Phase II Trial of Combined Resection, Intraperitoneal Chemotherapy, and Whole Abdominal Radiation for Treatment of Peritoneal Mesothelioma

Phase II trial of combined resection, intraperitoneal chemotherapy, and whole abdominal radiation for treatment of peritoneal mesothelioma.

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Patient Eligibility:

See Section 3.0 for details
Evaluation at the CPMC prior to study entry
Histologically documented malignant mesothelioma
ECOG Performance Status 0-2
Measurable or evaluable disease
>1 week since surgery
>6 weeks since CT (0-2 prior chemotherapy regimens)
No prior RT
No history of other malignancy within previous 5 years
No other serious medical/psychiatric illness
Informed Consent; IRB Approval
White cell count> 3,000/ul
Platelet count> 100,000/ul
Calculated creatinine clearance ³ 45 ml/min
Bilirubin< 1.5 x normal
Audiometric examination

Potential Toxicity: Neutropenia, thrombocytopenia, mucositis (see section 7.0 for details)

1.0 Introduction

1.1 Background on tumor

The annual incidence of malignant mesothelioma in the United States is approximately 2200 cases per year, of which approximately 25% are peritoneal mesotheliomas. The incidence appears to be increasing. Mesothelioma most commonly develops in the fifth to seventh decade (1).

The subset of patients with malignant peritoneal mesothelioma usually present with symptoms and signs of advanced disease including pain, ascites, weight loss, or an abdominal mass. Fever unresponsive to standard antipyretics and thrombocytosis are common and poor prognostic signs. The histology, histochemical, immunohistochemical and ultrastructural features are similar to those of pleural mesothelioma.

These tumors grow as a superficial glaze covering the entire peritoneal surface or as poorly vascularized excrescences. The tumor generally remains confined to the abdomen until late in its course, and even then is more likely to involve one or both pleural cavities than to disseminate hematogenously. Invasion into the abdominal wall, the diaphragm, or the intestinal wall is not uncommon. Most patients die without metastases or involvement of the chest.

No satisfactory staging system exists for peritoneal mesotheliomas. CT scans are helpful to assess the extent of disease, however patients may have advanced disease with relatively normal radiographic studies. Classic findings on CT scan include mesenteric thickening, peritoneal studding, and ascites. PET scans offer the possibility of improved tumor detection.

1.2 Background and rationale for new treatment

The median survival of untreated patients in most series is brief, 9 to 18 months depending on the histology. Those with sarcomatous features are more aggressive. Based on the 5 to 13 year disease-free survival of a few selected patients treated with multimodality therapy, peritoneal mesothelioma may even be curable in some individuals with early disease (1).

Complete surgical resection is rarely, if ever, feasible, and has not been shown to afford survival benefit in the absence of additional therapy. Nevertheless, surgical intervention can provide palliation for small bowel obstruction, relief of massive ascites by peritoneo-venous shunting or via Tenckhoff catheter paracentesis (2).

Because the disease is usually confined to the abdomen, whole abdominal radiation has been used as an adjuvant therapeutic modality. However, the large treatment volume needed and the radiation tolerance of multiple intra-abdominal organs limits radiation dose. The technique reported from the Joint Center for Radiation Therapy for ovarian carcinoma (3) has been adapted for use in peritoneal mesothelioma, but the role of radiation therapy in achieving long term survival as a sole treatment modality remains unclear.

Chemotherapy given systemically to patients with malignant mesothelioma has yielded disappointing results. The agents that produce response rates in 10% to 20% of patients include doxorubicin, detorubicin, epirubicin, mitomycin, cyclophosphamide, ifosfamide, cisplatin, and carboplatin. More recently combination therapy with gemcitabine and cisplatin for patients with pleural mesothelioma have shown objective responses of 40%. Response rates in small studies have been reported with doxorubicin, high-dose methotrexate, and edatrexate at 26%, 37%, and 25%, respectively, but these have yet to be confirmed (4).

Intrapleural therapy using interferon gamma, particularly for small-volume disease, shows promise. In a prospective multi-institutional study, intrapleural treatment with gamma-interferon was administered intrapleurally at a dose of 40 million units twice a week for 8 weeks in patients with Butchart's Stages I and II epithelial or mixed malignant pleural mesothelioma. Of 89 patients accrued over 46 months, 8 histologically confirmed complete responses and nine partial responses were reported for an overall response rate (RR) of 20%. Most responses occurred for patients with early stage disease (RR for Stage I disease was 45%). Treatment with interferon was well tolerated. The main side effects were hyperthermia, liver toxicity, neutropenia, and catheter-related infection (5).

Intraperitoneal interferon has also been given as a single agent to patients with ovarian carcinoma and other neoplasms (6,7). An institutional pilot study of alternating weekly courses of intraperitoneal doxorubicin and cisplatin followed by a four week course of weekly gamma interferon has been conducted and tolerated well except for grade 1-3 ototoxicity in up to 15% of patients. Data on this pilot study is currently being analyzed.

Combined modality approaches were carried out at several institutions, mainly as feasibility studies

The first reported phase II trial of multimodal therapy for peritoneal mesothelioma was begun in 1982, and was first reported on in 1985 and subsequently in 1988 (8,9). After surgical resection of tumor nodules >1 cm and placement of an intraperitoneal Port-a-Cath, alternating cycles of cisplatin and doxorubicin were given IP every 2 weeks for 20 weeks. Second-look laparotomy allowed removal of the Port a Cath and assessment of disease response. Patients with no visible disease received whole abdominal XRT. Patients with macroscopic residual disease were treated with IV cyclophosphamide and doxorubicin, and then radiation therapy. Sixteen patients completed therapy. The median survival for the entire treated group was 16.4 months, with several patients doing well at 5 and 10 years. Toxicity was generally mild, with nausea and vomiting secondary to cisplatin, transient elevation in creatinine as high as 2.4, and mild to moderate hematologic toxicity.

