Comparing Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (CRS-HIPEC) Using Mitomycin-C Versus Melphalan for Colorectal Peritoneal Carcinomatosis

BACKGROUND: Peritoneal dissemination of cancer (peritoneal carcinomatosis) from
gastrointestinal malignancies, meaning tumor deposits along the inside abdominal or pelvic
wall and surfaces of the intestines and organs, has historically been considered a terminal
disease. Although peritoneal surface tumors can respond to systemic therapy as a sole form of
treatment, patient survival remains poor and cure is considered impossible.

A plasma-peritoneal barrier makes systemic therapy relatively ineffective against peritoneal
surface disease. In the 1990's, cytoreductive surgery and hyperthermic intraperitoneal
therapy (CRS-HIPEC) began to be popularized as a more effective treatment.

Hyperthermic intraperitoneal chemotherapy has several advantages. High-dose chemotherapy can
be used due to the plasma-peritoneal barrier resulting in little absorption into the blood
stream. Hyperthermia itself has cytotoxic effects and can increase the depth of tumor
penetration by the chemotherapeutic agent up to 3 mm and moreover can potentiate its
antineoplastic effects. Although CRS-HIPEC has been considered standard treatment for
ruptured appendiceal neoplasms and primary peritoneal mesothelioma, in the past decade its
indications have broadened to other peritoneal surface malignant processes.

Historically, morbidity and mortality associated with CRS-HIPEC was considerably higher than
other complex operations, and thus its use was often discouraged. However, in recent times,
especially in high-volume centers, morbidity and mortality has drastically improved. Due to
recent improvements in mortality after major surgical interventions, including HIPEC, the
focus has shifted toward other endpoints besides efficacy, such as morbidity, quality of life
and cost.

While HIPEC is universally felt to be a vital component after cytoreductive surgery, there is
a lack of consensus on the optimal regimen, especially the chemotherapeutic agent that should
be used. In the United States, the most commonly used agent during HIPEC is mitomycin-C,
however, it remains unknown if mitomycin-C is the optimal drug to use with regards to
toxicity and survival.

Randomized prospective studies are needed comparing the toxicity and effectiveness of HIPEC
with mitomycin-C to other agents.

OBJECTIVE: To compare morbidity and mortality after CRS-HIPEC utilizing mitomycin-C versus
melphalan.

METHODS: In this study, patients will be randomized to one of two treatment arms: Arm 1.)
Mitomycin-C initial dose of 15 mg/m2, 45 minutes into the perfusion a maintenance dose of 5
mg/m2 will be administered; or Arm 2): Melphalan 60 mg/m2 45 minutes into the perfusion.
Morbidity will be measured during immediate and short-term surgical recovery (up to 90 days
post-hospital discharge). Mortality will be measured beginning with the date of surgery and
ending with the date of participant death.

Inclusion Criteria

- Ability to understand and the willingness to sign a written informed consent.

- Peritoneal Surface Disease (PSD) due to Colorectal Cancer or High-Grade Appendiceal
Cancer

- No clear evidence of systemic metastases

- No prior CRS-HIPEC treatment

- Patient has a planned CC0 (Complete Macroscopic Cytoreduction (visual)) cytoreduction
- NOTE: randomization occurs during surgery and not before; if, during surgery, the
PI/SubI discerns that all disease cannot be removed surgically, the participant will
be considered a "screen failure", HIPEC will not be performed, and the participant
will be removed from the study. If participant is removed from the study, PI / surgeon
will decide if standard of care surgery will proceed.

- Age 18 - 75

- ECOG (Eastern Cooperative Oncology Group) Score 0 - 2

- Recorded ASA (American Society of Anesthesiologist Classification) classification - as
determined by the anesthesiologist (particular value not required - only recording of
the classification is required).

- Medically fit to undergo complex major abdominal surgery, as determined by examination
by PI / Sub-Is.

- Medically fit to receive systemic chemotherapy, as determined by examination by PI /
Sub-Is.

- Adequate organ and marrow function as defined below:

- leukocytes ≥ 3,000/mcL (microliter)

- absolute neutrophil count ≥ 1,500/mcL

- platelets ≥ 100,000/mcL

- total bilirubin within normal institutional limits

- AST (Aspartate aminotransferase) (SGOT [Serum Glutamic Oxaloacetic Transaminase])
≤ 2.5 X institutional upper limit of normal

- ALT (Alanine Aminotransferase) (SPGT [Serum Glutamic Pyruvic Transaminase]) ≤ 2.5
X institutional upper limit of normal

- creatinine within normal institutional limits

- Women of child-bearing potential and men with partners of child-bearing potential must
agree to use adequate contraception (hormonal or barrier method of birth control;
abstinence) prior to study entry, for the duration of study participation, and for 90
days following completion of therapy. Should a woman become pregnant or suspect she is
pregnant while participating in this study, she should inform her treating physician
immediately.

- A woman of child-bearing potential is any female (regardless of sexual
orientation, having undergone a tubal ligation, or remaining celibate by choice)
who meets the following criteria:

- Has not undergone a hysterectomy or bilateral oophorectomy; or

- Has not been naturally postmenopausal for at least 12 consecutive months
(i.e., has had menses at any time in the preceding 12 consecutive months)

- Men of child-bearing potential must not donate sperm while on this study and for
90 days after the study treatment (surgery with HIPEC).

Exclusion Criteria Participants meeting any of the exclusion criteria at baseline will be
excluded from study participation.

- Current or anticipated use of other investigational agents while participating in this
study.

- Patient has received systemic chemotherapy or radiotherapy within 4 weeks prior to
study enrollment.

- Patient has not recovered sufficiently (PI will judge patient recovery status) from
adverse events due to agents administered more than 4 weeks prior to enrollment on
this study.

- Patient has history of or currently has non-peritoneal surface metastatic disease in
addition to peritoneal surface malignancy.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to mitomycin-C or melphalan.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris,
life-threatening cardiac arrhythmia, severe pulmonary disease, uncontrolled diabetes,
severe kidney disease or psychiatric illness/social situations that would limit
compliance with study requirements.

- Pregnant or nursing. There is a potential for congenital abnormalities and for this
regimen to harm nursing infants.

- Patient actively being treated for other malignancy (current active treatment of early
stage squamous or basal cell carcinomas of the skin is allowed, excluding treatment
with other investigational agents and systemic chemotherapy or radiotherapy).