Surgery and Heated Chemotherapy for Adrenocortical Carcinoma

Background:

- Adrenocortical carcinoma (ACC) is a rare tumor with an incidence of 1.5 to 2 per

million people per year and has a very poor prognosis with an overall 5-year mortality

rate of 75 - 90% and an average survival from the time of diagnosis of 14.5 months.

- The treatment of choice for a localized primary or recurrent tumor is surgical

resection. For unresectable metastatic or recurrent disease, mitotane,

aminoglutethimide, metapyrone, and ketoconazole are used.

- Cisplatin is one of the most effective chemotherapeutic agents for ACC. In the

Surgery Branch we have conducted Phase I and II trials using heated intraperitoneal

(IP) chemotherapy with cisplatin for primary peritoneal mesothelioma, low grade

appendiceal adenocarcinoma, ovarian malignancies, and high grade adenocarcinoma

of the gastrointestinal tract. Synergy has been demonstrated for cisplatin and

hyperthermia

- The purpose of this trial is to determine if an aggressive surgical approach with

intraperitoneal administration of heated cisplatin when tumor volume is minimal, can

impact and improve on progression free survival.

Objectives:

- To determine IP progression free survival after optimal debulking and heated IP

chemotherapy with cisplatin in patients with IP spread of adrenocortical cancer

Eligibility:

- Histologically proven ACC evalauable by CT imaging with the majority of disease

confined to the peritoneal cavity and surgically resectable to a residual size of less

than 1 cm or amenable to radiofrequency ablation in patients who are > 18 years of

age.

Design:

- This is a classic phase 2 trial to determine efficacy of this therapeutic strategy in

ACC. Patients will undergo cytoreductive surgery to achieve a CCR of 0 or 1.

Patients who are successfully debulked will then undergo HIPEC with cisplatin.

Patients will be evaluated by associate investigators in coordination with the Principal

Investigator for eligibility. Due to its exploratory nature, up to 30 patients may be

enrolled to obtain 24 evaluable patients. (Patients must undergo successful debulking

and HIPEC to be considered evaluable.)

- INCLUSION CRITERIA

- Histologically proven ACC with the majority of disease confined to the peritoneal
cavity and resectable or amenable to radiofrequency ablation

- Disease evaluable by CT or PET imaging

- All disease should be deemed resectable based on imaging studies e.g.:

- Hepatic metastases (unilateral or bilateral less than or equal to 5 lesions, less
than or equal to 15 cm total diameter)

- Note: Hepatic lesions must be amenable to complete resection

- Primary peritoneal metastases (small disease load less than or equal to P2
disease) without massive ascites or intestinal obstruction

- Lung metastases (less than or equal to 3 unilateral/bilateral, 9 cm total
diameter)

- Note: lung lesions must be amenable to complete resection

- Note: Patients with both pulmonary and hepatic metastases will be enrolled at the
discretion of the PI

- Note: In situations where resection to Completeness of Cytoreduction Score (CC) 0
or 1 is uncertain, patients may undergo diagnostic laparoscopy prior to
enrollment to determine feasibility of resection.

- Greater than or equal to 18 years of age

- Able to understand and sign the Informed Consent Document

- Clinical performance status of ECOG less than or equal to 2

- Life expectancy of greater than three months

- Patients of both genders must be willing to practice birth control during and for four
months after receiving chemotherapy

- Hematology:

- Absolute neutrophil count greater than 1500/mm^3 without the support of
Filgrastim.

- Platelet count greater than 75,000/mm^3.

- Hemoglobin greater than 8.0 g/dl.

- Chemistry:

- Serum creatinine less than or equal to 1.5 mg/dl unless the measured creatinine
clearance is greater than 60 mL/min/1.73 m2

- serum AST and ALT within 5 times the upper limit of normal and a total serum
bilirubin of less than 3 times the upper limit of normal, both of which define
the upper limit of grade 2 treatment related toxicities.

- PT within 2 seconds of the upper limit of normal (INR less than or equal to 1.8)

- Recovered from any toxicity to grade 2 or less from all prior chemotherapy,
immunotherapy or radiotherapy and be at least 30 days past the date of their last
treatment with the exception of mitotane which may be continued.

- Able to understand their disease and the exploratory nature of combining surgery and
HIPEC for this histology.

EXCLUSION CRITERIA

- Concomitant medical problems that would place the patient at unacceptable risk for a
major surgical procedure.

- History of congestive heart failure and/or an LVEF less than 40%

Note: Patients at increased risk for coronary artery disease or cardiac dysfunction (e.g.,
greater than 65yo, diabetes, history of hypertension, elevated LDL, first degree relative
with coronary artery disease) will undergo full cardiac evaluation and will not be eligible
if they demonstrate significant irreversible ischemia on stress thallium or an ejection
fraction less than 40%.

- Significant COPD or other chronic pulmonary restrictive disease with PFT s indicating an
FEV1 less than 50% or a DLCO less than 40% predicted for age

Note: Patients who have shortness of breath with minimal exertion or who are at risk for
pulmonary disease (e.g., chronic smokers) will undergo pulmonary function testing and will
not be eligible if their FEV1 is less than 50% of expected.

- Grade 2 or greater neuropathy

- Women of child-bearing potential who are pregnant or breastfeeding because of the
potentially dangerous effects of the chemotherapy on the fetus or infant.

- Brain metastases or a history of brain metastases

- Childs B or C cirrhosis

- Evidence of severe portal hypertension by history, endoscopy, or radiologic studies

Note: Any diagnosis of portal hypertension or clinical stigmata of such including but not
limited to gastric or esophageal varices, umbilical vein varices or telangectasias.

- Weight less than 30 kg

- Active systemic infections, coagulation disorders or other major medical illnesses of
the cardiovascular, respiratory or immune system, myocardial infarction, cardiac
arrhythmias, obstructive or restrictive pulmonary disease