Trial Information

A Phase II Study of Induction Chemotherapy Followed by Concurrent Chemotherapy With Radiotherapy in Locally Advanced Pancreatic Cancer

Induction chemotherapy will be administered on a biweekly basis. Reported adverse events and
potential risks for gemcitabine, oxaliplatin, 5-FU and leucovorin are described in Section
6. Appropriate dose modifications for are described in Section 5. No investigational or
commercial agents or therapies other than those described below may be administered with the
intent to treat the patient's malignancy.

4.1.1 Treatment schedule of induction chemotherapy

For each dose of GOFL chemotherapy, intravenous infusion of gemcitabine at a fixed rate of
10 mg/m2/min will be immediately followed by a 2-hour intravenous infusion of oxaliplatin
and then a 48-hour intravenous infusion of 5-FU and leucovorin.

4.1.2 Premedication before chemotherapy

Patients will receive 4mg of dexamethasone and anti-histamine and appropriate anti-emetics
(serotonin antagonists) before each dose of chemotherapy.

4.2 Supportive Care Guidelines

Prophylactic G-CSF or GM-CSF will not be routinely used in this study. In case of febrile
neutropenia, patients should be treated with appropriate antibiotics. Therapeutic G-CSF may
be used at the discretion of attending physicians

4.3 Duration of Induction Chemotherapy

In the absence of treatment delays due to adverse events, treatment may continue for 6
cycles or until one of the following criteria applies:

C Disease progression, C Intercurrent illness that prevents further administration of
treatment, C Unacceptable adverse events(s), C Patient decides to withdraw from the study,
or C General or specific changes in the patient's condition render the patient unacceptable
for further treatment in the judgment of the investigator.

4.4 Agents and Radiation Administration during Concurrent Chemoradiotherapy

4.4.1 Treatment schedule during concurrent chemoradiotherapy

4.4.1.1 Patient selection

Patients were evaluated after 6 cycles of induction chemotherapy. Patients who have
progressive disease either due to distant metastasis or locoregional progression will be
given salvage systemic chemotherapy and will not be enrolled into concurrent
chemoradiotherapy. Patients who achieve complete remission, partial remission or stable
disease will be enrolled into 2nd phase of the study, concurrent chemoradiotherapy, 3-4
weeks after the last dose of induction chemotherapy.

4.4.2 Study Agents

Gemcitabine 400mg/m2 will be dissolved in 250ml normal saline and infused intravenously at a
fixed rate of 10mg/m2/min for 40 mins.

4.4.1.2 Treatment schedule

Gemcitabine 400mg/m2 in 250ml normal saline will be iv infused for 40mins, 2hrs before RT on
day 1, 8, 15, 22, 29, 36. Radiation will be given 180cGy per day, 5 days a week for 28
fractions to totally 5040cGy.

4.4.1.3 Premedication for concurrent chemoradiotherapy

Patients were given dexamethasone 2mg orally three times a day (tid) from the morning of
their first radiotherapy fraction. The prophylactic dexamethasone will be continued until
after they had received their fifth radiation treatment. Therefore, depending on the day of
the week the patients started treatment, dexamethasone will be taken for 5 to 7 days. All
patients will be issued with rescue medication, prochlorperazine 10mg every 6 hours orally
if they develop nausea and vomiting. If patients still have nausea and/or vomiting during
treatment of dexamethasone and prochlorperazine or after the fifth day of radiotherapy,
ondansetron 8mg orally or iv one to three times per day or granisetron 1mg per os or iv once
everyday 30mins before radiotherapy should be given.

4.4.3 Radiation

4.4.3.1 Radiation technique

Radiation should be performed by high-energy linear accelerators. Three-dimensional
radiation treatment planning was used in all cases. Patients will be immobilized in a foam
cradle in a supine position, and the treatment planning CT was obtained. Tumor mapping
should be performed according to treatment planning CT and the diagnostic CT before
induction chemotherapy. Treatment planning was performed with the isocenter calculated at
100% and the 95% line encompassing the planning target volume. The spinal cord was limited
to 4600cGy. If one kidney was to receive more than 20Gy then more than 90% of the remaining
kidney was excluded from the primary beam. Generally, a three-field no-axial beam
arrangement (opposed lateral with an anterior-inferior oblique) was used.

4.4.3.2 Radiation volume

The gross tumor volume is the primary tumor identifiable on CT scan before induction
chemotherapy. The clinical target volume was defined as the gross tumor volume plus 0.5cm.
The planning target volume was the clinical target volume plus 0.5cm for daily patient
set-up variation. No prophylactic nodal irradiation will be given.

4.4.3.3 Radiation dosage

A total dose of 5040cGy in 28 fractions, 180cGy per fraction, one fraction per day, 5 days
per week, will be given.

4.5 Surgery

4.5.1 Surgical evaluation

Patients completed induction chemotherapy and concurrent chemoradiotherapy will be evaluated
for surgical resection. If there is evidence of distant metastasis, surgery will not be
arranged. The feasibility of surgical resection will be evaluated by qualified surgeon
according to contrast-enhanced abdominal CT or MRI. Laparoscope is optional for pre-surgical
evaluation.

4.5.1.1 Resectable l No distant metastases l Clear fat plane around celiac and superior
mesenteric arteries (SMA) l Patent superior mesenteric vein (SMV)/portal vein 4.5.1.2
Borderline resectable l Severe unilateral SMV/portal impingement l Tumor abutment on SMA l
Gastroduodenal artery (GDA) encasement up to origin at hepatic artery l Colon or mesocolon
invasion l Adrenal, colon or mesocolon, or kidney invasion 4.5.1.3 Unresectable l Distant
metastases l SMA, celiac encasement l SMV/portal occlusion l Aortic, inferior vena cava
(IVC) invasion or encasement l Invasion of SMV below transverse mesocolon l Rib, vertebral
invasion

4.5.2 Treatment schedule of surgery

Surgery will be performed within 4-6 weeks after chemoradiotherapy complete.

4.5.3 Surgical technique

Patients whose tumor are considered to be resectable will undergo laparotomy. If complete
surgical resection is feasible, optimal surgery will be performed. If complete surgical
resection is impossible, biopsy with or without palliative surgery (eg. bypass surgery) may
be performed. 4.6 Adjuvant/Maintenance Chemotherapy

4.6.1 Treatment schedule

Patients who have curative surgical resection will receive 6 cycles of adjuvant GOFL
chemotherapy within 4 weeks after surgery and then followed up until tumor progression.
Patients who are not feasible for curative resection, will receive continued chemotherapy of
GOFL 3-4 weeks after chemoradiotherapy complete. The regimen will continue till disease
progression. Patients who develop progressive disease during GOFL will shift to salvage
chemotherapy.