Utilizing the concept that hyperthermia may potentiate the cytotoxic effects of chemotherapeutic agents, this modality has also been used for the treatment of peritoneal mesothelioma (10-12). Cisplatin has been the most commonly used chemotherapeutic agent in the treatment of peritoneal mesothelioma.

A second institutional pilot study of 21 patients studied eight alternating weekly courses of intraperitoneal doxorubicin and cisplatin (one week interval after cisplatin) followed by a four week course of weekly gamma interferon, second look surgery with hyperthermic chemotherapy, and subsequent abdominal and pelvic radiation therapy has been conducted. This regimen was tolerated well except for grade1-3 ototoxicity in up to 15% of patients. Fifteen patients are alive, ten with no evidence of disease with a median survival of 22 months, and five with disease and a median survival of 20 months (abstract submitted to ASCO 2001).

Encouraged by the results on the initial Phase I/II study, we are proposing to modify the treatment plan and schedule, to assess for possible greater efficacy.

One modification will be to give gemcitabine concurrently with cisplatin. This combination will be alternated with intraperitoneal doxorubicin.

Exposure of peritoneal surfaces to gemcitabine is significantly increased with intraperitoneal gemcitabine (13). Synergy between gemcitabine and cisplatin has been established (14).

A phase I/II trial of intraperitoneal cisplatin and gemcitabine for patients with epithelial cancer attempted to determine the optimal dose of this drug combination (15,16). Hematologic dose limiting toxicity was reached at dose level 1; cisplatin 75 mg/m2 and gemcitabine 500 mg/m2. Intraperitoneal cisplatin was given on day 1, and intraperitoneal gemcitabine on days 1 and 8, with the cycle repeated every 21 days.

A second modification will be to administer weekly infusions of gamma-interferon 30 million units/m2 rather than twice weekly.

At the time of initial resection and peritonectomy, as part of the overall care of the patients and to plan for subsequent trials of chemotherapeutic agents, tissue will be banked and analyzed for extreme drug resistance assays, expression of MRP, MDR1, MDM2, and p53, as well as for other gene analyses which might affect chemotherapy resistance. These assays will be performed on the tissue samples obtained at initial surgery and second look laparotomy to assist in formulating treatment options should alternative therapies be required.

2.0 Objectives

2.1 Primary Objective

To determine the response rate, duration of response, duration of survival and toxicity of combined resection, intraperitoneal chemotherapy, and whole abdominal radiation for treatment of peritoneal mesothelioma.

3.0 Eligibility Criteria

Patients must fulfill the following criteria:

3.1 Histologically confirmed malignant mesothelioma

3.2 Ineligible for other high priority national or institutional study.

3.3 Prior therapy allowed:

0-2 prior chemotherapy regimens; > 6 weeks since chemotherapy
>1 week since surgery (Prior surgical resection preceding disease recurrence is acceptable)
No prior abdominal or lower chest radiation therapy

3.4 Non pregnant, non lactating

3.5 Clinical Parameters

Life expectancy

> 2 months

Age

> 18 years

Performance status

0-2 (SWOG) (Appendix II)

3.6 Required initial laboratory data (see also Sec. 8.0)

White cell count

>3000/ul

Platelet count

>100,000/ul

BUN

<1.5 x normal

Calculated creatinine clearance

>= 45 ml/min

Bilirubin

<1.5 x normal

Performance status

0-2 (SWOG) (Appendix II)

3.7 Informed Consent: Each patient must be completely aware of the nature of his/her disease process and must willingly give consent after being informed of the procedure to be followed, the experimental nature of the therapy, alternatives, potential benefits, side-effects, risks, and discomforts.

3.8 No prior malignancy within the past five years (other than curatively treated carcinoma in-situ of the cervix or skin cancer).

3.9 No serious medical or psychiatric illness preventing informed consent or intensive treatment (e.g., serious infection). HIV status or other severe illnesses will be assessed using medical records.

4.0 Patient Entry

4.1 Referrals: Referral from the consultation service may take place only with the agreement of the responsible attending physician

4.2 Staging: Evaluate all areas of original disease

4.3 Required Forms:
Eligibility Criteria Form
Informed Consent
On Study Form

5.0 Treatment Plan

5.1 Initial Surgery: All patients will undergo exploratory laparotomy through a midline vertical incision, with a total omentectomy and excision of all gross peritoneal, retroperitoneal and pelvic disease. An attempt will be made to remove all nodules of >1 cm in diameter. Peritoneal catheters will be placed bilaterally and tunneled through the abdominal wall to prevent leakage of the intraperitoneal chemotherapy. A sample of resected tissue will be sent for studies of extreme drug resistance.

Ordinarily, it is not intended that parenchymal organs be removed as part of the surgery, except for resection of involved segments of ileum or colon. Should resection not be possible without organ removal, because of tumor involvement as determined by inspection by the operating surgeon, the patient will be dropped from the protocol.

5.2 Intraperitoneal (IP) Chemotherapy: Approximately three to four weeks following surgery intraperitoneal therapy will be initiated according to the following schedule:

Intraperitoneal doxorubicin alternating with gemcitabine/cisplatin

A series of intraperitoneal infusions of doxorubicin alternating with intraperitoneal infusions of gemcitabine in combination with cisplatin will be given every two weeks.

