Treatment of Mesothelioma with Radiotherapy

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1 41 Treatment of Mesothelioma with Radiotherapy Ryan P. Smith and Stephen M. Hahn General Principles of Radiation Therapy Radiation therapy is a therapeutic modality that uses ionizing radiation to treat cancers and some nonmalignant conditions. Ionizing radiation kills cells by damaging DNA (1). Approximately two thirds of the DNA damage caused by ionizing radiation is from indirect action, that is, damage caused by free radicals generated mostly from the ionization of water (1). The remainder of the damage caused by radiation is through direct ionization of DNA. Radiation damage is also highly dependent on the presence of oxygen. The cytotoxicity of radiation is approximately three times greater in the presence of oxygen than that which occurs in an anoxic environment (1). Hypoxia in human tumors has been extensively investigated and may be a physiologic cause for radiation resistance (2 4). The absorbed dose of radiation therapy is prescribed in units called gray (Gy). The clinical use of radiation therapy in the United States is usually fractionated, that is, delivered in small doses daily. In general, for definitive or curative radiation therapy courses, a daily dose of 180 or 200cGy per day is used. A total dose of radiation therapy for a curative course is usually between 5000 and 7000 cgy. For palliative courses of radiation therapy, daily doses between 250 and 400cGy are used for a total dose of between 2000 to 3500cGy. The biologic basis for fractionation is that greater tumor cell kill can be achieved with fractionation relative to normal tissue effects by exploiting the 4 Rs: cellular repair, reassortment of tumor cells into sensitive phases of the cell cycle, reoxygenation of tumor cells, and repopulation of normal tissues. The total dose of radiation therapy used clinically is, in general, dependent on the radiation doses that the normal tissues within the radiation field can tolerate (so-called tolerance doses). There are some tumors that are quite radioresponsive, and for these tumors, doses below normal tissue tolerances can be used. However, for most solid tumors, including mesothelioma, the dose of radiation therapy that is prescribed is based on the tolerance of the normal tissues. In the case of mesothelioma, normal tissues that are sensitive to the effects of radiotherapy are 616

2 within the radiation field. These normal tissues limit the doses that can be administered and include the lungs, heart, esophagus, spinal cord, liver, and stomach. In general, the acute side toxicities of radiation during radiotherapy for mesothelioma include skin redness, esophagitis, fatigue, and nausea. The potential long-term toxicities of radiotherapy for mesothelioma include radiation pneumonitis, cardiac damage, radiation myelitis, and radiation damage to the liver. Specialized radiation treatment planning methods can be used to shape the radiation field with the goal of increasing the dose to the tumor and reducing the dose to normal tissues. The radiation treatment planning process involves the identification of a tumor or region that requires treatment followed by an evaluation of the radiation dose distributions provided by different field arrangements. Advances in computer hardware and software have enhanced the efficiency of this process. It is considered standard in many clinical situations to use three-dimensional radiation treatment planning for the delivery of three-dimensional conformal radiation therapy (3DCRT), which allows the physician to conform the radiation dose to a three-dimensional target volume (the tumor plus any additional tissues that require treatment) while also minimizing the dose to the surrounding normal tissues. In the typical situation, 3DCRT is delivered using a number of fixed radiation beams that are shaped using blocks or a multileaf collimator. The intensity of the radiation beam across the radiation field is mostly uniform (there are exceptions to this). A new version of the treatment planning process called intensity modulated radiation therapy (IMRT) is being used by some centers to treat complex regions and tumors (5). It involves a treatment planning process and delivery that uses nonuniform radiation beam intensities across the radiation field. Computer optimization techniques are used by the physician, radiation physicists, and radiation dosimetrists to determine the appropriate radiation dose distribution. The potential advantage of IMRT over conventional 3DCRT is the ability to deliver higher doses of radiation to the tumor while further minimizing the doses to adjacent normal tissues compared