Dear Mr. Worthington:

By this letter, I would like to introduce myself to you, as I understand you have a special interest in mesothelioma. I am the principal investigator and the thoracic surgeon in charge of the mesothelioma program her at the University of Washington Medical Center. Eighteen months ago, we initiated a Phase II Trial which is addressing the multi-modality approach to diffuse malignant mesothelioma of the pleura, combining induction chemotherapy followed by radical surgery which we then follow with adjuvant fast neutron radiation therapy. I include for your file and interest, an outline of this trial. I also include a copy of an abstract I have recently submitted to one of the local societies which describes our very early experience with this approach.

Finally, I include a copy of a biosketch I have recently submitted to one of the oncology societies for you information.

Lastly, I do note that you have a website on the disease. It has appeared to me that many of the patients that we have seen here in consultation are very familiar with this website and I want to thank you for this endeavor. I also note that many of the protocols that are available out there are listed and described on this site. I would be very interested in having our protocol listed as well. I would be glad to actively participate to have this occur if it was necessary.

I hope that the provided information is useful.

Sincerely,
Eric Vallieres, M.D.
Thoracic Surgery
University of Washington Medical Center
Seattle, Washington

TRI-MODALITY THERAPY FOR PLEURAL MESOTHELIOMA (DMM)

Eric Vallieres MD, Douglas Wood MD, Riyad Karmy-Jones MD, Robert Livingston MD, Karen Hunt MD, Keith Stelzer MD.

Introduction: Extrapleural pneumonectomy (EPP) remains the most effective therapeutic modality to locally control DMM but both systemic and local recurrences are common. The addition of effective chemotherapy and radiation therapy to EPP could potentially improve both local and systemic control and improve survival. This trial evaluates the feasibility of induction cisplatin methotrexate and vinblastine chemotherapy (PMV), EPP and adjuvant neutron radiotherapy (NRT) in the treatment of DMM.

Methods: Patients with clinical stages I-III DMM, Karnofsky 80% or better and who have adequate pulmonary reserves receive induction PMV followed by EPP and adjuvant whole hemithorax NRT. Data is collected prospectively.

Results: Eight patients (7M, 1F), ages 51 to 68, stages I (3), II (2) and III (3) have initiated this protocol. Three patient are completing induction PMV. In the other 5, a clinical response to PMV was seen in 3 patients. Five patients have undergone EPP (4 right, 1 left) and all 5 had positive microscopic margins. There were 3 epithelial DMM and 2 mixed type, pathological stages III (3) and IV (2). There was no operative mortality and hospital stays ranged from 6 to 10 days. Delayed morbidity was major in 3 patients. Four patients have completed adjuvant NRT and 3 remain free of disease at 19, 16 and 5 months.

Conclusion: Induction PMV, EPP and FNRT. appears feasible and safe in this early experience.

Multimodality Approach to Diffuse Malignant Mesothelioma (DMM) of the Pleura
A Phase II Prospective Trial
UWMC-97

Participants:
P.I.: Dr. E. Vallieres
Medical Oncology: Drs. K.J. Hunt & R.B. Livingston
Radiation Oncology: Dr. K.J. Stelzer
Pathology: Dr. R.A. Schmidt
Biostatistics: Dr. J.J. Crowley
Thoracic Surgery: Drs. D.E. Wood & E. Vallieres

Introduction
DMM is an uncommon neoplasm which unfortunately remains usually lethal with a median survival of 4 to 18 months and for which there continues to be no accepted effective curative treatment. (). If anything, the enthusiasm that prompted many new approaches to the potential cure of the disease in the late 70s and early 80s seems to have waned and a nihilistic philosophy to the problem is now often observed. (Lewis, Faber) An overall palliative attitude to these patients is, with rare exceptions, the clinical rule. The us of radical surgery (Butchart, Da Valle, LCSG), combination systemic chemotherapy (reference), external radiation therapy (MSKCC), intracavitary chemotherapy (Markman), intracavitary radiation therapy (MSKCC), photodynamic therapy (Bethesda) and immunotherapy (Boutin) have all been reported alone or in various combinations (DFCI, MSKCC, Clev. Cl.). Unfortunately, these have all been small non-randomized trials, with early hints of effectiveness but without any effect on long-term survival when comparing to historical contrails of supportive care only.