Drug

Dose

Schedule

Doxorubicin

25mg total dose in 1000cc NS
Infused over 2 hours

weeks 1, 4, 7, 10

alternating with

Cisplatin

50mg/m2 } combined in 1000cc NS

weeks 2, 5, 8, 11

Gemcitabine

250 mg/m2

An additional 500cc NS will be administered IP following infusion of intraperitoneal chemotherapy.

Solucortef 100mg in 100 ml NS will be given intraperitoneally prior to doxorubicin.

Mannitol 20% solution will be administered intravenously at 50 ml/hr for 6 hours post intraperitoneal cisplatin in combination with gemcitabine.

Dosage Modifications:

If no grade 3 or 4 hematologic toxicity is seen after the 2^nd cycle (WBC > 4 at time of 3^rd cycle), an escalation to 300mg /m2 of gemcitabine for subsequent cycles will be allowed with subsequent cycles.

If WBC is <3.0 or platelet count <100,000, delay treatment until count recovery, and reduce both drug doses by 50% for subsequent cycles.

Delay treatment for one week for grade 2, and discontinue for grade 3 or 4 hepatic (bilirubin or transaminase), renal, neurologic or ototoxicity.

5.3. Intraperitoneal (IP) Immunotherapy

Interferon-gamma: (Actimmune, Genentech) Gamma-interferon 9 million units week 13, 30 million units (300 µg) in 2000 ml N/S q weekly x 3 weeks; weeks 14, 15, 16.

5.4 Second Look Surgery: Approximately 2-4 weeks following the final infusion of interferon-gamma, the patient will undergo surgical exploration of the abdomen and pelvis.

If no gross disease (nodules < 1cm) is present, multiple biopsies will be obtained and chemotherapy (mitomycin 10/mg/m2 and cisplatin 75 mg/m2 in 2 liters NS at 40.5 – 42.5 C) will be infused over 90 minutes via suprahepatic inflow and pelvic outflow catheters connected to a recirculating circuit with a roller pump heat exchanger. Mitomycin alone will be infused if creatinine clearance is 45 ml/min.

For technically resectable gross disease (nodules > 1cm) intraoperative chemotherapy as above will be administered. Further resection will be performed post chemotherapy. Patients with technically unresectable disease will be taken off study and alternative therapeutic options will be discussed. Catheters will be removed.

5.5 Radiation Therapy: Approximately two to four weeks following surgery, all patients except those with unresectable residual disease will commence a course of radiation therapy. In the immediate post-operative period appropriate patients will be referred to Karen Fountain MD, radiation oncologist. The course of therapy will be 5-7 weeks.

For patients who have not received a full course of intraperitoneal chemotherapy: Use a 67% partial transmission block to attenuate the dose given to the abdomen above a line drawn through the L5-S1 interspace. Give daily fractions of 120 cGy in the upper abdomen and 180 cGy in the pelvis (prescribed to the central axis) 5 times weekly to parallel and opposed AP-PA portals, utilizing the 6 MV photon beam. Add full-thickness AP and PA kidney blocks after 1800 cGy. Treat to a total dose of 3000 cGy to the upper abdomen and 4500 cGy to the pelvis.

For patients who have received a full course of intraperitoneal chemotherapy: Do not use partial transmission blocks. Treat the upper abdomen and pelvis uniformly at the rate of 100-150 cGy per fraction; Add kidney blocks after 1400-1550 cGy to both the anterior and posterior portals, and treat to a total dose of 3000-3080 cGy to the abdomen and pelvis.

For all patients: Use custom Cerrobend blocking for all blocks. Treat each field each day. Give treatment breaks for WBC < 1500 or platelets < 75,000, or for intractable nausea and vomiting. Place blocks over the lower portion of the heart (but include the leaves of the diaphragm) and over the femoral heads and associated soft tissue of the pelvis.

The patients will be monitored for myelosuppression and other toxicities by the treating radiotherapist with periodic CBC and physical exams. Any radiotherapy-related toxicity requiring hospitalization (grade IV Leukopenia or thrombocytopenia + neutropenic sepsis), (grade III-IV GI toxicity [CTC criteria group G 101-110 and F116, F118]) will be cause for discontinuing radiotherapy and taking the patient off protocol.

6.0 Potantial Toxicity, Dose Modifications and Management

The NCI Common Toxicity Criteria will be used (see appendix II).

Definitions

A. Serious adverse event: any experience that is fatal or life-threatening, is permanently disabling, requires inpatient hospitalization, or is a congenital anomaly, or overdose.
B. Associated with the use of the drug: there is a reasonable possibility that the experience may have been caused by the drug.
C. Unexpected adverse event: any adverse event that is not identified in nature, severity, or frequency in the current investigators brochure or package insert (whichever applies to this study).

Reporting

A. Adverse events will be reported as required by section 312.32 of the Code of Federal Regulations.
B. RPR will be provided with a copy of all the serious adverse event reports filed with the FDA.

Report to the IRB within 24 hours:

A. All life-threatening (Grade 4) and (Grade 5) unexpected reactions.
Written report to follow within 10 working days.

B. Report in writing within 10 working days:
1) Life-threatening and lethal (Grade 4 and 5) unexpected reactions (except myelosuppression)
2) Grade 2 and 3 unexpected reactions

6.1 Gemcitabine: Myelosuppression is the dose-limiting toxicity, with some patients exhibiting severe neutropenia. Packed cell transfusions may also be required for anemia. Nausea and vomiting are mild but common. Diarrhea and edema are sometimes seen. Elevated transaminases are common, as is fever during drug administration. Hematuria and proteinuria are uncommon. Acute dyspnea and rash can occur but are uncommon. Paresthesias and central nervous system depression are rare.