to conventional 3DCRT. Early reports of IMRT for prostate cancer, head and neck cancer, and brain tumors suggest that tumor radiation dose escalation may be feasible without increasing acute or late normal tissue side effects (6,7). However, there are several issues that have not been completely resolved with IMRT, which may be significant drawbacks to this technique (8). First, IMRT involves significantly more time and effort from physicians, physicists, dosimetrists, and radiation therapists. Second, there may be an increased risk of error because of the complexity of the treatment planning and delivery process; this requires a substantial program of quality assurance and verification of the radiation treatment fields. Third, the treatment times for patients are longer than for conventional radiation therapy. Typical treatment times for conventional 3DCRT are 3 to 5 minutes, while IMRT treatment times may range from 15 to 30 minutes. Fourth, although the immediately adjacent normal tissues may receive a lower dose of radiation compared to the tumor, a significantly greater normal tissue volume R.P. Smith and S.M. Hahn 617

3 618 Chapter 41 Treatment of Mesothelioma with Radiotherapy receives a low to moderate radiation dose compared to standard approaches. This higher whole-body dose of low-dose radiation may increase the risk of second cancers. There are no long-term data currently available to address this issue. Radiation therapy can be delivered externally as photons or electrons usually from a linear accelerator. Photons are a more penetrating type of radiation and can be used to deliver radiation to deep-seated tumors. Electrons are a superficial type of radiation through which the dose can be deposited to superficial structures such as the skin. Intraoperative radiation involves the use of external beam radiation (usually electrons) during the surgical procedure when exposure of a tumor bed is at its maximum. Radiation therapy can also be delivered with radioactive isotopes, which is called brachytherapy. This includes radiation seeds or implants, which are placed directly into the site of the tumor. One of the advantages of brachytherapy is that high doses of radiation are delivered to a localized area with relative sparing of the surrounding normal tissues. One form of brachytherapy that has been used for mesothelioma is the instillation of a radioactive 32 P or 198 Au solution within the pleura in order to expose the entire pleural surface to radiation (9,10). Curative Radiation Therapy as a Single Modality Treatment of malignant pleural mesothelioma, with definitive radiotherapy as a single modality is not a curative treatment strategy. The main limitation of radiotherapy in this setting is the inability to treat a large volume of disease in the chest with a curative radiation dose (>60 Gy) because of the risks of severe normal tissue toxicity. Several groups have reported their results with definitive radiotherapy. Law et al (11) administered radiation using a rotational technique to deliver 5000 to 5500cGy to the pleural space. Survival in this group of patients ranged from 3 to 10 months, with the exception of one patient who was alive and well 4 years after the completion of treatment. The authors concluded that radiotherapy had a palliative benefit in a small number of patients but that it was of no value in other patients. Ball and Cruickshank, (12) from the MacCallum Cancer Institute in Australia, reported the results of radical radiotherapy in 12 patients with malignant pleural mesothelioma. These patients were treated with 5000 cgy to the entire hemithorax. Median survival of these patients was 17 months compared to 7 months for those offered palliative treatment only. This difference is likely the result of a selection bias, with those fit enough to undergo a full course of radiation likely to have a greater survival regardless of treatment given. In addition, in these 12 patients, two had toxicity that led to their deaths, one with radiation hepatitis and one with radiation myelopathy. The authors concluded that radiotherapy did not appear to be effective in prolonging survival in patients with mesothelioma. A larger study of patients with malignant pleural mesothelioma, which included patients treated with definitive radiotherapy, was

