Trial Information

A Phase II Trial Of Adjuvant Chemoradiation Following Pancreatic Resection For Adenocarcinomas Of The Pancreas Using 3-D Conformal Radiation With Cisplatin, 5FU, And Alpha-Interferon As Radiosensitizing Agents Followed By Gemcitabine

The adjuvant therapy of pancreas cancer has remained a challenge for oncology specialists
from all disciplines since the initial development of the pancreaticoduodenectomy by Whipple
in 1935 (Whipple, Ann Surg, 1935). A variety of phase II experiences utilizing radiation
therapy and 5FU-based chemotherapy following curative surgery for pancreas cancer have
consistently produced the disappointing survival results of 18-24 months median survival,
40%-50% 2-year survival and 10%-20% 5-year survival (Evans, in DeVita, et.al Cancer
Principles and Practices of Oncology, 1997). Indeed, whether any adjuvant therapy following
pancreaticoduodenectomy for pancreas cancer is of benefit to patients remains a debated
question. The landmark study performed by the GITSG in patients with pancreatic cancer
displayed a survival advantage for patients receiving postoperative radiation therapy and
5FU compared to those receiving pancreaticoduodenectomy only (2-year survival 43% vs. 18%,
p=0.03). As a result, this study became to some the standard of care for patients with
resected pancreas cancer in the US (GITSG, Cancer 1987). However, this study rightfully has
been criticized from a variety of perspectives over the years; furthermore, recent
experiences by the EROTC and ESPAC have failed to reproduce the GITSG results (Klinkenbijl,
Ann Surg 1999,Neoptolemos, Proc ASCO 2000). However, the results of these two studies have
also received significant criticisms. The EORTC data are underpowered and the study failed
to use post-radiation chemotherapy to optimum advantage. The ESPAC data have been criticized
as being statistically invalid by trial desig10/14/02n and analysis. Thus, the optimization
of adjuvant therapy following pancreaticoduodenectomy for pancreas cancer remains a subject
of debate and poses essentially the same challenge to oncology specialists at the beginning
of the 21st century as it has for the past sixty years.

Confronted with these issues, investigators at the Virginia Mason Clinic began in 1995 a
phase II trial utilizing cisplatin and alpha-interferon in conjunction with 5FU and
radiation therapy following pancreaticoduodenectomy for pancreatic adenocarcinoma. The logic
behind this protocol was as follows:

1. Recurrence following surgery and adjuvant chemoradiation in protocols for resected
pancreas cancer to that date had been associated with a high incidence of both local
and systemic recurrence; thus treatment must focus on improvement in relapse rates in
both areas.

2. No chemotherapy regimens (as of 1995), either single agent or multi-agent, had shown
response rates markedly different from that seen with single agent 5FU (typically on
the order of 10%)

3. Therapeutic advance in the adjuvant therapy of pancreas cancer must therefore focus on
systemic agents that have the potential to synergize the tumoricidal activity of
radiation therapy and/or each other.

4. Cisplatin and alpha-interferon, like 5FU, do have radiosensitizing activity in
experimental tumor systems and thus potentially could be added to 5FU to create a
"combination" radiosensitizing agent analogous to the way chemotherapy agents are
combined for systemic effect.

5. These chemotherapeutic agents also have direct synergistic anticancer activity with
respect to each other in experimental tumor systems .

6. These agents also have, to a large extent, non-overlapping toxicities and can be
delivered on an outpatient basis.

Using the above logic, a novel phase II protocol (with radiation therapy) for the adjuvant
therapy of pancreas cancer was developed. The protocol was constructed as follows:

- XRT 5000cGy/200cGy fractions given daily M-F wks 1-5

- CDDP 30 mg/m2 d 1 wks 1-5

- IFN-A 3,000,000U sq qod wks 1-5 beginning d 1

- 5FU 200mg/m2 wks 1-5 beginning d 1; repeated wks 10-15 and wks 18-23 (2 6 wk
chemotherapy courses post chemoradiation ).

Patients, in general, were treated within 8 weeks following pancreaticoduodenectomy (in
general, performed as a pylorus preserving procedure without extended lymph node dissection)
and included patients with adenocarcinomas of the head, body and tail of the pancreas. Other
periampullary cancers were not included in this study.