6.2 Cisplatin: Cisplatin produces a dose-dependent impairment of renal tubular function manifested as a rise in serum creatinine or BUN peaking l0-l5 days after therapy. Various hydration schedules ± mannitol have been used effectively as prophylaxis. Nausea and vomiting are characteristically severe and prolonged. Thrombocytopenia and leukopenia are usually mild. High frequency hearing loss, tinnitus and occasionally deafness may occur. Peripheral neuropathies (paresthesias or sensory loss in a glove/ stocking distribution or as muscular weakness) increase with increasing cumulative dose. Anaphylactic reactions have been reported which require epinephrine, antihistamines, and corticosteroids.

6.3 Doxorubicin: Doxorubicin is a vesicant. Extravasation into tissues can cause severe cellulitis and ulcerative necrosis requiring skin grafting. A single intravenous dose of doxorubicin causes alopecia of the scalp, and much of eyebrow and body hair in over 90% of recipients, usually within three weeks. Hair growth resumes after about four months, even if doxorubicin is still being given. Doxorubicin causes myelosuppression, and can cause pancytopenia, leading to infection and hemorrhage. It is toxic to the GI tract, causing nausea and vomiting soon after each dose and oral and intestinal ulcerations 7-10 days later. Characteristically, the urine turns red after each dose due to excretion of drug metabolites. Perhaps the most significant toxicity is congestive heart failure, which occurs in a cumulative, dose-dependent fashion: approximately 5% of patients receiving >450mg/m2 doxorubicin develop CHF. When given intraperitoneally, doxorubicin may cause peritoneal pain, ileus, adhesions, fibrosis, and sterile abscess.

6.4 Interferon-gamma: The acute side effects are high fever, chills, malaise, or flu-like symptoms. Generally these symptoms abate with repeat treatments and are controlled with antipyretics. Leukopenia and elevated hepatic transaminases may occur. Side effects of interferon on other systems such as the GI, renal, metabolic and hormonal tracts have been described. Most are reversible Common side effects include neutropenia and thrombocytopenia, anorexia, weight loss, lethargy and decreased concentration. Other side effects such as confusion and mood alterations and seizures with EEG abnormalities may occur, as well as those of the cardiovascular system, orthostatic hypertension and atrial and ventricular arrhythmias. Antibodies to interferon have been reported, but they have not been associated with hypersensitivity reactions. These effects have not been observed after intraperitoneal injection of interferon, which has, in general, been well tolerated, except for fever, malaise and transient elevation of hepatic transaminases.

6.5 Mitomycin C: Intraperitoneal administration of mitomycin/cisplatin may result in abdominal pain, adhesions, and obstruction. Hyperthermia may increase drug absorption. Frequently, the drug produces nausea, vomiting, anorexia, and alopecia. Leukopenia and significant thrombocytopenia occur frequently, especially with repeated doses. A rare but severe toxicity is hemolytic-uremic syndrome. These toxic effects are usually related to the total dose given, and have not been seen in the pilot study.

6.6 Radiation Therapy: Risks due to or intensified by whole abdominal radiation therapy may include but may not be limited to nausea, vomiting, fatigue, adhesions, bowel obstruction, fistula formation loss of kidney function, liver toxicity and/or prolonged depression of the blood counts.

As some of these effects may develop months after the completion of radiation therapy, patients will need careful monitoring. Generally, radiation therapy to the entire abdomen utilizing modern techniques is well tolerated.

7.0 Drug Formulation, Availability and Preparation

7.1 Gemcitabine: Gemcitabine is supplied as lyophilized powder in vials containing 200 and 1000 mg of drug. Vials of powdered drug should be discarded after expiration date. Reconstituted drug is stable at room temperature for at least 24 hours. 5ml or 25 ml of normal saline should be added to 200 mg or 1000 mg vials, respectively, and shaken to dissolve. This 40-mg/ml solution can be further diluted in normal saline to give the total drug amount in 100 ml to 250 ml.

7.2 Cisplatin: Cisplatin is supplied as lyophilized powder in sealed vials of 10 mg and 50 mg, and as a 1-mg/ml solution in bottles of 50 and 100 mg/bottle. Vials and solutions are stored at room temperature. Diluted drug is stable at room temperature for 96 hours. Powder should be diluted to 1 mg/ml in normal saline, then diluted in half-normal or normal saline to desired total volume. Unstable in D5W; may precipitate with aluminium; should not be mixed with metoclopramide, sodium bicarbonate solutions, sodium thiosulfate, 5-fluorouracil, or mesna.

7.3 Doxorubicin: Doxorubicin is supplied as vials of lyophilized powder containing 10 to 150 mg of drug, and as vials of 2mg/ml solution in 10 to 200 mg vials. Powder vials are to be stored at room temperature; vials of solution should be refrigerated. Stock solutions of the drug are stable for 35 days at room temperature and 6 months at 4 C or when frozen. Diluted solutions in saline are stable for 14 days at room temperature. Vials in solution are ready to use or dilute further in saline. The powder should be dissolved in preservative-free normal saline to a concentration of 2 mg/ml.

7.4 Interferon-gamma: Available as vials of sterile aqueous solution containing 100 µm (3 million U) of drug. Drug withdrawn into a syringe should be used within 12 hours. Unused reconstituted drug should be discarded.

7.5 Mitomycin C: Available as vials of powder of 5, 20, and 40 mg. Vials should be stored at room temperature and discarded after the listed expiration date. Reconstituted drug is stable for 7 days at room temperature at 0.5 mg/ml. More dilute solutions are less stable and should be used within 3 hours. Sterile water should be added to the vials to reach a concentration of 0.5 mg/ml. This solution can be further diluted in D5W or normal saline.