4 reported by Ruffie et al (13). Radiation was given to a total of 49 patients. In those patients where the dose exceeded 4500 cgy, the course of radiation was defined as radical. The median survival was 9.8 months in patients treated with radical radiotherapy, which was no different from those treated with palliative radiation. Alberts et al (14) used a split course of radiotherapy in patients with pleural mesothelioma. In this study, 13 patients were treated with definitive radiation alone. Patients received variable schedules of radiation. Some received 1000cGy in 1 week (five 200-cGy fractions) every 6 weeks up to a maximum of four courses. Others received 150-cGy fractions for 10 days, followed by a rest period of 2 weeks. This was followed by an additional 3000 cgy in 2 weeks, using 300-cGy fractions. Hence, they received a total of 4500cGy throughout the entire course. One patient had a complete response to radiation, one patient had a partial response ( 50% reduction in the size of disease), and three patients had stability of their disease. The median duration of response was 133 days. Though direct comparisons were difficult to make between the groups of patients in this nonrandomized study, the duration of response to radiation was much shorter than with other treatment modalities. Holsti et al (15) have also reported their results with radical hemithoracic radiotherapy in patients with pleural mesothelioma. Fifty-seven patients were treated with a variety of fractionation schedules. The 2-year survival rate of the group overall was 21% and the 5- year survival rate was 9%. Two patients were reported to be long-term survivors. This group has reported that the toxicity to the intact lung is severe, with total loss of function on the irradiated side (16). Definitive radiotherapy alone is not curative therapy in malignant pleural mesothelioma and is associated with substantial toxicities. The basic problem is that it is not possible to deliver curative doses to the hemithorax given the geometric limitations of the thoracic cavity and the sensitivity of the surrounding normal tissues. R.P. Smith and S.M. Hahn 619 Combined Chemotherapy and Definitive Radiotherapy The poor results reported for definitive radiotherapy (RT) alone have led to studies evaluating the combination of chemotherapy and radiation. Alberts et al (14) treated patients with a variety of chemotherapy regimens, all concurrent with RT. These included RT plus doxorubicin, RT plus cyclophosphamide, RT plus procarbazine, and RT plus cyclophosphamide, vincristine, and actinomycin D. Radiation was given in a variety of schedules as well. Some received 1000cGy in a week (in five 200-cGy fractions) every 6 weeks up to a maximum of four courses. Others received 150-cGy fractions for 10 days, followed by a rest period of 2 weeks. This was followed by an additional 3000cGy in 2 weeks, using 300-cGy fractions. Hence, they received a total of 4500 cgy throughout the entire course. Though the response rates and response durations were increased with the addition of chemotherapy compared to radiation alone, the median survival was not significantly increased over those patients who received radiation alone. Ruffie et al

5 620 Chapter 41 Treatment of Mesothelioma with Radiotherapy (13) treated mesothelioma patients with chemotherapy consisting of doxorubicin-based regimens and other combination chemotherapy regimens. There was a significant increase in survival in those patients receiving chemotherapy (median survival time of 12.3 months vs. 7.3 months) compared to those who did not receive chemotherapy. Although the chemoradiation group only had nine patients, their median survival was 14.2 months, among the highest of any group in the study. Median survivals were higher in doxorubicin groups (14.7 months) compared to those in groups using the chemotherapy regimens (11.9 months). Linden et al (17) treated patients with hemithoracic radiotherapy (40 Gy in 20 daily fractions) followed by chemotherapy in good performance status patients. The chemotherapy consisted of doxorubicin and cyclophosphamide. In this nonrandomized trial, the response rates were no different in patients treated with radiotherapy alone, chemotherapy alone, or combined treatment. The median survival was highest (13 months) in patients treated with combined modality therapy. The differences in survival among the different treatment groups are likely the result of a selection bias in favor of the combined modality group. Some investigators have evaluated the addition of radiation sensitizers with definitive radiation therapy (18,19). Herscher et al, (18) from the U.S. National Cancer Institute, studied the use of a 5-day continuous infusion of paclitaxel with radical radiotherapy in patients with mesothelioma and non small-cell lung cancer. In mesothelioma patients, hemithoracic radiation was delivered initially. This was followed by a boost of radiotherapy to the gross tumor volume for a total dose of 5760 to 6300cGy. The maximally tolerated dose of paclitaxel in combination with radiation