Chemoradiation followed by surgery for patients with cT4 oesophageal cancer

Current treatment of cT4 (locally irresectabel) oesophagus carcinoma is subject
of debate, but mostly consits of chemoradiation therapy.However, the results of
definite CRT in cT4 oesophageal carcinoma remain poor with only 20% of patients
alive at 3 years from the start of CRT and a local recurrence rate of up to
60%. The occurrence of a local recurrence has no curative options and prognosis
is infaust in the majority of patients within six months after start of
therapy. Furthermore local recurrence leads to severe symptoms, mostly caused
by perforation or obstruction of the oesophagus, and has a high influence on
quality of live.

These poor results lead to the hypothesis that local control and survival might
be improved by surgical resection following chemoradiation for CT4 oesophageal
cancer. Only small series concerning this topic in patients with a cT4
oesophageal carcinoma exist at present time, suggesting feasibility and
improved local control. Previous reports on surgery following CRT for cT3 and
cT4 oesophageal carcinoma report of high peri-operative mortality (up to 12,8 %
of patients) and morbidity (postoperative complication (major/minor in up to
70% of patients), but none the less a trend toward better cancer-free survival
(64,3% vs. 40,7% progression free survival) and reduced local recurrence rates
(66,4 % vs. 57%) in operated patients.

In these series, the high morbidity and mortality of surgery after neoadjuvant
teatment, might be contributed to the schedules that were used. These consisted
of chemotherapy with cisplatinum and 5-fluorouracil in combination with
radiotherapy. More recently, studies with taxanes as concurrently administered
cytotoxic drugs show promising results, with acceptable toxicity. A randomized
phase III study was conducted in the Netherlands, comparing neoadjuvant
chemoradiation followed by surgery versus surgery alone for patients with
adenocarcinomas or squamous cell carcinomas of the esophagus. Weekly
neoadjuvant carboplatin and paclitaxel with concurrent radiotherapy was
demonstrated to be a very tolerable regimen and can be given in an outpatient
setting. An interim analysis, after inclusion of 250 patients, revealed a
surgical mortality of less than 3%, which was not different between the two
study arms (referentie CROSS). Also, in this study a high response rate of
neo-adjuvant treatment was observed (pCR rate (32%) in de CROSS studie. , which
leads to the hypothesis that resection might be possible, even in advanced
tumors.

The aim of this phase-2-study is to assess the feasibility of surgery following
CRT in patients with cT4 oesophageal carcinoma with regard to morbidity,
mortality and the possibility to achieve a R0 resection.

This is a Phase II, non-randomized trial. Eligible subjects will be treated
with the current standard schedule for definite CRT (Weekly carboplatin and
paclitaxel with 50.4 Gy radiation therapy in fractions of 1.8 Gy for 5.5 weeks)
followed by surgical resection of the esophagus.

Chemotherapy regimen: Paclitaxel 50 mg/m2 and Carboplatin AUC = 2 will be given
by intravenous infusion on days 1, 8, 15, 22 and 29. This is the standard
regimen for definite chemoradiation therapy in our institution and dose
adjustments in case of toxicity will follow the regular protocols.

Radiotherapy treatment: A total dose of 50.4 Gy will be given in 28 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. This is the standard treatment protocol for
patients with cT4 oesophageal carcinoma in our institution.

Surgery: Surgical procedure will consist of a transthoracic oesophageal
resection (open, right thoractomy) with en-bloc two-field lymphadenectomy. If
needed, resection of adjacent structures (eg pleura, lung, pericardium,
diaphragm) will be conducted. The per-operative need for a tracheobronchial,
aortic, cardiac or vertebral resection will be considered a contra-indication
for resection. In those cases resection will not be performed and patients will
have received the standard treatment for cT4 oesophageal cancer.

A wide local excision including is carried out, including a standard excision
of paraoesophageal, subcarinal and celiac lymph nodes. The continuity of the
digestive tract will be restored by a gastric tube reconstruction or colonic
interposition procedure with an anastomosis in the neck.

Risks associated with participation are the risks of standard treatment with
chemoradiation, which all patients with cT4 oesophageal carcinoma undergo
according to the current protocol.
Furthermore, if the tumour is found to be resectable on restaging modalities,
patients will undergo surgical resection which is associated with the risk of
developing several complications (eg anastomotic leakage, chylous leakage,
pulmonary complications).