Our recent experience with the use of weekly methotrexate-vinblastine and cisplatin chemotherapy in the treatment of 17 inoperable DMM has yielded a 53% overall response rate and a projected 2 year survival of 35%, significantly better than previously report with such advanced disease. (Hunt, Chest 1996; 109: 1239-42) The purpose of this trial is to evaluate, in the treatment of more favorable disease, the application of such a combination regimen in an induction mode, followed b an attempt at complete resection by extrapleural pneumonectomy (EPP) or debulking and consolidation fast neutron beam radiation therapy to the whole hemithorax. Feasibility, toxicity, response rates, resectability rates, operative morbidity and survival will be evaluated.

Objectives

1. To determine the feasibility and toxicity of combining methotrexate, vinblastine and cisplatin induction chemotherapy, surgical resection and adjuvant fast neutron radiation therapy in the treatment of DMM.
2. To determine the patterns of recurrence (local and systemic) after this combined modality approach.
3. To determine the disease-free and overall survival rates after this combined approach.
4. To determine the importance of previously identified prognostic factors on response- rates and long-term outcome.
5. To evaluate the value of PET scanning is assessing DMM and correlating it findings with prognostic and survival.

Rationale for a New Approach

Single modality approaches to early stage DMM have never been shown to improve survival. Aggressive radical surgery by EPP historically carried a prohibitive operative mortality risk of 30%. (Butchart, Da Valle) More recent series have reported improved operative mortality rates of 0 to 9%, as a result of better patient selection, improved surgical technique and peri-operative care. (Sugarbaker, Da Valle, Delaria)

EPP remains the most effective therapeutic modality to achieve local control but systemic and local recurrences are common. (LCSG) The effectiveness of EPP to achieve local control decreases significantly in the presence of residual microscopic or gross disease, a situation encountered in 74% of resected patients in one of the recent series. (Sugarbaker) In addition, DMM are relatively radiosensitive tumors but the necessary large doses and volumes required are technically difficult to deliver while sparing the underlying lung, liver, spinal cord and heart. The combination of EPP and adjuvant radiation therapy is thus attractive: an attempt at complete resection including removal of the lung, followed by high dose radiation therapy could improve local control. The high relative biological effectiveness of neutron radiotherapy enhances local control for sarcomas compared that with photons or electrons. (ref) Since a substantial proportion of DMM have sarcomatous components, fast neutron radiation may provide a therapeutic gain over photons or electrons.

In the management of clinically early stage disease, systemic failures are common after EPP. The LCSG trial reported 11 patients out of 17 (65%) who survived EPP (presumed localized disease at the time of resection) with distant failures. The addition of an effective systemic regimen thus appears to be necessary in the management of this malignancy, even in its clinically early stages. Our choice for the use of the combination of cisplatin, methotrexate and vinblastine is based on the safety and effectiveness of this regimen as we have reported with more advanced stage disease. (Hunt) We acknowledge our reported experience with this regimen is small and the reported series warrants more maturity but to our knowledge, no other chemotherapeutic regimen has shown such promising early results.

By combining the best reported local and systemic measures to treat DMM, we hope to improve outcome and survival.

Protocol Outline

Arm 1: Good surgical candidates: Induction chemotherapy methortrexate 30mg/m² (days 8,15,22), vinblastine 3mg/m² (days 8,15,22), cisplatin 100mg/m² (day 1), 2 to a maxumum of 4 28-day cycles, depending on the maximal response by CT evaluation, foloowed in 4 to 6 weeks by EPP resection in responders or non progressive disease (definitions as per Hunt's paper, p. 1240), folloed by adjuvant whole hemithorax fast neutron radiation therapy. Radiation will be initiated 4 to 6 weeks after surgery. A treatment planning CT scan will be performed to delineate the pleural space and any area of gross or microscopic positive surgical margin. Initila hemithorax fields (AP/PA) will be treated to a dose of 9 Gy (at midplane) using 1 Gy fractions delivered 4 days per week. Three-dimensional comuterized treatment planning will be used to focally boost sites of residual disease for an additional 9 Gy at 1 Gy per fraction (total dose 18 Gy). On the right side, a surgical effort will be made to lower the underlying liver ouside of the adjuvant radiation therapy field.

Arm 2: Less good surgical candiates: Induction chemotherapy methotrexate 30mg/m² (days 8,15,22), vinblastine 3mg/m² (days 8,15,22), cisplatin 100mg/m² (day 1), 2 to a maximum of 4 28-day cycles as per CT response, followed in 4 to 6 weeks by parietal pleurectomy + decortication (debulking), followed by whole hemithorax fast neutron radiation therapy. Radiation will be initiated 4 to 6 weeks after surgery. A treatment planning CT scan will be performed to delineate the pleural space and any area of gross or microscopic positive surgical margin. Initial hemithorax fields (AP/PA) will be treated to a dose of 9 Gy (at midplane) using 1 Gy fractions delivered 4 days per week. Three-dimensional computerized treatment planning will be used to focally boost sites of residual disease for an additional 9 Gy at 1 Gy per fraction (total dose 18 Gy).