was 105mg/m 2 as a 120-hour continuous infusion. The toxicities were neutropenia, nausea and vomiting, grade 2 lung injury, and persistent cough. The authors concluded that this treatment was well tolerated. Chen et al (19) evaluated pulsed paclitaxel delivered during radiotherapy in a phase I trial. A 12% complete response rate and an 88% partial response rate were reported for disease within the radiotherapy field. The authors reported that the treatment was well tolerated. Although these approaches are interesting, it is not likely that the addition of radiation sensitizers to radical radiotherapy will be a curative. Definitive chemoradiotherapy should be considered unproven for patients with mesothelioma. Combined Surgical Resection and Definitive Radiotherapy Surgical resection, when feasible, is the desired treatment for patients with malignant pleural mesothelioma. Surgery alone, however, is unlikely to sterilize the hemithorax. Adjuvant, postoperative external beam radiotherapy is one approach that has been used to eradicate residual microscopic disease after surgical resection (20). The rationale behind this approach is that debulking the tumor mass maximizes the effectiveness of radiation (21). After an extrapleural pneumonectomy,

6 radical radiotherapy can be administered without concern for damage to the underlying ipsilateral lung since it has been removed surgically. However, radical radiotherapy after a pleurectomy continues to place the ipsilateral lung at risk for substantial loss of function. Law et al (11) reported the results of decortication followed by radiation therapy to a dose of 5000 to 5500cGy in eight patients with pleural mesothelioma. The median survival for these patients was 18 months, which was not increased from patients treated with decortication alone (20 months) or those patients who did not receive treatment (18 months). Toxicities from this regimen were minimal, with nausea and malaise in six patients, transient radiation hepatitis in one patient, and mild esophagitis in one patient. Ruffie et al (13) reported the treatment of 12 patients with surgery followed by radiation. The median survival was 11.7 months, which was no different from the survival reported for those treated with radiation alone, with chemotherapy alone, with surgery and chemotherapy, or with trimodality therapy. Some investigators have used brachytherapy or intraoperative external beam radiation in combination with surgery. Hilaris et al treated 41 patients with pleural mesothelioma after a parietal pleurectomy. Using this surgical procedure, however, resulted in residual disease being left behind in the majority of patients. Either brachytherapy or radioisotopes were used to eradicate gross residual disease. Permanent 125 I brachytherapy implants were used in patients who had measurable gross residual disease. If the residual disease was too diffuse, temporary 192 Ir implants were placed 3 to 5 days after the pleurectomy. If gross disease was noted on the surface of the lung, a solution of 32 P was instilled into the pleural cavity 5 to 7 days after thoracotomy. External beam radiation to a dose of 4500cGy was delivered to the pleural surface 4 to 6 weeks after surgery via a combination of photons and electron. There was no mortality and minimal toxicity from this treatment strategy. Six patients (15%) developed complications from treatment. Two patients developed subcutaneous emphysema, one patient developed pneumonitis, one developed pulmonary fibrosis, one developed pericardial effusion, and one developed esophagitis. The median survival was 21 months, with 1-year and 2-year survivals of 65% and 40%, respectively. Only 17% of the patients failed locally, which may be a reflection of the aggressive local therapy. The authors conclusions were that, while aggressive surgical resection is an essential portion of treatment, it is often very difficult to remove all sites of disease. By the results reported in this study, intraoperative brachytherapy followed by external beam radiation therapy was an effective method of controlling local recurrence. It is not clear if an increased local control rate will translate into a survival advantage. Rusch and colleagues (22) at the Memorial Sloan-Kettering Cancer Center completed a phase II trial of surgery followed by postoperative radiation in patients with pleural mesothelioma. Eighty-eight patients with biopsy-confirmed mesothelioma were treated. Twenty-one patients were unresectable and taken off study. The majority of patients (n = 62) underwent an extrapleural pneumonectomy (EPP), followed by 54Gy delivered through anterior and posterior fields in 30 fractions R.P. Smith and S.M. Hahn 621

