 2nd cycle of DOC and chemo-RT,
respectively. All arm B pts received chemo-RT.
33 (7/21) of arm A and 48 (10/21) of arm B pts
achieved PCR (p0.53). Among pts undergoing
surgery, 94 (16/17) and 100 (20/20) of arm A
and B pts had complete resection (p0.46). 38
and 29 of arm A and B pts experienced at least
one grade 4 adverse event at least possibly
related to treatment (p0.74).  Conclusions  Ext
ended neoadjuvant therapy in pts with locally
advanced esophageal or GEJ adenocarcinoma failed
to improve the PCR rate.  Follow-up in regard to
survival and rate of recurrence is ongoing.
Schema

• Despite combined modality therapy the rate of
  recurrent esophageal cancer remains high
• Extended neoadjuvant therapy has demonstrated
  improved responses in other tumor types
• Extended neoadjuvant therapy in this trial was
  possible without significant added toxicity
• A higher than expected PCR was seen with the
  control arm
• Despite the addition of two cycles of DOC prior
  to combined modality therapy, no improvement was
  noted in the pathologic complete response rate
• Further follow-up is required to determine if
  extended neoadjuvant therapy alters OS or DFS

Figure 1 CONSORT Diagram
Table 1 Patient Characteristics
Randomization portion
DOC ? 5FU/Oxaliplatin/RT
Early toxicity assessment portion
R
DOC ? 5FU/Oxaliplatin/RT
5FU/Oxaliplatin/RT
Docetaxel 60 mg/m2 day 1, Oxaliplatin 85
mg/m2 day 1, and Capecitabine 1250 mg/m2/day days
1-14 x 2 cycles DOC 5-FU 180 mg/m2/day
continuous IV through radiation Oxal 85
mg/m2 days 1,15,29 50.4 Gy radiation (chemo-RT)

• Patient Eligibility Criteria
• Inclusion Age 18, histological confirmation
  of adenocarcinoma of the esophagus, EGJ, or
  gastric cardia T3-4N0 to TanyN disease amenable
  to radiation and surgery ECOG PS 0-2
• Exclusion evidence of distant metastases
  T1-2N0M0 disease co-morbid systemic illnesses
  immunocompromised patients uncontrolled
  intercurrence illness or diabetes receiving
  current treatment or prior treatment prior
  radiation to gt 30 of the marrow cavity
• Patient Evaluation
• Hematology was assessed prior to any treatment,
  weekly during pre-operation, before and after
  surgery
• Biochemistry was assessed prior to any
  treatment, chemo-RT, before and after surgery
• FDG PET/CT imaging prior to registration,
  chemo-RT, and surgery, CT scans every 3 months
  thereafter for two years
• Event monitoring every 3 months until
  PD/recurrence, then every 6 months up to5 years
• Statistical Design and Analysis
• Primary endpoint Pathologic complete response
  defined as no gross or microscopic tumor
  identified in the surgical specimen.
• Study design Group sequential design with a
  single interim analysis evaluating efficacy
  (Lan-DeMets OBrien-Fleming a spending function)
  and futility (Rho family, Rho2, ß spending
  function)
• H0 PCR ratecontril PCR rateexp 25
• HA PCR ratecontril lt PCR rateexp 45
• Total sample size 82 in randomized portion
• One-sided type I error rate 15 power 80
• Interim decision rules (1st 42 patients)
  Ineffective, if z lt -0.262 Effective, if z gt
  1.703 otherwise continue the accrual
• Analysis methods Wilcoxon rank sum and Fishers
  exact tests

• CONCLUSION

Table 2 Pathologic Complete Responses
Table 3 Adverse Events
Combined modality therapy with chemotherapy and
radiation, prior to surgery, remains the standard
of therapy for patients with adenocarcinoma of
the esophagus and GEJ

• GOALS

• Primary
• To compare the pathologic complete response (PCR)
  rate between patients receiving standard
  neoadjvant /- DOC
• Secondary
• To assess and compare the adverse event (AE)
  profile
• To assess and compare the overall survival (OS)
  and disease-free survival (DFS)
• To assess and compare the clinical tumor response
  rate measured before surgery
• To evaluate the profiles of pharmacogenetic and
  proteomic biomarkers and FDG PET/CT measures

• REFERENCES

• Donohue JM, Nichols FC, Li Z, et al. Complete
  pathologic response after neoadjuvant
  chemoradiotherapy for esophageal cancer is
  associated with enhanced survival. Ann Thorac
  Surg 87392-9, 2009.
• Evans D, Miner T, Akerman P, et al. A phase I
  study of docetaxel, oxaliplatin, and capecitabine
  in patients with metastatic gastroesophageal
  cancer. Am J Clin Oncol 30346-9, 2007.

• Overall status Study was activated on
  01/22/2010 and closed to accrual on 12/21/2012.
• Early toxicity assessment The AE data on 6
  patients in the early safety analysis cohort were
  available and analyzed in early December 2010. No
  grade 5 adverse events have been reported.
• Interim analysis results The z-score (test
  statistics) comparing PCR rates between two arms
  was -0.953 (lt -0.262, upper futility boundary of
  rejecting HA). Based on interim efficacy decision
  rules, we will terminate the accrual and conclude
  that the experimental regimen is not superior to
  the control regimen in this population.
• AE profile during randomized portion As of
  4/15/2013, 56 randomized patients (28 arm A, 28
  arm B) are evaluable for adverse events. The most
  common grade 4 AEs are
• DOC/Chemo-RT Neutrophil count decreased
  (21.4), lymphocyte count decreased (10.7),
  respiratory failure (10.7), and sepsis (10.7)
• Chemo-RT dyspnea (10.7), lymphocyte count
  decreased (14.3), and respiratory failure
  (14.3).

This study was conducted as a collaborative trial
of the North Central Cancer Treatment Group, Mayo
Clinic and the Alliance and was supported in part
by Public Health Service grants CA-25224,
CA-37404, CA-35431, CA-35269, CA-35101, CA-35448,
CA-60276, CA-35113, CA-35267, CA-35090, CA-35415,
CA-35119, and CA-63848 from the National Cancer
Institute, Department of Health and Human
Services. The content is solely the
responsibility of the authors and does not
necessarily represent the views of the National
Cancer Institute or the National Institute of
Health.