Trial Information

Phase II Trial of Pre-operative Bevacizumab and FOLFOX Chemotherapy (5-fluorouracil/Leucovorin With Oxaliplatin) in Locally Advanced Esophageal Cancer

Surgery alone had been the standard treatment for early stage esophageal cancer. The
Radiation Therapy Oncology Group studied chemoradiation verses chemotherapy in a phase III
prospective randomized trial evaluating the efficacy of 5-fluorouracil and cisplatin plus
50Gy of radiation therapy compared to 64 Gy of radiation therapy alone. This was done with
patients with adenocarcinoma or squamous cell carcinoma of the thoracic esophagus. 121
patients were randomized. The median survival was 8.9 months in the radiation treated
patient compared to 12.5 months in the patients treated with chemotherapy and radiation.
Statistically significant differences were observed in 12 month (50%vs.33%) and 24 month
(38vs.10%) survival ratios (p<.001). Concurrent therapy with cisplatin and 5 fluorouracil
and radiation is superior to radiation therapy alone in patients with localized carcinoma of
the esophagus. This became the standard of care for patients with inoperable disease and the
results were not notably different from those obtained in series of resectable patients.

The evidence for effective radiosensitization and the ability to use a lower dose of
radiotherapy raised the question of whether the pre-operative use of chemoradiation would
downstage cancers to permit higher resection rates, greater success in local control with
resection, and early treatment of micrometastatic disease. A series of phase II and small
phase III studies have addressed this question.

A prospective randomized trial with 113 patients in Ireland was undertaken to evaluate
preoperative concurrent chemoradiotherapy with surgery alone. Patients assigned to
multimodality therapy received 2 courses of chemotherapy in weeks 1&6(5-fluorouracil,
15mg/kg for five days, and cisplatin, 75 mg/m2 on day 7) and a course of radiotherapy (40
Gy) over a 3 week period beginning with the first course of chemotherapy. The patient then
had surgery. The other arm consisted of surgery with no preoperative therapy. At time of
surgery, 23 out of 55 patients who had preoperative therapy (42%) had positive nodes or
metastasis versus 45 of 55 (82%) for surgery alone (p<.001).Thirteen of 52 (25%) had a CR
after chemoradiation. Median survival was longer for combined modality therapy 16 months vs.
11 months(p=.01). At 3 years, overall survival statistically favored the multimodality arm
as compared to the surgery alone, 32% vs. 6% (p=.01). This study has been criticized for the
use of inadequate staging at baseline, a criticism that is the more to the point as survival
in the surgery alone arm was markedly inferior to historical controls; however, other trials
have also supported or tended to support an advantage for preoperative chemoradiation for
patients with Stage II-IVa squamous cell carcinoma or adenocarcinoma of the esophagus.

In a prospective randomized Intergroup trial of trimodality therapy versus surgery alone for
the treatment of stages I-III esophageal cancer. Patients were randomized to surgery alone
or cisplatin (100mg/m2) and 5-fluorouracil (1000mg/m2 x 4d) with concurrent radiation
therapy followed by esophagectomy with lymph node dissection. 56 of a planned 475 patients
were randomized. The study was terminated because of the poor accrual; nonetheless,
informative results regarding the primary endpoint of overall survival were obtained.
Median survival was 4.5 years after trimodality therapy, vs. 1.8 years after surgery alone
(p=.02). This randomized study demonstrated a long term survival advantage with the use of
chemoradiation therapy followed by surgery in the treatment of esophageal cancer. Since this
presentation, trimodality therapy has been accepted as a standard of care.

