Clinical Trial of Intraperitoneal Hyperthermic Chemotherapy

PSC is, by definition, a metastatic stage of malignancy. Ovarian cancer, and clinically
identical entities (fallopian tube and primary peritoneal cancer) are most commonly found to
spread as a PSC. These diseases seldom spread outside of the peritoneal cavity even after
multiple recurrences. Therefore, clinical experience with IPHC is nearly all from ovarian
(and related) cancers.

Ovarian cancer is the leading cause of death from a gynecologic malignancy in the United
States. There are approximately 26,000 new cases and 14,500 deaths annually. Primary
peritoneal and fallopian tube carcinomas are significantly less frequent than ovarian
cancer, but outcomes and treatments are identical. The recommended initial treatment for
these diseases is to perform a staging operation with aggressive debulking of tumor. These
patients then receive intravenous, or intraperitoneal, taxane and platinum-based
chemotherapy to treat the residual disease. This treatment yields overall median survivals
of approximately 37 months in patients that were suboptimally debulked (residual tumor, >1.0
cm in diameter) and 49 months in those with optimally debulked disease (residual tumor, 1.0
cm in diameter). Overall, approximately 75% of those with Stage II-IV ovarian cancer will
respond to their initial adjuvant chemotherapy and 50% are clinically without evidence of
disease at the completion of their adjuvant chemotherapy cycles. However, 50% of these
patients would have persistent disease identified at the time of a second look laparotomy.
Of those with a negative second look laparotomy, 50% will experience a recurrence of their
disease. Second Look Laparotomy is a controversial choice for patients who have no evidence
of disease by non-invasive means after their primary treatment. It appears that some
patients may benefit in Progression Free Survival (PFS) when complete cytoreduction of
residual disease is possible, but no randomized trial exists to prove 5 year survival
benefit. Patients that recur after their initial adjuvant chemotherapy will generally die
from their disease, as salvage therapy has not been very effective. At the present time, the
initial adjuvant regimen consists of a platinum and paclitaxel-based regimen as the standard
therapy for these patients. Cisplatin was originally used for the intravenous regimens and
continues to be used for intraperitoneal (IP) therapy. In fact, the GOG has now made IP
cisplatin a part of the standard adjuvant regimen for optimally debulked ovarian cancer
patients. This shift was based on the analysis of three randomized trials that support the
IP cisplatin route. Patients in this Gynecologic Oncology Group (GOG) trial underwent
optimal cytoreductive surgery and were randomly assigned to a control group receiving
intravenous paclitaxel and intravenous cisplatin or to an experimental group receiving
intravenous paclitaxel on day 1, intraperitoneal cisplatin on day 2, and intraperitoneal
paclitaxel on day 8. At a median follow-up of 50 months, there was a statistically
significant prolongation of median progression-free survival and overall survival in the
intraperitoneal treatment group (a benefit of 5.5 and 15.9 months, respectively). This
represented a 25 percent reduction in the risk of death. This 15.9-month improvement in
median overall survival is one of the longest survival benefits ever observed for a new
therapy in gynecologic oncology.

Uterine disease may be divided into cancer of the cervix, and cancer of the corpus, which
behave quite differently, even when compared by similar histology subtype.

