Dr. Robert N. Taub

This was provided to us by a wife of a patient who has been diagnosed with peritoneal mesothelioma. The family will spend approximately six months in New York receiving treatment. If you would like updates on the his health status with Dr. Taub, please call us. The family will be treated by Dr. Tuab and Dr. John Chabot, who is a surgical oncologist.

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

PI: Dr. Robert N. Taub
Co-investigators: Drs. John Chabot, Karen Fountain

A Purpose/Rationale

OBJECTIVES: The purpose of this study is to evaluate the effectiveness and toxicity of combined resection, intraperitoneal chemotherapy, and whole abdominal radiation for treatment of peritoneal mesothelioma.

Background: The epidemiology, pathology, staging, clinical course, and treatment modalities summarized below are reviewed in detail by Antnan et al. (1).

The annual incidence of malignant mesothelioma in the United States is approximately 12.1 per million white men or 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 (median age 60).

The subset of patients with malignant peritoneal mesothelioma usually present with symptoms and signs of advances disease including pain, ascites, weight loss, or an abdominal mass. Fever unresponsive to standard antipyretics and thrombocytosis are common and poor prognostic signs. Other common clotting abnormalities include phlebitis, emboli, hemolytic anemia an disseminated intravascular coagulation.

The ascitic fluid may be a watery transudate or a viscous fluid rich in mucopolysaccharides. 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 the course and even then is more likely to spread to one or both pleural cavities than to disseminate hematogenously. A cake of tumor in the omentum may be palpable as an epigastric mass. Invasion into the abdominal wall. The diaphragm, or the intestinal wall in infrequent and late. Most patients die without metastases or involvement of the chest.

No satisfactory staging system exists for peritoneal mesotheliomas. CT scans are helpful to asses the extent of disease, however patients may have advanced disease with relatively normal CTS. Classic finding on CT scan include mesenteric thickening, peritoneal studding, hemorrhage within the tumor mass and ascites. MRI offers the possibility of improved resolution.

The median survival of untreated patients in most series is short, 4 to 12 months. However, based on 5 to 13 year disease-free survival of a few selected patients treated with multi modality therapy, peritoneal mesothelioma may even be curable in some percentage of those with early disease. Because mesothelioma has been regarded as uniformly fatal, any substantial percentage o disease-free survivors would obviate the need for a randomized trial.

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 perito-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 (3). (See Description of Study Procedures for details) for ovarian carcinoma has been adapted for use in peritoneal mesothelioma, but the role of radiation therapy in achieving long term survival remains unclear.

Chemotherapy given systemically to patients with malignant mesothelioma has yielded disappointing results. Agents that produce response rated in 10% to 20% of patients include doxorubicin, epirubiein, mitomycin, cyclophosphamide, ifosfamide, cisplatin, and carboplatin. Response rates in small studies have been reported with detorubicin, high-dose methotrexate, and edatrexate at 26%, 37% and 25%, respectively , but these have yet to be confirmed. Combination chemotherapy trials do not demonstrate a consistently greater response rate than single-agent. However, the combination of doxorubiein, cisplatin, bleomycin, and mitomycin demonstrated a response rate of 44% (95% confidence interval, 27% to 63%), but this remains unconfirmed. (See [4] for review).

Intrapleural therapy using interferon gamma, particularly for small-volume disease, shows promise. In a prospective multi-institutional study of outpatients, intrapleural treatments with gamma-interferon in patients with Butchart's Stages I and II epithelial or mixed malignant pleural mesothelioma, interferon was administered intrapleurally via a catheter or an implantable port at a dose of 40 million units twice a week for 8 weeks. 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 in patients with early stage disease (RR for Stage I disease was 45%). Tolerance of interferon was good. The main side effects were hyperthermia, liver toxicity, neutropenia, and catheter-related infection (5). Intraperitoneal interferon has been given as a single agent to patients with ovarian carcinoma and other neoplasms, and was well tolerated at doses > 40 million U/m2 (6). The use of combined intraperitoneal interferon gamma and cisplatin or doxorubiein has not been explored.

Combined modality approaches are being studied at several institutions (6,7,8) One of four patients treated at Seattle with surgery, radiotherapy and chemotherapy had no tumor by follow-up Ct scan at the time of publication, (8). Three sequential series of patients have been treated at the Dana Farber Cancer Institute/JCRT (Boston) with surgery, radiotherapy and chemotherapy. One of 9 patients treated with surgery, intravenous cyclophosphamide, doxorubicin, and DTIC (before and after whole abdominal radiotherapy) remains alive and >10 years after diagnosis.(6). Patients treated on a second phase I trial between 1982 and 1985 were initially evaluated by computerized tomography. The protocol surgeon was unwilling to attempt resection in 7 of 13 patients with large bulky tumors. The remaining six patients underwent resection of all lesions >1 cm in size and placement of either a Tenckhoff catheter or a Port-a-Cath intraperitoneal access device. (Two of these six patients had received prior debulking surgery and intravenous chemotherapy.) They then received doxorubiein (6-50 mh/m2) and cisplatin (60-100 mg/m2) separately administered intraperitoneally for a total of 8 to 12 treatments. At the time of second laparotomy for removal of the access device, all six patients had at least an objective 50% decrease in the size of the tumor. (Non of the 7 patients who presented with inoperable tumor had more than a minimal response to IV or I.P. chemotherapy.) Chemotherapy was followed by whole abdominal irradiation in 4 patients. (One patient did not receive radiation because of prior limited-field irradiation for Hodgkin's disease and a second refused.) At present, 4 of the 6 patients (including 3 of the 4 who received irradiation) remains disease-free at 36, 48, 60, and 61 months after diagnosis (6,7). Acute toxicity was substantial (life-threatening Salmonella diarrhea an intraperitoneal hemorrhage, allergic reaction to cisplatin, and Staphylococcus aureas peritonitis in one patient each); one patient currently requires chronic intravenous hyperalimentation due to malabsorption. The remaining 3 patients have normal performance status. Thus a substantial percentage of selected early stage peritoneal mesotheliomas may response to intensive combined modality therapy (3,4,6).