8.0 Required Data

q 3 months x 1 year; the q 6 months x 3 years; then yearly x 5 years

If ccessible to physical examination. Obtain q cycle X 2 if measurable only on X-ray or scan then q 2 cycles

If initially positive. Chest x-ray not required if patient is getting chest CT

PRN When clinically appropriate

Tests and Observations

On Study

Day 1
Each
Treatment

Post-treatement
Follow-up*

Signed informed consent

X

History & interval note

X

X

X

Physical Examination

X

X

X

Pulse, Blood Pressure

X

X

Height, Surgace Area

X

X

X

Weight

X

X

X

Performance Status

X

X

X

Tumor Measurements

X

A

A

Drug Toxicity

X

X

Staging

CT chest

X

*

CT abdomen/pelvis

X

B

B

PET Scan

Optional

Optional

EKG

X

Laboratory

CBC, Platelet Count & diff

X

X

X

Creatinine

X

X

X

Electrolytes

X

X

X

Calculated creatinine clearance

X

SGOT or SGPT & Bili.

X

X

PRN

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* q 3 months x 1 year; the q 6 months x 3 years; then yearly x 5 years

A If accessible to physical examination. Obtain q cycle X 2 if measurable only on X-ray or scan then q 2 cycles

B If initially positive. Chest x-ray not required if patient is getting chest CT

PRN When clinically appropriate

9.0 Criteria For Evaluation

9.1 Complete response: Disappearance of all measurable disease, signs, symptoms, and biochemical changes related to the tumor, for >4 weeks, during which no new lesions may appear. With respect to surgical debulking, a demonstrable complete gross and microscopic absence of detectable tumor at second look.

9.2 Partial response: When compared with pretreatment measurements, a reduction of > 50% in the sum of the products of the perpendicular diameter of all measurable lesions lasting > 4 weeks, during which no new lesions may appear. With respect to surgical debulking, a demonstrable near-complete gross and microscopic absence of tumor at second look. No tumor mass greater than 5mm. All masses fully resectable.

9.3 Stable disease: A < 50% reduction or < 25% increase in the greatest diameter of all measured lesions, and the appearance of no new lesions for > 8 weeks. With respect to surgical debulking, persistenceof small amount of tumor at second look, incompletely resectable, or cytologically positive ascitic fluid, without change over the observation period.

9.4 Objective Progression

9.4.1 An increase in the longest diameters of any measured lesion by > 25% over the size present at entry on study or for patients who respond the size at the time of maximum regression. With respect to surgical debulking, persistence of tumor at second look or incompletely resectable tumor.

9.4.2 The following in and of themselves do not constitute progression; however, they should initiate a new evaluation for extent of disease.

Deterioration in performance status, > 10% loss of pretreatment weight, or deterioration in prior symptoms.

9.5 Time to treatment failure. Time from day 1 of surgical resection to death or disease progression.

10.0 Removal of Patients From Protocol Therapy

10.1 Response or Stable disease: Continue treatment at the highest tolerated prescribed dose until the appearance of disease progression.

10.2 Disease Progression: Any patient with rapid disease progression may be removed from study. Otherwise, deliver intraperitoneal chemotherapy and interferon-gamma up until the time of second look surgery. Document details including tumor measurements on flow sheets. Dosage will be modified as described in Section 6.0 for patients with toxicity.

10.3 Extraordinary Medical Circumstances: If at any time the constraints of this protocol are detrimental to the patient's health, the patient shall be withdrawn from treatment. In this event:

Notify the Study Chairperson.
Document reason(s) for withdrawal on the flow sheets.
Follow the patient for progression and survival.

10.4 Unexpected, Life-threatening or Lethal Toxicity:

Notify the Protocol Office and Study Chair within 3 business days.

11.0 Ancillary Therapy

11.1 Patients should receive full supportive care including transfusions of blood products, antibiotics, antiemetics, etc., when appropriate. The reason(s) for treatment, dosage, and the dates of treatment should be recorded on the flow sheets.

11.2 Treatment with hormones or other chemotherapeutic agents is not permitted while the patient is on study, except for steroids administered for antiemesis, premedication, adrenal failure, or septic shock or hormones administered for non-disease-related conditions (e.g., insulin for diabetes)

12.0 Statistical Aspects

The primary objective of this pilot study is to investigate the safety and efficacy of combined resection, intraperitoneal chemotherapy, and whole abdominal radiation for treatment of peritoneal mesothelioma. Efficacy will be evaluated in terms of gross microscopic disease at time of second look surgery. Fifteen patients will be enrolled in this study. With 15 patients in the study a 95% confidence interval for the response rate will extend no more than +- 25% around the true response rate. Duration of response and time to disease progression will be summarized by Kaplan-Meier curves. With 15 patients in the study we will have 90% probability of detecting any unforeseen event that has a prevalence of at least 14%.

13.0 References

1. Antman KH, Li FP, Pass HI, Corson J, Delaney T. Benign and malignant mesothelioma. In: De Vita, Hellman, Rosenberg, eds. Cancer: Principles and Practice of Oncology. 4th ed. Philadelphia: J.B. Lippincott Co.; 1993:1489-508.

2. Lomas DA, Wallis PJ, Stockley RA. Palliation of malignant ascites with a Tenckhoff catheter. Thorax. 1989;44:828

3. Lederman GS, Recht A, Herman T, Osteen R, Corson J, Antman KH. Long-term survival in peritoneal mesothelioma. The role of radiotherapy and combined modality treatment. Cancer. 1987;59:1882-6.