Corpus epithelial cancer is a common Gynecologic malignancy, with 41,200 projected 2006
cases resulting in an estimated 3,750 deaths. This is by far more prevalent than
ovarian-related cancers, and usually quite curable at early stage. Approximately 10-15% of
cases, however, are found outside of the uterus (Stage III or IV) at presentation. These
cases have a poor outcome, with only 30% of Stage III patients (disease spread to regional
lymph nodes, peritioneal fluid, or pelvis) and less than 5% of Stage IV (spread to abdominal
cavity) surviving 5 years. Recurrent disease occurs in approximately 29% of Stage I patients
Patients with recurrence ultimately die of disease, and often are treated medically with a
survival of 13-15 months. However, recent retrospective studies have shown that patients
with recurrent disease can reasonably be offered surgery, with better outcomes from complete
cytoreduction. Median survival times are range from 35 to 43.0 months, for those with small
or no residual tumor, compared to 10-13.5 months for those patients with gross residual
disease. Sarcomas of the uterus are rare, representing only 2-5% of all corpus cancers.
These are staged and treated much like high-grade epithelial cancer, but these patients have
poorer survivals when compared to similar stage for common histologic subtypes. Early stage
patients survive to five years less than 50% of the time. Those with more advanced disease
has a 0-20% five-year survival (median survival 4-26 months). Studies on these diseases have
been subjected to low numbers, due to the rarity of disease, and few conclusions can be
drawn. However, surgical debulking is thought to be probably beneficial.

Cervical cancers are expected to account for 9,710 cases with 3,700 deaths in 2006. The
disease is often discovered at early stage, confined to the cervix (Stage I) and is often
curable. Cure rates in these patients are directly related to cervical disease volume, with
survivals ranging from 71-90%. However, between 14.4-25.6% of patients with early disease
will recur after initial radiation or surgical therapy, within 3 years. Recurrent disease is
usually in the pelvis, and treatable fairly successfully with surgical exenteration.
Extrapelvic spread of disease is only confined to the peritoneal cavity in 8% of cases, but
treatment of these patients is currently considered futile.

To determine treatment response to surgical debulking and intra-operative Intraperitoneal
Hyperthermic Chemotherapy (IPHC) in patients with the following malignancies:

Gynecologic cancers (ovarian, primary peritoneal or fallopian tube, and uterine/cervical
cancers).

Mesotheliomas. GI cancers (Gallbladder, liver, small intestine, pancreas, stomach, colon,
appendix).

To monitor the toxicities and complications of this treatment regimen. To measure treatment
related QOL changes after IPHC. To contribute outcomes data to national and local efforts
toward IPHC registries.

PATIENT ELIGIBILITY

Presumptive clinical diagnosis of a peritoneal surface cancer (PSC) prior to surgery, with
no metastases outside of the abdomen.

Patients must have a performance status of 0, 1, or 2.

Patients must have adequate:

Bone marrow function: absolute neutrophil count more than or equal to 1500 and platelet
count more than or equal to 100,000 Renal function: creatinine less than or equal to 1.5
mg/dl Hepatic function: bilirubin less than or equal 1.5times upper limit of normal, SGOT
and alkaline phosphatase less than or equal 2.5 times upper limit of normal range Patients
must have signed an informed consent. Patients of childbearing potential must have a
negative serum pregnancy test prior to study entry and be practicing an effective form of
contraception.

Patients are at least 18 years of age, and under 75 years of age.

At the time of surgery, operative assessment and frozen section diagnosis of one of the
following:

Primary ovarian cancer (POC) with Stage IC or greater stage Recurrent or persistent
ovarian cancer (ROC) Ovarian cancer patients who desire Consolidation Chemotherapy (CC).
These patients would ordinarily choose to have 12 cycles of Taxol given after standard
first-line surgery and chemotherapy, and instead choose one course of IPHC as their CC.

Uterine malignancy of the corpus, or cervix with primary tumor Stage IIIA or greater, or
recurrent tumor confined to the abdomen.

Metastatic mesothelioma or sarcoma confined to the abdomen. Recurrent or primary
gastrointestinal cancer, with regional spread confined to the peritoneal cavity

PATIENT INELIGIBILITY

Patients with known extra-abdominal disease, or unresected bulky abdominal retroperitoneal
lymph nodes.

Patients with any evidence of another malignancy within the last five years (except
non-melanoma skin cancer) Patients with a known sensitivity to cisplatin, Mitomycin C, or
Adriamycin. Patients with significant co-morbid medical conditions that would prevent the
patient from completing treatment on this protocol, per Investigator discretion.

Patients desiring future fertility.