Local failure alone occurs in fewer than 10% of patients treated with trimodality therapy.
The majority of patients who fail will do so at metastatic sites, and the interval
development of metastatic disease is also an important cause of failure to achieve resection
after neoadjuvant chemoradiation. One way to address distant metastatic recurrence is to
add post-operative adjuvant therapy. A phase II trial evaluated cisplatin and 5-fluorouracil
combined with radiotherapy followed by esophagectomy. The objective of the trial was to
determine complete pathologic response rate, survival rate, toxicity, pattern of failure and
feasibility of administering adjuvant chemotherapy in patients with resectable cancer of the
esophagus treated with preoperative chemoradiation. 11 out of 29 patients enrolled on the
trial achieved pathologic CR (pCR = 26%). The low pathologic CR rate may to some extent have
been related to the high pre-therapy stage of patients enrolled in this study. Paclitaxel
and cisplatin were given as adjuvant therapy. Of the 35 patients with potentially curative
resections who were candidates for adjuvant chemotherapy, 26(74%) received at least one
course of paclitaxel and cisplatin, whereas 6 refused further treatment and 3 had inadequate
Karnofsky performance status (60%) for further chemotherapy. 16 patients (62%) received 100%
of the total paclitaxel dose, whereas 15 patients (58%) received 100% of the total cisplatin
dose. Despite the high baseline stage of patients in this trial, and the relatively low
pathologic CR rate, the 2 yr survival was 62%. This provides some support that
post-operative adjuvant therapy with a non cross resistant agent may reduce distant
metastasis. The pattern of initial failure after this pre-operative approach in the study
cited above and a prior study which had not included adjuvant therapy was reported with
longer follow-up: local/regional alone in 6% (5 of 90), local/regional plus distant in 3% (3
of 90); distant metastases without locoregional recurrence were the initial manifestation of
relapse in 47% (42 of 90). The predominance of distant failure after aggressive
pre-operative therapy indicates that further intensification of local therapy is unlikely to
significantly improve long-term outcome for these patients, and that advances in the
systemic therapy of esophagogastric therapy should be brought to bear early in the course in
therapy of micrometastatic disease.

Radiation may preclude further intensification of systemic therapy. The use of
perioperative regimens to surgery without radiation was examined in the MAGIC Trial.
Cunningham et al assessed whether the addition of perioperative regimen of Epirubicin,
Cisplatin, 5-FU (ECF) to surgery improves outcomes among patients with potentially curable
gastric cancer. 503 patients were randomly assigned with resectable adenocarcinoma of the
stomach, esophagogastric junction, or lower esophagus to either perioperative chemotherapy
and surgery or surgery alone. Chemotherapy consisted of 3 preoperative and 3 postoperative
cycles of epirubicin, cisplatin, and fluorouracil. Primary end point was overall survival.
The perioperative-chemotherapy group had a higher likelihood of survival(HR .75; 95% CI .6
to .93). 5 year survival favored the perioperative chemotherapy verses surgery 36 to 26%
p=.09. It also favored progression free survival (HR .66, p<.001). With operable gastric or
lower esophageal adenocarcinomas, the perioperative regimen of ECF decreased tumor size and
stage and improved significantly progression free and overall survival.

The introduction of the platinoid oxaliplatin yields an active regimen in esophagogastric
cancer, with somewhat less toxicity than the ECF combination. In a Phase I study, the safety
and activity of radiotherapy with 5-fluorouracil, leucovorin, and oxaliplatin were assessed
in 33 patients with inoperable esophageal cancer. Three cycles of oxaliplatin, 5-FU, and
folinic acid with standard dose level oxaliplatin/5-FU starting on D1, D15, and D29
concomitant with 5 week's radiotherapy. An additional 3 cycles of standard FOLFOX4 were
administered every 2 weeks after the end of radiotherapy. The ORR was 61% (3 CR, 14PR),
median Thrombotic Thrombocytopenic Purpura 5 months (95% CI 3-6 mo) and the overall survival
9 months (95% CI 5-13 months). This showed that this regimen of oxaliplatin (85mg/m2) was
well tolerated and active.

Also, Mauer et al ran a phase II trial evaluating the efficacy and tolerability of FOLFOX in
patients with advanced esophagus cancer. Thirty-five patients with recurrent or metastatic
esophageal cancer enrolled. All were evaluated for toxicity and 34 were evaluable for
response. The overall response rate was 40% (95% CI 24-57%). The overall survival was 7.1
months and th one year survival was 31%. The predominant toxicity was neutropenia, with 29%
having grade 4 neutropenia. Cumulative peripheral neuropathy, grade 2 or 3, occurred in
26%. Thus, FOLFOX has favorable toxicity profile and anti tumor activity in patients with
metastatic carcinoma of the esophagus.