4. Ong ST, Vogeizang NJ. Chemotherapy in malignant pleural mesothelioma. J Clin Oncol. 1996;14:1007-17.

5. Boutin C, Nussbaum E, Monnet I, et al. Intrapleural treatment with recombinant gamma-interferon in early stage malignant pleural mesothelioma. Cancer. 1994;74:2460-7.

6. Windbichler GH, Hausmaninger H, Stummvoll W, Graf AH, Kainz C, Lahodny J, Denison U, Muller-Holzner E, Marth C. Interferon-gamma in the first-line therapy of ovarian cancer: a randomized phase III trial. Br J Cancer. 2000;82(6):1138-44.

7. Freedman RS, Kudelka AP, Kavanagh JJ, Verschraegen C, Edwards CL, Nash M, Levy L, Atkinson EN, Zhang HZ, Melichar V, Patenia R, Templin S, Scott W, Platsoucas, CD.

8. Antman K, Osteen R, Klegar K, et al. Early peritoneal mesothelioma: a treatable malignancy. Lancet. 1985;ii:977-82.

9. Weissman L, Osteen R, Corson J, Herman T, Antman K. Combined modality therapy for intraperitoneal mesothelioma. Proc Am Soc Clin Oncol. 1988;7:274.

10. Ma GY, Bartlett DL, Reed E, Figg WD, Lush RM, Lee KB, Libutti SK, Alexander HR. Continuous hyperthermic peritoneal perfusion with cisplatin for the treatment of peritoneal mesothelioma. Cancer J Sci Am. 1997;3(3):174-9

11. Park BJ, Alexander HR, Libutti SK, Wu P, Royalty D, Kranda KC, Bartlett DL. Treatment of primary peritoneal mexothelioma by continuous hyperthermic peritoneal perfusion (CHPP). Ann Surg Oncol. 1999; 6(6):582-90.

12. Mongero LB, Beck JR, Kroslowitz RM, Argenziano M, Chabot JA. Perfusion. 1999;14(2):141-5.

13. Pestieau SR, Stuart OA, Chang D, Jacquet P, Sugarbaker PH. Pharmacokinetics of intraperitoneal gemcitabine in a rat model. Tumori. 1998: 84(6): 706-11.

14. Peters GJ, Bergman AM, Ruiz van Haperen VW, Veerman G, Kuiper CM, Braakhuis BJ. Interaction between cisplatin and gemcitabine in vitro and in vivo. Semin Oncol. 1995;22(4 Suppl 11):72-9.

15. Aghajanin C, Sabbatini P, Hensley M, Tong W, Soignet S, Hoskins W, Brown C, Poynor E, O’Connor S, Pezzulli S, Barakat R, Spriggs D. A phase I trial of intraperitoneal (IP) cisplatin with IP gemcitabine in patients (Pts) with epithelial ovarian cancer. ASCO. 1999; 18: 1428.

16. Sabbatini P, Aghajanian C, Hensley M, Tong W, Soignet S, Hoskins W, O Flaherty C, Pezzulli S, Barakat R, Spriggs D. A phase I/II trial of intraperitoneal (IP) cisplatin (CDDP) with IP gemcitabine (GEM) in patients (pts) with epithelial ovarian cancer. Proceedings of the 11^th NCI-EORTC-AACR Symposium. 2000:458[Abstract].

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Cancer Center Protocol

INFORMED CONSENT

IRB #7723, Phase II Trial of Combined Resection, Intraperitoneal Chemotherapy, and Abdominal Radiation for Treatment of Peritoneal Mesothelioma

Institutional P.I.: Robert N. Taub MD PhD., Mary Lou Keohan MD; Co-investigators: John Chabot MD, Karen Fountain MD, Susan Talbot MD.

IRB APPROVAL DATE_____________________________________

APPROVAL EXPIRATION DATE_____________________________

Columbia Presbyterian Medical Center - Consent to Participate in a Research Study

The purpose of this consent form is to provide you with the information you need to consider in deciding whether to participate in this research study.

INTRODUCTION

You are invited to take part in a research study to determine the effectiveness of surgery, chemotherapy and radiation used in combination for treatment of your peritoneal mesothelioma tumor which we hope will arrest the growth and reduce it in size. Your physicians feel that your tumor will continue to grow without effective treatment. Because of these problems, we are always in search of new treatments that may be effective. The proposed treatment has been tried in other institutions with arrest of the tumor in some but not all patients who received it. We wish to further evaluate this treatment at our institution, to confirm and extend these earlier findings. Thus, this study is designed to scientifically investigate whether such treatment is of any benefit for patients like you. It is also designed to increase our knowledge of the side effects that might be caused by this treatment, how often they occur, and how they may be reduced. Since this particular combination of treatments has not been used extensively, we cannot be sure of its potential effectiveness or side effects.

It is important that you read and understand several general principles that apply to all who take part in this study: a) this is a research study and taking part in the study is entirely voluntary, b) personal benefit may not result from taking part in the study, but knowledge may be gained that will benefit others, and c) you may withdraw from the study at any time without penalty or loss of any benefits to which you are otherwise entitled. The nature of the study, the potential risks, inconveniences, discomforts, and other pertinent information about the study are discussed below. You are urged to discuss any questions you have about this study with the staff members who will explain it to you.

PROCEDURES

If you decide to participate, you will undergo two operations: initially, you will undergo exploratory surgery (called laparotomy). While you are under general anesthesia a longitudinal 12-15 inch incision (cut) will be made in your abdomen, and the surgeon will then attempt to remove all visible tumor. If, and when this is accomplished, he will implant a device called a port-a-cath, which consists of a tube leading into the abdominal cavity attached to a small chamber sewn beneath the skin.

