Chemoradiation combined with panitumumab followed by surgery for patients with operable esophageal cancer

Neoadjuvant chemoradiotherapy significantly benefit patients with resectable
carcinomas of the esophagus. One of the potential strategies to improve the
local effects of chemoradiation is the concurrent inhibition of EGFR, a
membrane tyrosine kinase receptor involved in cell proliferation,
anti-apoptosis and chemo and radiotherapy resistance. Since EGFR is expressed
in 50-80% of all esophageal cancer, this receptor appears to be an attractive
target for chemo and radiosensitization. Moreover, preclinical models have
suggested synergy between EGFR inhibition, paclitaxel, cisplatin and radiation.
Recently a study as been published combining cetuximab, paclitaxel, carboplatin
and concurrent radiation for esophagogastric cancer. This combination was
feasible with no increase in esophagitis or other radiation-enhanced toxicity.
It was notable that 70% of the patients treated with this combination had a
complete clinical response. Of the 49 patients that underwent resection 27% had
a pathologic complete response.
These data suggest that combining EGFR inhibition with chemoradiation is a very
promising and relatively safe regimen. Because of the similarities between
cetuximab and panitumumab, the latter with an even better safety profile, it is
tempting to investigate panitumumab as additive to weekly carboplatin,
paclitaxel and radiotherapy as neaodajuvant treatment in patients with
resectable esophageal cancer.
Since pathologic complete response has a clear correlation with outcome, in
this study we will use pathologic complete response as primary objective.

A consistent finding in many studies in patients with operable esophageal and
gastro-esophageal junction (GEJ) cancer is that response to preoperative
therapy, particularly the absence of residual disease in the surgical specimen,
is an indicator of better disease-free and overall survival. Therefore in our
trial we will evaluate the pathologic response of panitumumab in combination
with neoadjuvant chemoradiation as first line treatment of operable
adenocarcinomas, undifferentiated or squamous cell carcinomas of the esophagus.

This is a Phase II, non-randomized trial. Eligible subjects will be treated
with panitumumab plus carboplatin, paclitaxel and radiotherapy followed by
surgical resection of the esophagus.

Panitumumab administration schedule:
Panitumumab will be administered as a 60-minute ± 15 minutes IV infusion, prior
to administration of chemotherapy at a dose of 6 mg/kg on day 1, 15 and 29.
If the first infusion is well tolerated (without any serious infusion related
reactions) all subsequent infusions may be administered over 30 minutes ± 10
minutes.

Chemotherapy regimen:
Paclitaxel 50 mg/m2 and Carboplatin AUC = 2 will be given by intravenous
infusion on days 1, 8, 15, 22 and 29. Both drugs will be infused over one hour.

Radiotherapy treatment:
A total dose of 41.4 Gy will be given in 23 fractions of 1.8 Gy, 5 fractions
per week, starting the first day of the first cycle of chemotherapy. All
patients will be radiated by external beam radiation, using 3-D conformal
radiation technique.

Surgery:
Surgery will be performed preferably within 6 weeks after the completion of the
chemoradiation and panitumumab. For carcinomas distal of the tracheal
bifurcation but proximal to the gastro-esophageal junction, a transthoracic
approach is preferred. For distal tumors involving the gastro-esophageal
junction a transhiatal esophageal resection is preferred.
A wide local excision including the N1 lymph nodes is carried out in both
techniques including a standard excision of the lymph nodes around the coeliac
axis. The continuity of the digestive tract will be restored by a gastric tube
reconstruction or colonic interposition procedure with an anastomosis in the
neck

Before the operation patients will recieve radiation for a period of 5 weeks.
During this period weekly chemotherapy will be added and panitumumab, in total
3 times. The radiation will start at the first day of the chemotherapy
infusion. Chemotherapy consists of paclitaxel and carboplatin. These infusions
will be given weekly at the medical oncology ward and takes about 4 hours, a
total of 5 courses. At day 1, 15 and 29, panitumumab will be given by
intravenous infusion. This takes one hour the first time and if the first
infusion is well tolerated all subsequent infusions may be administered over 30
minutes. Weekly, before the start of a new course patients will be seen by the
medical oncologist to register side effects and to adjust the dose if necesary.
Also the radiotherapist will see the patient on a regular base during
treatment. Prior to the start of the irradiation a planning CT scan will be
made from the thorax, with the patient in treatment position. Radiation is
daily, 5 times a week and takes only a few minutes.