A Phase II trial was begun in 1986 and was first reported on in 1988. (7). After surgical resection of tumor nodules >1 cm and placement of an intraperitoneal Port-a-Cath, alternating cycles of cisplatin and doxorubiein were given I.P. 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 doxorubiein , and then radiation therapy. Sixteen patients have completed therapy. Three died of disease 4, 6, and 8 months after starting therapy. At second-look laparotomy, 13 patients had responded to therapy (7 partially and 6 completely) although random biopsies were positive in all patients). Three patients with partial responses relapsed at 8, 24, ad 25 months. At that time all 6 patients with complete responses had remained remain in remission from 9 to 30 months (median 2.5 months). The median survival of the entire treated group was 16.4 months. Toxicity was generally mild, with nausea and vomiting secondary to cisplatin, transient creatinines as high as 2.4 and mild to moderate hematologic toxicity. Two episodes of small bowel obstructions in responding patients resolved without surgical intervention. No patient discontinued therapy due to toxicity. Thus intensive multi modality therapy produces a high response rate and may prolong survival for this otherwise rapidly fatal disease.

We hope to at least replicate the results of this study at Columbia, with specific modifications to the previous regiments to reduce toxicity and potentially enhance effectiveness: The first modification will be to substitute eight biweekly intraperitoneal injections of interferon-gamma given over four weeks in dose of 40 Mu/m2 (as used in the French study for the last doses each of doxorubiein an cisplatin, thus lengthening the course of intraperitoneal treatment to 12 weeks.

We will also obtain tumor specimens at primary and secondary surgery to assess chemoresistance to mitomycin/cisplatin. If no resistance to these agents is found, hyperthermic perfusion with mitomycin/cisplatin will be given at the time of the second operation.

The third modification will be to slightly alter the radiation fields doses to be delivered to the upper abdomen to optimize effectiveness and minimize toxicity to liver and kidneys

Phase I/II trial of Combined Resection, Intraperitoneal Chemotherapy, and whole Abdominal Radiation for Treatment of Peritoneal Mesothelioma

LAY SUMMARY:

A. Purpose: the purpose of this study is to evaluate the effectiveness of combined resection, intraperitoneal chemotherapy and whole abdominal radiation for treatment of peritoneal mesothelioma.

B. Experimental Design: This is a Phase III, one armed, non-randomized efficacy study. Patients with either measureable or evaluable peritoneal mesothelioma will be treated with multimodality therapy comprising Laparotomy with excision of all gross disease and insertion of a portacath peritoneal access device; twelve courses of intraperitoneal chemotherapy with doxorubicin (Adrimycin), cisplatin, and interferon-gamma; "second-look" surgery with a further single course of intra-operative intraperitoneal chemotherapy with heated chemotherapy drugs, and removal of the portacath; additional systemic chemotherapy if necessary; and whole abdominal radiation. Endpoints measured include reduction in measurable of evaluable disease, and disease-free and overall survival. Drug toxicities will also be monitored.

C. Study subjects: Up to 10 subjects/year for three years anticipated to be enrolled at CPMC.. All will be adult patients. Patients will only be approached after his or her responsible physician has already ascertained that the patient is willing to discuss a research study procedure. The patient will receive treatment every one to four weeks as per schedule, and will be monitored with weekly, then monthly and three-monthly blood counts and laboratory studies, history and physical examination and tumor assessments.

D. Issues: No specific ethical or physical risk issues can be identified at this time.

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Dr. Taub Recruiting Patients for Clinical Trials

I appreciate your posting this gentleman's experience.

There are some small factual errors in the description of the protocol. For example, Laser surgery is not performed. Rather, our current protocol calls for (1) surgical debulking for those with resectable disease, consisting of the removal of all accessible tumor nodules > 1 cm. in diameter --an intraperitoneal catheter attached to a subcutaneous port is implanted at that time.

(2) Intensive intraperitoneal chemotherapy with alternating adriamycin and Cisplatin (total of eight cycles), followed by intraperitoneal interferon-gamma (another eight cycles) over a period of about four months.

(3) "Second-Look surgery, with biopsy of suspected reasidual disease, a single dose of heated (44 degrees C.) mitomycin/cisplatin infused intra-operatively into the peritoneal cavity, and removal of the catheter and portacath.

(4) If all gross disease has been removed, then followup radiation to the entire peritoneal cavity (with appropriate shielding of the kidneys and femoral heads) is administered over about six weeks. The entire treatment lasts about six months.

This protocol is an extension and intensification of previous work done by Dr. Antman and her colleagues in the eighties--in those poor-risk patients, about 25% of them had prolonged (>5yr) survival with good QOL. We hope to do better.

We have treated 10 patients, eight of whom are still in good shape.

If you wish, I can send you a complete copy of our institutional IRB-approved protocol. Some of this work will very likely be presented in Milan in early November; I will be happy to forward an abstract of our results to you at that time.

We are very interested in both pleural and peritoneal mesothelioma, and wish to recruit patients to our clinical trials in both these diseases. We currently are a very active site for treatment of mesothelioma patients with Onconase (now in a Phase III randomized trial against single-agent doxorubicin).

I appreciate your interest.

Robert N. Taub, MD PhD
Professor of Clinical Medicine
Columbia-Presbyterian Medical Center

** POSTED SEPTEMBER 3, 1997 **