After you recover from this operation, you will receive chemotherapy with several different drugs (Cisplatin, Gemcitabine, Doxorubicin, Gamma-interferon). Doxorubicin alternating with cisplatin and gemcitabine (one week interval after each cycle of this drug combination) will be given for a total of four cycles of each drug combination, weeks 1-12. Gamma-interferon will be given weekly for four weeks, weeks 13, 14, 15, and 16.

Afterward, you will undergo a second operation similar to first, where the abdomen will be re-inspected for any remaining or regrowing tumor so that we can determine whether you need additional chemotherapy. A single treatment with heated chemotherapy drugs (cisplatin/mitomycin) will be washed through your abdominal cavity for 90 minutes and the port-a-cath will be removed. If tumor remains in the abdomen after these treatments, you may be given supplemental intravenous chemotherapy with a different drug, and therefore be removed from the study.

You will then receive 5 weeks of radiation therapy (Monday through Friday) directed to the whole abdomen. This will, complete your treatment.

Your doctor will evaluate you initially, then every week during treatment, then at one-month intervals for six months, then at two to three month intervals. The initial evaluation will consist of a physical examination; three (3) blood tests (3 teaspoons of blood); a chest x-ray and tomographic x-rays ("CT scans") of the chest, abdomen, and pelvis as needed to evaluate your condition. Electrocardiograms will be performed throughout to monitor your heart functions, to help avoid the possibility of any cardiac problems as a result of taking these experimental medications.

During treatment, the physical examination, blood tests, and x-rays will be obtained at least every eight weeks to monitor your progress. Samples of urine will also be obtained at the beginning of each chemotherapy treatment and when you finish the study. X-rays and scans will be taken in order to monitor your progress before and during the treatment, similar to those tests that are done in connection with your condition in any case.

RISKS:

Risks of Chemotherapy:

Bone marrow suppression (Gemcitabine, Doxorubicin, Mitomycin) Blood cells are made in the bone marrow and are responsible for fighting infection (white blood cells), carrying oxygen (red blood cells) and causing blood to clot (platelets). A reduction in the number of these blood cells (marrow suppression) can lead to an increased risk of bleeding and infection. Should these effects occur, they can be treated with blood products (transfusions) and antibiotics. This effect would be expected to occur 10~21 days after beginning each cycle of treatment and generally lasts about 3~14 days.

Nausea and vomiting; loss of appetite (Gemcitabine, Doxorubicin, Cisplatin, Mitomycin, Gamma-interferon): Although some patients may have no nausea and vomiting, some will experience some nausea and several episodes of vomiting. For some patients, vomiting will be more severe and more prolonged. Anti-nausea medications will be prescribed if yon need them.

Abdominal Cramping, intestinal blockage. Certain of these drugs irritate the lining of the abdominal cavity after injection (Cisplatin, Doxorubicin, Interferon, Mitomycin) and may cause abdominal cramps and stoppage of intestinal function with resulting blockage. Scarring may sometimes occur, necessitating further surgery to correct any abnormality in bowel function.

Mouth or stomach ulcers or diarrhea: (Gemcitabine, Doxorubicin, Mitomycin) Temporary irritation to the mouth may lead to mouth ulcers (similar to canker sores); irritation of the lining of the bowel may result in diarrhea. Anesthetic medications may ease the mouth discomfort and anti-diarrhea agents will reduce the cramping and discomfort associated with frequent bowel movements. This effect may occur about 8-14 days after each cycle of chemotherapy. If severe, your dose of chemotherapy may be adjusted.

Hair loss: (Gemcitabine, Doxorubicin, Mitomycin) Hair will fall out about three weeks after the first dose of chemotherapy but should begin to grow back 6-8 weeks after chemotherapy is discontinued.

Hearing Loss: (Cisplatin) Hearing loss may occur, most often in the higher tones (above speech range). Eventually a hearing aid may be required if there is progressive hearing loss.

Tissue damage: (Doxorubicin) Severe tissue damage may occur if certain of the drugs spill out of the vein during injection. Please inform your physician of any unusual discomfort associated with the injection of study medication

Irregular menstrual cycle or sterility: (Doxorubicin, Mitomycin) The menstrual cycle may be temporarily regular or may cease permanently resulting in an inability to conceive. Men may become sterile.

Allergic reaction: (Interferon) A fast heart rate, wheezing, low blood pressure, sweating and rash can occur in some patients with any drug. These reactions have generally been controlled with steroids or adrenaline, however, they can be life-threatening.

Liver toxicity: (Gemcitabine, Doxorubicin, Mitomycin, Interferon) In some patients, blood tests have indicated that alterations in liver chemistry have occurred following these drugs. These have thus far been unassociated with any symptoms, and were rapidly reversible after the dose of drug was reduced.

Kidney toxicity: (Cisplatin, Mitomycin) In some patients, kidney damage has been reported, with fluid retention and change in concentrations of salts in the blood. Rarely, severe failure of the kidneys with a need for dialysis or kidney transplant, has occurred. Your physicians will take extra precautions in the form of frequent monitoring of liver function with blood tests to guard against serious kidney damage.

Neurological Toxicity: (Gemcitabine, Cisplatin) In some patients high frequency hearing loss (above speech range), ringing in the ears, and occasionally deafness may occur. Peripheral neuropathies (sensory loss in a glove/ stocking distribution or as muscular weakness) increase with increasing cumulative dose.

Cardiac toxicity: (Doxorubicin) can cause damage to heart muscle with symptoms of heart failure (accumulation of fluid in the legs and lungs, decreased ability of the heart to pump blood, altered heart beat). Rarely, fatalities have occurred after treatment with other drugs of this class.

