Induction Chemotherapy, FOLFIRINOX Followed With Concurrent Capecitabine and Radiation Therapy in Inoperable Locally Advanced Cancer of the Pancreas

This prospective cohort, phase II, trial is studying induction chemotherapy combination, FOLFIRINOX regimen, consisted of oxaliplatin, irinotecan, leucovorin and fluorouracil (5-FU), for 4 cycles, followed by consolidation concurrent radiotherapy with capecitabine in non-progressed cases, in treating patients with locally advanced cancer pancreas.

Design \& Methodology:

1. Nature of the study:

   It is ( prospective cohort study).
2. Study subjects:

   \*Target Population: Patients, fulfilling the inclusion criteria for the research, will be selected from Assiut clinical oncology department in Assiut University Hospitals.
   * Sample size:

     20 patients.
   * Characteristics of subjects:

     * Inclusion criteria:

   Disease characteristics:
   * Histological and radiological confirmation of locally advanced cancer pancreas
   * Inoperable disease
   * Disease must be able to be encompassed within a radical radiotherapy treatment volume
   * Not metastatic

   Patient characteristics:
   * ECOG performance status 0 or 1
   * Life expectancy \> 3 months.
   * Glomerular filtration rate ≥ 60 mL/min.
   * WBC \> 3,000/mm³.
   * Absolute neutrophil count \> 1,500/mm³.
   * Hemoglobin \> 10.0 g/dL.
   * Platelet count \> 100,000/mm³.
   * Alkaline phosphatase ≤ 1.5 times upper limit of normal (ULN)
   * Gamma-glutamyl-transferase \< 1.5 times ULN.
   * Transaminases ≤ 1.5 times ULN.
   * Bilirubin ≤ 1.5 times ULN.
   * No medically unstable conditions (e.g., unstable diabetes, uncontrolled arterial hypertension, infection, hypercalcemia, or ischemic heart disease)
   * Not pregnant or nursing.
   * No other previous or current malignant disease likely to interfere with protocol treatment or comparisons
   * No prior chemotherapy or radiotherapy.
3. Patients \& Methods:

   Patients are randomized to one treatment arm. Induction 4 times chemotherapy, FOLFIRINOX regimen, consisted of Oxaliplatin at a dose of 85 mg/m2 on day 1 only, administered as a 2-hour intravenous infusion, with the addition, after 30 minutes, of Irinotecan at a dose of 180 mg/m2 on day 1 only given as a 90-minute intravenous infusion. immediately will be followed by Leucovorin at a dose of 200 mg/m2, given as a 2- hour intravenous infusion, day 1 and day 2 This treatment will be followed by fluorouracil (5-FU) dosed at 400 mg/m2, administered as an intravenous bolus on day 1 and day 2, followed by a continuous intravenous infusion of 600 /m2 over a 20- hours period on day 1 and day 2. Treatment will be administered every 2 weeks. G-CSF will be administrated according to the need.

   In non-progressed cases, induction chemotherapy will be followed by consolidation radiotherapy concurrent with capecitabine 625 mg/m2 BID.

   Radiotherapy :

   A fractionated dose of 50.4Gy /28 fraction/15 MeV photon energy generated by Dual-energetic Linear Accelerator.
   * Gross Target Volume (GTV): visible tumor and lymph nodes.
   * Clinical Target Volume (CTV): \[tumor/ affected lymph node + 1-2 cm\] + regional lymphatics Lymphatics :corpus: upper and lower pancreaticoduodenal, superior and inferior pancreatic, celiac Head: corpus lymphatics + porta hepatis lymphatics Tail: corpus lymphatics (except pancreaticoduodenal LN) + splenic hilum LN
   * PTV: CTV + 1-1.5 cm

     * All patients will undergo a complete classical evaluation at the time of presentation which will be enrolled in a separate sheet for each patient. This will include a detailed history with estimation of the age of onset, the duration of the disease,.
     * Detailed physical examination will be carried out Treatment evaluation . Laboratory examination include
     * complete blood count (CBC),
     * liver function test (LFT)
     * Renal function test (RFT),
     * Serum electrolytes at presentation and before each cycle of chemotherapy.

   Radiographic examination include
   * Abdominal Multi Detector Computed Tomography (MDCT Abdomen )
   * Chest X-ray Before starting treatment, 2 weeks after ending phase 1 of treatment then 4 weeks after ending phase 2 of treatment then every 3 months for 18 months.

     ● Bone scan will be done in those complaining from bone pain; elevated serum alkaline phosphatase or transaminase level
   * Quality of life is assessed at baseline, monthly for 6 months, and then at each follow-up visit.

   After completion of study treatment, patients are followed periodically. Response Assessment : will be carried out, using (RECIST) Response Evaluation Criteria In Solid Tumors, Version 1.1 Chemotherapy Toxicity Assessment: will be carried out, using (CTCAE) Common Terminology Criteria for Adverse Events, Version 4.0
4. Data analysis:

Data will be analysed using the computer program, Statistical Package for the Social Science (SPSS V.16).

Expected outcomes:

The outcome of the study will be compared statistically with previous local and international trails.

Ethical considerations:

1. Risk-benefit assessment:

   There is an acceptable risk may affect the patient in this research study as regard the acceptable side effects of Gemcitabine, Oxaliplatin and radiotherapy.
2. Confidentiality:

   Any data taken from the patient either from history, the examination or the investigations will be very confidential.
3. Research statement:

   All patients subjected to this study will be informed about the procedures of the research.
4. Informed consent:

   The study procedures will be discussed to all patients and consent will be taken from them.
5. Other ethical concerns:

The research will be conducted only by scientifically qualified and trained personnel.

Eligibility Criteria:
Inclusion Criteria:

* Disease characteristics:

  * Histological and radiological confirmation of locally advanced cancer pancreas
  * Inoperable disease
  * Disease must be able to be encompassed within a radical radiotherapy treatment volume
  * Not metastatic

Patient characteristics:

* ECOG performance status 0 or 1
* Life expectancy \> 3 months.
* Glomerular filtration rate ≥ 60 mL/min.
* WBC \> 3,000/mm³.
* Absolute neutrophil count \> 1,500/mm³.
* Hemoglobin \> 10.0 g/dL.
* Platelet count \> 100,000/mm³.
* Alkaline phosphatase ≤ 1.5 times upper limit of normal (ULN)
* Gamma-glutamyl-transferase \< 1.5 times ULN.
* Transaminases ≤ 1.5 times ULN.
* Bilirubin ≤ 1.5 times ULN.
* No medically unstable conditions (e.g., unstable diabetes, uncontrolled arterial hypertension, infection, hypercalcemia, or ischemic heart disease)
* Not pregnant or nursing.
* No other previous or current malignant disease likely to interfere with protocol treatment or comparisons
* No prior chemotherapy or radiotherapy.

Exclusion Criteria:

* ECOG performance status \> 2
* Life expectancy \< 3 months.
* Glomerular filtration rate \< 30 mL/min.
* Absolute neutrophil count \< 1,500/mm³.
* Alkaline phosphatase \> 1.5 times upper limit of normal (ULN)
* Gamma-glutamyl-transferase \> 1.5 times ULN.
* Transaminases\>1.5 times ULN.
* Bilirubin \>1.5 times ULN.
* medically unstable conditions (e.g., unstable diabetes, uncontrolled arterial hypertension, infection, hypercalcemia, or ischemic heart disease)
* pregnant or nursing.
* prior chemotherapy or radiotherapy.