7 622 Chapter 41 Treatment of Mesothelioma with Radiotherapy of 1.8Gy. Five patients were treated with a pleurectomy, which was followed by intraoperative radiation therapy to a dose of 15Gy, using a high-dose iridium applicator. This was followed by 54Gy to the hemithorax via anterior and posterior fields, in the same fractionation schedule as those who underwent EPP. There were seven postoperative deaths, all primarily related to pulmonary complications in patients who had undergone an EPP. A total of 33 patients had some complications, with the most common being atrial arrythmias (n = 17), respiratory failure (six), pneumonia (five), and empyema (five). In general, radiation was well tolerated, with grade 3 toxicities mainly related to fatigue, nausea, and esophagitis. There were five grade 4 toxicities, the most serious being an esophagopleural fistula. Only the patients who underwent EPP were considered for survival analysis. The median survival was 17 months, with an overall survival of 27% at 3 years. Only 13% had locoregional recurrence, with the majority of patients failing with distant metastases. The authors concluded that their approach of aggressive surgery with EPP, followed by high-dose radiation to the entire hemithorax, provided a favorable outcome for those patients who were able to complete the therapy compared to historical data. It should be noted that almost one quarter of the patients in this study were unresectable and were not included in the survival analysis, which introduces a bias in the reported results. An additional number of patients were unable to complete radiation. Therefore, although this treatment regimen appears to be associated with excellent clinical outcome, it is difficult to evaluate the relative impact of the treatment regimen from the patient selection factors. Lee et al (23) recently retrospectively reviewed the efficacy and toxicity of surgery with intraoperative radiotherapy followed by chemotherapy. Twenty-six patients with malignant pleural mesothelioma were included in the analysis. Twenty-four patients were treated with surgery consisting of a pleurectomy/decortication followed by intraoperative radiotherapy, consisting of 4 to 9 MeV electrons to median dose of 15Gy (range, 5 15Gy). External beam radiation was delivered by 3DCRT in 14 patients and IMRT in 10 patients. The goal of the external beam radiation therapy was to treat the pleural surface of the lung and all surgical scars while sparing the underlying lung parenchyma. The median dose of radiation delivered was 41.4 Gy (range, Gy). Chemotherapy consisting of cisplatin, doxorubicin, and cyclophosphamide was administered to selected patients beginning 1 to 2 months after radiation was completed. There were no deaths caused by the therapy and few postoperative complications (three cases of atrial fibrillation and one patient with a persistent air leak). Radiation was also well tolerated, with symptoms of pneumonitis noted in only four patients and pericarditis in one patient. In all cases, these symptoms resolved with conservative management. The median overall survival was 18.1 months and the median progressionfree interval was 12.2 months. Locoregional relapse was the most common site of failure. The authors concluded that this approach was a potential treatment option for adjuvant radiotherapy in patients who were unable to tolerate an EPP.

8 Intensity modulated radiation therapy offers the potential for administering higher doses of radiotherapy to the hemithorax while minimizing normal tissue toxicities (5). Stevens et al, at the M.D. Anderson Cancer Study, have treated 28 patients with IMRT after EPP (24,25). The hemithorax was treated with doses of 4500 to 5000 cgy. Some regions of the hemithorax were boosted to a total dose of 6000cGy. Radiation dose homogeneity to the entire hemithorax was excellent. Side effects included nausea, vomiting, dyspnea, and esophagitis. The median follow-up is 9 months and the local control rate is 100%. One year survival is 65%. These early results are encouraging and are worthy of additional study. R.P. Smith and S.M. Hahn 623 Prevention of Scar Recurrences Malignant seeding along thoracentesis tracts, biopsy tracts, chest tube sites, and surgical incisions is a common complication of procedures in patients with malignant mesothelioma (26). The frequency of malignant seeding has been reported to occur in approximately 20% to 50% of mesothelioma patients who undergo these procedures (13,27 29). Cutaneous recurrences usually present as painful subcutaneous nodules and may be unresponsive to conventional therapies. Boutin et al (26) have investigated the use of radiation to prevent