Multi-Modality Management of Early Stage Diffuse Malignant Mesothelioma
I spoke to Dr. Doug Wood recently (April 7, 1998) in an effort to help a patient from Portland, Oregon find a medical team that offered a multi-modal approach to treating mesothelioma. Dr. Wood and his team of surgeons, oncologists and pathologists, led by Dr. E. Vallieres, are accepting mesothelioma patients who qualify at the University of Washington in Seattle. Dr. Wood is very candid about the protocol. His team wants to be part of the solution, but Dr. Wood acknowledges that treatment regimens to date have been largely ineffective in substantially prolonging the life of mesothelioma patients. The Vallieres/Wood protocol is designed to take the best treatments from other regimens and combine them into a single trial. It may take another 5 to 10 years to determine the efficacy of the Vallieres/Wood trial. Dr. Wood is a cardiothoracic surgeon at the University of Washington School of Medicine in Seattle, Washington.
--Roger Worthington
Multimodality Approach to Diffuse Malignant Mesothelioma (MNN)
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 70's and early 80's 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 use of radical surgery (Butchart, Da Valle, LCSG), combination systemic chemotherapy, 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, MSDCC, Clev. Clin.). 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 controls 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 years survival of 35%, significantly better than previously reported with such advanced disease. (Hunt) 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 by an attempt at complete resection by extra-pleural 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
- 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.
- To determine the patterns of recurrence (local and systemic) after this combined modality approach.
- To determine the disease-free and overall survival rates after this combined approach.
- To determine the importance of previously identified prognostic factors on response- rates and long term outcome and evaluate new prognosticators such as PET scanning.
Rationale for 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 morality 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 of 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. 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 EP (presumed localized disease at the time of resection) with distant failures as their first site of recurrence, 6 being distant only and 5 with distant and local initial failures. The addition of an effective systemic regimen thus appears to be necessary in the management of this malignancy, even in it 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: Eligible Candidates for Extrapleural Pneumonectomy: Induction chemotherapy mexthotrexate 30mg/rn² (days 8, 15,22), vinblastine 3md/rn² (days 8, 15, 22), cisplatin 100mg/rn² (day 1), 2 to a maximum of 4 28-day cycles, depending on the maximal response by CT evaluation, followed in 4 to 6 weeks by EPP resection in responders or non progressive disease, followed 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. 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 addition 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 outside of the adjuvant radiation therapy field.
Arm 2: Ineligible Candidates for Extrapleural Pneumonectomy: Induction chemotherapy methotrexate 30mg/rn² (days 8, 15, 22), vinblastine 3mg/rn² days (8, 15, 22), cisplatin 100mg/rn² (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).
Patient Eligibility
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age over 18 years
- Karnofsky of 80% or better, or ECOG performance status 0-1
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No evidence of hematological, hepatic and renal dysfunction, [ANC>1200/mm³, platelers>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)]
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Clinical stage I, II and T1N2, T2N2, T3N0, T3N1 on pre-therapy CT of chest and abdomen. (No clinical evidence of T4, N3 or M1 disease).
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Biopsy proven (confirmed by ICC or EM) and UWMC reviewed (R.A.S) previously untreated DMM
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No previous treatment other than chemical pleurodesis
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No second malignancy within 5 years exvept non melanomatous skin cancer and treated Cis of the cervix
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Prior pleuroscopy or thoracotomy allowed only if done for diagnostic purposes
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Patients have been asessed by all members of the multidisciplinary team prior to registration.
Candidates for EPP: (within 21 days of surgery)
- preop CT chest and abdomen indicates 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 PCO2<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 than 65, 0-1 performance status, stage 1 disease, epithelial histology, DNA diploidy, no chest pain at presentation, more that 6 months syptoms 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 as clinically indicated. An attempt to confirm histologically all suspicion of recurrent disease will be encourged.
** POSTED APRIL 8, 1998 **