In the REAL 2 trial Cunningham et al aimed to establish the use of the third generation
platinum, oxaliplatin in substitution for cisplatin in advanced esophagogastric cancer. The
trial objective was a non inferiority trial for survival with capecitabine compared to
fluorouracil and oxaliplatin compared to cisplatin. 1002 patients were randomized in a 2x2
design. As seen in Table 1, oxaliplatin based therapy is non inferior to cisplatin based
therapy.

Alterations in neoadjuvant chemoradiation regimens have had only a modest impact on
survival, but the advent of novel therapies may permit more than incremental improvement.
Bevacizumab, a monoclonal antibody to VEGF, may be one such agent. Bevacizumab has been
studied in a multitude of Phase I, II, and III clinical trials in more than 5000 patients
and in multiple tumor types. In addition, data are available from 3,863 patients enrolled in
two postmarketing studies in metastatic colorectal cancer (CRC). Approximately 130,000
patients have been exposed to bevacizumab as a marketed product or in clinical trials. The
following discussion summarizes bevacizumab's safety profile and presents some of the
efficacy results pertinent to this particular trial. Please refer to the bevacizumab
Investigator Brochure for descriptions of all completed Phase I, II, and III trials reported
to date.

In a large phase III study in patients with metastatic colorectal cancer, the addition of
bevacizumab, a monoclonal antibody directed against vascular endothelial growth factor
(VEGF), to irinotecan/5-fluorouracil/leucovorin (IFL) chemotherapy resulted in a clinically
and statistically significant increase in duration of survival, with a hazard ratio of death
of 0.67 (median survival 15.6 vs. 20.3 months; p < 0.001). Similar increases were seen in
progression-free survival (6.2 vs. 10.6 months; p < 0.001), overall response rate (35% vs.
45%; p < 0.01) and duration of response (7.1 vs. 10.4 months; p < 0.01) for the combination
arm versus the chemotherapy only arm.

Bevacizumab improves survival or disease-free survival in several other solid tumor
malignancies, including lung cancer. In a cooperative group study, 829 metastatic colorectal
patients previously treated with a fluoropyrimidine and irinotecan assigned to one of three
treatment groups. The primary end point was overall survival. Median survival treated with
FOLFOX4 and bevacizumab was 12.9 months compare to 10.8 months treated with FOLFOX4 alone
(HR =.75; p=.0011) and 10.2 months for bevacizumab alone. The median progression free
survival for FOLFOX4 with bevacizumab was 7.3 months compared to 4.7 months (p<.001). The
overall response rates for FOLFOX4 with bevacizumab was 22.7% and 8.6% with FOLFOX4 alone
(p<.0001).

The addition of bevacizumab to combination irinotecan/cisplatin chemotherapy has been
evaluated in 47 patients with metastatic or unresectable esophagogastric cancer. The study
aimed to demonstrate a 50% improvement in time to progression over historical values.
Median time to progression was 8.3 months (95% CI 5.5 to 9.9 months). The overall response
rate was 65 % (95% CI 5.5 to 9.9 months). Median survival was 12.3 months (95 % CI 11.3 to
17.2 months). The addition of bevacizumab did not increase the rate of hematologic toxicity
compared with prior experience. The most common non-hematologic toxicities were fatigue and
diarrhea. Thromboembolism was detected in 28% of the patients and 6% experienced perforation
of the gastrointestinal tract, which occurred at the primary tumor site. The study
demonstrated a striking 75% improvement in time to progression, a longer than expected
overall survival, and no increase in chemotherapy side effects, although the rates of
thrombotic events and bowel perforation may have been greater than with chemotherapy alone.

The present study aims to introduce bevacizumab into the peri-operative chemotherapy-based
management of esophagogastric cancer, utilizing FOLFOX to reduce toxicity. Radiotherapy will
not be included, as it was not in MAGIC, as the principal barrier to cure in these patients
is distant dissemination. The study will be closely monitored for the overall disease-free
survival rate.