The phase II trial from Virginia Mason has been published in a variety of forms, both
abstract (Picozzi, Proc ASCO 1999,2000) and manuscript (Nukui, Am J Surg 2000). To date, 38
patients have been treated at Virginia Mason using this method. Average patient age is 64.
Thirty three patients had cancers of the pancreas head, 5 patients had body and/or tail
cancers. Noteworthy in this series is a particularly high incidence of the adverse disease
prognostic factors for recurrence such as nodal involvement (79%) and non-surgical margin
positivity (32%). Using a prognostic model for disease recurrence developed at Johns Hopkins
incorporating the above factors plus tumor type (pancreatic head versus other periampullary
cancers), tumor size, tumor differentiation and estimated blood loss at surgery, 37/38
patients (97%) were judged to be at high risk for disease recurrence.

Results of this trial updated as of February, 2001include the following important results:

- All patients (38/38) treated to date have completed the chemoradiation phase of
treatment (wks 1-5); 35/38 patients completed the entire treatment course.

- Approximately 90% of planned chemotherapy was delivered; virtually all planned
radiation therapy was delivered.

- Toxicity has been almost entirely GI-related (anorexia/dehydration, mucositis,
nausea/vomiting, diarrhea).

- As a result of the above toxicity, the majority of patients required treatment delays
during chemoradiation and approximately 30% (13/38) required hospitalization. However,
there have been no treatment-related fatalities, and all patients have regained full
functional status.

- Median follow-up at present is greater than 2 years; 21/38 patients have been followed
for greater than 2 years. 28/38 (74%) patients remain alive, and 25/38 (67%) patients
remain alive and disease free.

- At present, the median survivorship of this patient cohort is in excess of 45 months
(45.8 months, 95% confidence limits 36-55 months); the actuarial 2-year and 5-year
survivorships are 65 % and 60 %, respectively. 13/21 patients followed for more than
two years remain alive at this time (including 3 patients alive more than 5 years from
initial diagnosis). If just the 33 patients with adenocarcinomas of the pancreas head
in this phase II trial are considered, the median survivorship rises to 49 months (95%
confidence limits 39-59 months). Actuarial 2-year and 5-year survivorships are 73% and
68% respectively.

- All recurrences have taken place between 5 and 22 months from the time of diagnosis
(none later).

- The recurrence pattern seen to date is as follows; 2 patients local recurrence, 7
patients systemic and 4 patients both local and systemic recurrence. The local control
rate has thus been approximately 85% (32/38 patients) and the systemic control rate
approximately 70% (27/38 patients).

More detailed data on all 38 patients with adenocarcinomas of the pancreas treated using
this protocol at Virginia Mason to date are displayed in Figure 1.

These data were presented to the Pancreas Cancer Committee of the ACOSOG in December,2000.
Meeting participants agreed to further development of this protocol given the treatment
results seen in comparison with the historical precedents previously cited. These outcomes
were seen as particularly favorable given the high-risk nature of the patient population
studied. However, the protocol also received the following criticisms from meeting
participants, including NCI reviewers. First, the protocol had only been studies to date at
a single institution. Second, the toxicity of the regimen was seen as quite significant,
especially during chemoradiation, when 30% of patients were hospitalized. Finally, the
post-chemoradiation phase of chemotherapy (infusional 5FU only) was seen as potentially
suboptimal, as several types of chemotherapy regimens, including both combination regimens
utilizing infusional 5FU(ref) and gemcitabine (ref) have produced superior response rates in
phase II trials to that seen with single agent 5FU. As a result of the above dialog, it was
decided by the ACOSOG Pancreas Cancer committee to develop a multi-institutional phase II
trial based upon the Virginia Mason protocol that would incorporate the above comments. It
was also felt that this effort should not conflict with a phase III protocol being planned
by the committee comparing a multi-agent 5FU-based regimen developed at UCLA with radiation
therapy with the single agent 5FU approach used by the GITSG.

To address the protocol-related concerns mentioned above, the following modifications in the
original Virginia Mason protocol are suggested:

The issue of toxicity during chemoradiation is addressed in three ways. First, radiation
therapy will be delivered to more confined fields, particularly given the predominance of
systemic recurrence in the therapeutic results to date. Second, the dose intensity of the
chemotherapy agents (cisplatin, 5FU, Alpha-interferon) given during radiation will be
reduced slightly. This is done remembering the majority of patients (approximately 70%) did
require a break in treatment during this phase of therapy. Finally, to assist other
providers new to this protocol, a supportive care pathway has been developed to assist in
avoidance of treatment related toxicity (e.g. nausea, gastritis, hyperglycemia) during
treatment.