Clinicopathological Staging UICC

Diffuse Pleural Malignant Mesothelioma

• T1 Primary tumor limited to ipsilateral parietal or visceral pleurae
• T2 Tumor invades ipsilateral lung, endothoracic fascia, diaphragm or pericardium
• T3 Tumor invades ipsilateral chest wall muscle, ribs, mediastinal organs or tissues
• T4 Direct extension to the contralateral pleura or lung, cervical tissues, peritoneum or abdominal organs

• N1 Ipsilateral bronchopulmonary or hilar nodal involvement
• N2 Ipsilateral mediastinal nodal involvement
• N3 Contralateral mediastinal, internal mammary, supraclavicular, scalene or axillary nodal involvement

• M1 Distant metastasis present

• Stage I T1N0, T2N0
• Stage II T1N1, T2N1
• Stage III T3N0, T3N1, T1N2, T2N2, T3N2
• Stage IV Any N3, T4 or M1

Patient Eligibility

• age over 18
• Karnofsky of 80% or better, or ECOG performance status 0-1
• No evidence of hematological, hepatic and renal dysfunction, [ANC>1200/mm³, platelets/100,000/mm³], [Bilirubin, AST, alkaline phosphatase<2 times the upper limit of normal], [Estimated creatinine clearance>60ml/min calculated according the formula, (140 -age) (wt. In kg) (0.85 for women)/72(serum creatinine)]
• Clinical stage I, II and T1N2, T2N2, T3N1 on pre-therapy CT of chest and abdomen. (No clinical evidence of T4, N3 or M1 disease).
• Biopsy proven (confirmed by ICC or EM) and UWMC reviewed (R.A.S) previously untreated DMM
• No previous treatment other than chemical pleurodesis
• No second malignancy within 5 years except non melanomatous skin cancer and treated Cis of the cervix
• Prior pleuroscopy or thoracotomy allowed only if done for diagnostic purposes
• Patients have been assessed by all members of the multidisciplinary team prior to registration

Candidates for EPP: (within 21 days of surgery)

• Preop CT chest and abdomen and PET Scan indicate that EPP would allow complete resection of all gross disease.
• Muga scan or 2D echo demonstrating normal right and left ventricular functions. (definitions)
• Pre operative PFTs allowing pneumonectomy (+ quantitative VQ scan)
• Pre operative ABG's CO2<45, PO2>60
• No significant other major medical problems that cannot be adequately controlled with appropriate therapy
• An elevated serum alkaline phosphatase warrants a bone scan

Prognostic Factors

Better prognosis: age less that 65, 0-1 performance status, stage 1 disease, epithelial histology, DNA diploidy, no chest pain at presentation, more than 6 months symptoms at diagnosis, stable weight, normal platelet count. Serum Ca125 and tumor p53 will be measured prospectively and correlated will clinical behavior.

Follow-up

A baseline CT of the chest and abdomen will be obtained post resection, pre adjuvant radiation therapy and every 3 months thereafter. Patients will be seen and examined every 3 months. Additional investigations will be obtained al clinically indicated. An attempt to confirm histologically all suspicion of recurrent disease will be encouraged.

Morbidity

Definitions of, as per LCSG's protocol

Analysis

Survival times will be determined from the date of diagnosis to the time of death and from the date of initiating treatment to the time of death, survival curves constructed using the Kaplan-Meier method...

Biosketch

Eric Vallieres MD,

Dr. Vallieres is an Assistant Professor of Surgery, Section of General Thoracic Surgery at the University of Washington in Seattle. He received his MD degree from L'Universite Laval in Quebec and trained in General Surgery at the University of Toronto where he also completed his General Thoracic Surgical Residency. Following a clinical fellowship with Professeur Louis Couraud in Bordeaux, France, he joined the Department of Surgery at the University for Alberta in Edmonton then the University of Ottawa and come to Seattle in 1996.

Dr. Vallieres was an Executive Member of the Lung Site Committee at the NCI Canada, Clinical Trials Group and is now Vice Chairman of the Lung Committee with SWOG. His main interests are the multi-modality approaches to thoracic malignancies and clinical trials in oncology.

*** POSTED NOVEMBER 5, 1998 ***