Other risks:

Specific Risks of Radiation: These include, but may not be limited to skin changes, intestinal cramps, intestinal blockage, protracted diarrhea, and damage and loss of function of sensitive abdominal organs including the kidney and liver. Radiation may also lower the blood counts and predispose you to infection, as for chemotherapy (See above). Precautions are taken to guard against such damage, and your radiation oncologist will be monitoring you closely for these effects.

The amount of radiation used in this study is within federal guidelines. However, the risks from radiation exposure are cumulative over a lifetime, therefore any unnecessary radiation exposure must be carefully considered

UNANTICIPATED SIDE EFFECTS may occur which have not been reported. If you have any unusual symptoms, report them immediately to your physician.

BENEFITS

The possible benefit for persons receiving this treatment (if it is found to be effective) is reduction in the size of the tumor and overall lengthening of your survival. However, your doctors cannot and do not guarantee that you will benefit if you participate in the study. In addition, the information which is obtained may he useful scientifically and possibly helpful to others.

ALTERNATIVES

Patients with peritoneal mesothelioma often, but not always receive some type of therapy to delay disease progression. There may be other treatments for your cancer such as other chemotherapy with other drugs or radiation therapy. Currently used drugs for therapy of mesothelioma include doxorubicin, cisplatin, carboplatin, mitomycin C, and ifosfamide, used intravenously or intraperitoneally, singly or in combination, which may help shrink your tumor with significant side effects. Their relative usefulness in your situation cannot be determined with certainty. An additional alternative is no therapy. Your doctor will discuss the benefits and side effects of alternative treatments. If new significant findings concerning your disease or treatment become known while you are on study, your doctor will discuss them with you.

STUDY TERMINATION

Your participation in the study may be terminated by your doctor without your consent if you are not benefiting from the treatment or if it is determined that the treatment is not appropriate for your condition or for other reasons at his/her discretion. This study may be terminated by your doctor, by the Presbyterian Hospital, or by Columbia University for any reason. Should the study be terminated prior to the completion of your participation, neither your doctor, nor the Presbyterian Hospital will be under any obligation to provide you with any drug used in the study after study termination. Your physician will work directly with you to decide upon further treatment after study termination.

COSTS

You will not receive any financial compensation for participating in this study. Laboratory tests (blood tests), x-rays and bone scans will be done at intervals to check the effects of the drug. These tests are felt to be part of good medical care and are covered by most types of insurance. You will be responsible for any costs not covered by insurance. Possible costs will be discussed with you prior to the beginning of the study.

CONFIDENTIALITY

Information about you obtained during this study will be kept strictly confidential and never identified in any report or publication unless you sign a release. However, it is understood that you consent to the publication of study results so long as the information is anonymous and/or disguised so that identification cannot be made. Data collected during the study will comply with U.S. regulations, as applicable, and may be stored and analyzed by computer whether in the U.S. or abroad. If results of this study are reported in medical journals or at scientific meetings, identification of study participants is withheld. Also please note that agents of the Food and Drug Administration, and the Principal investigator, Dr. Robert N. Taub may review your records.

VOLUNTARY PARTICIPATION

You are not obligated to participate in this investigational program or any other program in order to receive medical care for your disease. Participation in this study is voluntary. You are free to withdraw your consent to participate in this treatment program at any time without prejudice to your subsequent care. Dr. Taub may discontinue this study treatment at anytime if it appears to be in your best interest. Declining to participate or withdrawing from participation will involve no penalty or loss of benefits to which you are otherwise entitled. You are free to seek care from a physician of your choice at any time. In the event you withdraw from participation in the study, your doctor may continue to follow you and follow-up clinical data may continue to be collected from your medical records.

QUESTIONS

If you have any future questions about this study, you may contact the Principal Investigator, Dr. Robert Taub at (212) 305-4076. Also, if you have any questions about your rights as a research participant, you may contact the Institutional Review Board at (212) 305-5883.

PATIENT’S ATTESTATION - PERMISSION TO PROCEED

I have had the opportunity to ask questions about this study and to have them answered in clear and understandable language. I have been told that any questions that arise in the future will also be answered in clear and understandable language.

I have discussed this study with The Principal Investigator, Dr. Robert Taub, to my satisfaction. I understand that my participation is voluntary, and that I can withdraw from the study at any time without prejudice.

I have read the above and agree to enter this research study. Signing this form does not waive any of my legal rights. I have been informed that if I believe that I have sustained injury as a result of participation in a research study, I may contact the Principal Investigator, Dr. Robert N. Taub at (212) 305-4076 or the Office of Institutional Review Board at (212) 305-5883, so that I can review the matter and identify the medical resources which may be available to me.

I understand that:

a) The Presbyterian Hospital will furnish that emergency medical care determined to be necessary by the medical staff of this hospital.

b) I will be responsible for the cost of such care, either personally or through my medical insurance or other form of medical coverage:

c) No monetary compensation for wages lost as a result of injury will be paid to me by Columbia Presbyterian Medical Center.

d) I will receive a copy of this consent form.

DATE: _____________________________________________________________________

PATIENT'S
SIGNATURE: _______________________________________________________________

SIGNATURE OF
INVESTIGATOR OBTAINING CONSENT: _________________________________________

WITNESS'
SIGNATURE:_________________________________________________________________

The Institutional Review Board of the Columbia Presbyterian Medical Center has approved the solicitation of subjects to participate in this research proposal.

Eligibility Criteria:

Exclusion Critieria

CONTACT

Mary Hesdorffer, RN, BSN, Clinical Research Nurse
Columbia-Presbyterian Medical Center
161 Fort Washington Avenue
New York, NY 10032
Telephone: 212-305-1252
Fax: 212-305-6891
Email: mp317@columbia.edu

** POSTED NOVEMBER 14, 2001 **