malignant seeding after invasive diagnostic procedures. Forty patients were randomized, after an invasive diagnostic procedure, to either radiotherapy or no treatment. The radiotherapy regimen consisted of 21Gy in 3 days delivered with electrons to healing biopsy tracts and thoracoscopic sites and was delivered 10 to 15 days after the procedure. No patient in the radiation treatment group developed subcutaneous nodules. Alternatively, eight of 20 patients in the untreated group developed metastases. Tolerance to this local radiotherapy was excellent. This study supports the use of radiotherapy to the chest wall after diagnostic procedures to prevent cutaneous tumor recurrences. Palliation Palliation of symptoms takes on increasing importance in tumors such as mesothelioma in which curative treatment options do not exist for the majority of patients. Palliation of patients with mesothelioma commonly involves the management of dyspnea and chest pain. Dyspnea most often results from intractable pleural effusions, which can trap the lung. Uncontrolled local tumor can also cause encasement of the lung with tumor growing into the lung parenchyma. Chest pain is often the result of tumor invasion of chest wall structures including ribs, muscles, and intercostal nerves (30). Radiotherapy is most commonly used to palliate pain in patients with advanced mesothelioma (31). Investigators from the Netherlands have reported using palliative radiotherapy to treat painful chest wall metastases in patients with

9 624 Chapter 41 Treatment of Mesothelioma with Radiotherapy mesothelioma (31). A greater degree of palliation was reported in patients who were treated with fractions of 400 cgy compared with patients who were treated with 300 cgy. Unfortunately, pain recurrence within the treated field remained a significant problem. The authors reported that a total dose of 36 Gy in 400-cGy fractions provided local palliation in at least 50% of patients. Ball and Cruickshank (12) reported a 72% rate of symptom improvement using palliative courses of radiation therapy. These investigators reported that short courses of radiation (20Gy in five fractions) were as efficacious for symptom relief as more protracted courses of radiation (30 40 Gy in fractions). Ruffie et al (13) reported the results of palliative radiation therapy in 85 patients with mesothelioma. Palliation was often not achieved with radiation because adequate doses of radiation were not delivered to some patients. When doses greater than 4500 cgy were used, pain relief was attained in over 50% of the cases. An additional study by Gordon et al (32) reported results that supported the dose response relationship suggested by Ruffie et al. These authors found that radiotherapy provided a 38% palliation rate overall, and suggested that higher doses of 40 to 50Gy were needed to obtain pain relief. One of the largest studies of palliative radiotherapy in mesothelioma was reported by Davis et al (33). Of 111 patients who were followed, 71 were treated with radiation for symptoms. Although pain was the most common symptom requiring palliation, other symptoms related to superior vena caval obstruction, mass effect, and effusion were also treated. The authors found that greater than 60% of patients had some symptomatic benefit from radiation therapy. Unlike previous studies, the authors reported that the palliative response did not vary with dose. Therefore, the authors standard approach is to offer patients short courses of treatment (20Gy in five fractions) rather than longer courses of radiotherapy. These studies support the use of radiation as a useful tool in the palliation of mesothelioma. Peritoneal Mesothelioma Peritoneal mesothelioma is an uncommon presentation of mesothelioma. Radiation therapy is not commonly used because of the large volume of tissue that would require treatment when the peritoneal cavity is involved with disease. The toxicities to the small bowel, liver, kidneys, and other abdominal organs would preclude the delivery of curative doses of radiation in the majority of cases. The largest series of radiation therapy in peritoneal mesothelioma was reported by investigators at the Memorial Sloan-Kettering Cancer Center (34). Twentyfive patients with peritoneal mesothelioma in this series underwent surgical debulking. Seven patients received external beam radiotherapy and six patients received external beam radiation combined with the intracavitary instillation of a 32 P solution. The median survival was 12 months from the time of diagnosis. Only four patients survived more than 5 years, and all four of these patients were treated with intracavitary 32 P and external beam radiation therapy.

