FDG-PET Directed Treatment in Improving Response in Patients With Locally Advanced Stomach or Gastroesophageal Junction Cancer

Impact of Early FDG-PET Directed Intervention on Preoperative Therapy for Locally Advanced Gastric Cancer: A Random Assignment Phase II Study

This randomized phase II trial studies how well fludeoxyglucose F-18 (FDG)/positron emission tomography (PET) directed treatment improves response in patients with stomach or gastroesophageal junction cancer that has not spread past the stomach and is not responding to the usual treatment. PET scans are a different way to take pictures of cancer and can be used to look at how much energy (such as glucose) is being used by the cancer. Using PET scans early to monitor the success of treatment may allow doctors to measure response and change treatment accordingly.

Pre-registered patients receive standard pre-operative chemotherapy comprising epirubicin intravenously 50mg/m^2 (IV) on day 1; oxaliplatin 130 mg/m^2 IV or cisplatin 60 mg/m^2 IV on day 1; and capecitabine 625 mg/m^2 orally (PO) twice daily (BID) or fluorouracil 200 mg/m^2/day IV continuously on days 1-21; and undergo FDG-PET following course 1 (days 15-19). Patients defined as FDG-PET non-responders are registered and randomized to 1 of 2 treatment arms.

Primary objective

To assess and compare the overall survival (OS) of patients with locally advanced gastric cancer classified as FDG-PET non-responders after one cycle of pre-operative chemotherapy randomly assigned to receive either salvage chemotherapy before and after surgery or immediate surgery followed by fluorouracil sensitized radiotherapy.

Secondary objectives

1. To assess and compare progression-free survival (PFS) between the treatment arms (Arms A and B).
2. To assess and compare R0 resection rate between the treatment arms (Arms A and B).
3. To assess and compare pathologic complete response (pCR) rate between the treatment arms (Arms A and B).
4. To assess the adverse events (AE) profile and safety of each treatment arm (Arms A and B), including post-operative mortality rate, 30-day post-operative targeted adverse events (i.e., dehiscence, significant infection, and re-operation rate).
5. To examine the changes of FDG-PET SUV induced by pre-operative chemotherapy at different time points (from baseline to completion of one cycle of treatment before randomization, and 2 cycles of salvage treatment) in patients randomized to salvage treatment arm (Arm B).
6. To collect measurement of fatigue and overall perception of QOL at registration of the study (Alliance registration QOL assessment study).

Pre-Registration Eligibility Criteria

1. Documentation of Disease

   1.1 Histologically confirmed adenocarcinoma of the stomach or gastroesophageal junction (Siewert type II, III)

   1.2 Pre-treatment clinical stage of T3-4N any M0 or T any N positive M0 as determined by laparoscopy, CT scan (or PET/CT), or endoscopic ultrasound (histologic confirmation of lymph involvement is not required). Therefore, patients can have measurable or non-measurable disease.

   1.3 Patients with T1-2N0M0 tumors or patients with metastatic disease are NOT eligible.

2. Patients must be eligible for curative intent surgical resection.

3. FDG Avid malignancy - Patients must have an FDG avid tumor(s). FDG avid tumors are defined as a primary tumor with an increased uptake in the region of the tumor that has an SUV of > 5.0 or a tumor:liver SUV ratio of > 1.5.

4. No prior history of congestive heart failure - NYHA class I to IV or known DPD deficiency

5. No current grade 2, 3, or 4 of neuropathy.

6. No known hypersensitivity to epirubicin, oxaliplatin and cisplatin, capecitabine and 5-flurouracil, docetaxel or irinotecan.

7. Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects.

   7.1 Therefore, for women of childbearing potential only, a negative serum pregnancy test pregnancy test done ≤ 7 days prior to pre-registration is required.

   7.2 A female of childbearing potential is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months).

8. Age ≥ 18 years

9. ECOG Performance Status 0 or 1

10. Required Initial Laboratory Values:

    • Absolute Neutrophil Count (ANC) ≥ 1,500/mm^3
    • Platelet Count ≥ 100,000/mm^3
    • Creatinine ≤ 1.5 x upper limit of normal (ULN)
    • Total Bilirubin ≤ 1.5 x ULN, except in patients with Gilbert's disease
    • AST and ALT ≤ 2.5 x ULN
    • Alkaline Phosphatase ≤ 2.5 x ULN

Registration Eligibility Criteria to Treatment Arms A or B

1. Patient must continue to be eligible for curative intent surgical resection.

2. Disease Progression: FDG avid malignancy that is classified as an FDG PET non- responder. PET non-responders are defined as having < 35% reduction in the FDG uptake of the primary tumor when compared to baseline.

3. Concomitant Medications -

   3.1 Chronic concomitant treatment with strong inhibitors of CYP3A4 is not allowed on this trial. Patients on strong CYP3A4 inhibitors must discontinue the drug 14 days prior to the start of study treatment.

   3.2 Chronic concomitant treatment with strong CYP3A4 inducers is not allowed. Patients must discontinue the drug 14 days prior to the start of study treatment.

4. Patient must have received only one cycle of the following regimens during the pre-registration time period and no other therapy for gastric or gastroesophageal junction cancer:

   • Epirubicin, Oxaliplatin, and Capecitabine
   • Epirubicin, Oxaliplatin, and Fluorouracil
   • Epirubicin, Cisplatin, and Capecitabine
   • Epirubicin, Cisplatin, and Fluorouracil

5. Toxicity recovery should include the following:

   • Grade ≤ 2 neuropathy
   • Grade ≤ 2 diarrhea
   • Grade ≤ 2 mucositis

6. Pre-registration chemotherapy given within 42 days of treatment (treatment meaning surgery if Arm A, chemotherapy if Arm B)