10 R.P. Smith and S.M. Hahn 625 Conclusion The role of radiation therapy in the treatment of mesothelioma has yet to be fully defined. Definitive radiotherapy as a single modality therapy is not curative and is not of clear benefit to patients. Additional study is needed to evaluate definitive radiotherapy in combination with novel radiation sensitizers and chemotherapy in patients with unresectable disease. Postoperative external radiation therapy may have a role as adjuvant treatment after extrapleural pneumonectomy in selected patients. Every effort should be made to deliver radiation doses of 45 to 60Gy in standard fractions of 180 to 200cGy. The complex geometry of the thoracic cavity after surgical resection complicates the delivery of radiotherapy and underscores the need to treat these patients with modern treatment planning techniques. Threedimensional conformal radiation therapy planning is needed to plan radiation therapy in this patient population. The early results with intensity-modulated radiation therapy appear encouraging and should be investigated further. Postoperative radiotherapy in patients who have undergone a pleurectomy/decortication is more complicated because of the underlying lung. The preliminary results of using intraoperative external beam radiation or brachytherapy warrant further evaluation. The major use of radiation therapy in the treatment of mesothelioma currently continues to be in palliation and in the reduction of scar recurrences. References 1. Hall E. Radiobiology for the Radiologist, 5th ed. Philadelphia: Lippincott Williams & Wilkins, Evans S, et al. Detection of hypoxia in human squamous cell carcinoma by EF5 binding. Cancer Res 2000;60: Evans SM, et al. Hypoxic heterogeneity in human tumors: EF5 binding, vasculature, necrosis, and proliferation. Am J Clin Oncol 2001;24(5): Brizel DM, et al. Oxygenation of head and neck cancer: changes during radiotherapy and impact on treatment outcome. Radiother Oncol 1999; 53(2): Intensity-modulated radiotherapy: current status and issues of interest. Int J Radiat Oncol Biol Phys 2001;51(4): Zelefsky MJ, et al. High dose radiation delivered by intensity modulated conformal radiotherapy improves the outcome of localized prostate cancer. J Urol 2001;166(3): Eisbruch A, et al. Intensity-modulated radiation therapy for head and neck cancer: emphasis on the selection and delineation of the targets. Semin Radiat Oncol 2002;12(3): Glatstein E. Intensity-modulated radiation therapy: the inverse, the converse, and the perverse. Semin Radiat Oncol 2002;12(3): Brady LW. Mesothelioma the role for radiation therapy. Semin Oncol 1981;8(3): Richart R, Sherman CD. Prolonged survival in diffuse pleural mesothelioma treated with Au198. Cancer 1959;12:799.

11 626 Chapter 41 Treatment of Mesothelioma with Radiotherapy 11. Law MR, et al. Malignant mesothelioma of the pleura: a study of 52 treated and 64 untreated patients. Thorax 1984;39(4): Ball DL, Cruickshank DG. The treatment of malignant mesothelioma of the pleura: review of a 5-year experience, with special reference to radiotherapy. Am J Clin Oncol 1990;13(1): Ruffie P, et al. Diffuse malignant mesothelioma of the pleura in Ontario and Quebec: a retrospective study of 332 patients. J Clin Oncol 1989;7(8): Alberts AS, et al. Malignant pleural mesothelioma: a disease unaffected by current therapeutic maneuvers. J Clin Oncol 1988;6(3): Holsti LR, et al. Altered fractionation of hemithorax irradiation for pleural mesothelioma and failure patterns after treatment. Acta Oncol 1997;36(4): Mattson K, et al. Multimodality treatment programs for malignant pleural mesothelioma using high-dose hemithorax irradiation. Int J Radiat Oncol Biol Phys 1992;24(4): Linden CJ, et al. Effect of hemithorax irradiation alone or combined with doxorubicin and cyclophosphamide in 47 pleural mesotheliomas: a nonrandomized phase II study. Eur Respir J 1996;9(12): Herscher LL, et al. Phase I study of paclitaxel as a radiation sensitizer in the treatment of mesothelioma and non-small-cell lung cancer. J Clin Oncol 1998;16(2): Chen Y, et al. Schedule-dependent pulsed paclitaxel radiosensitization for thoracic malignancy. Am J Clin Oncol 2001;24(5): Kindler H, Vogelzang N. Mesothelioma. In: Vokes E, Golomb H, eds. Oncologic Therapies. Berlin: Springer-Verlag, 1999: Sugarbaker DJ, et al. Extrapleural pneumonectomy in the multimodality therapy of malignant pleural mesothelioma. Results in 120 consecutive patients. Ann Surg 1996;224(3): ; discussion Rusch VW, et al. A phase II trial of surgical resection and adjuvant highdose hemithoracic radiation for malignant pleural mesothelioma. J Thorac Cardiovasc Surg 2001;122(4): Lee TT, et al. Radical pleurectomy/decortication and intraoperative radiotherapy followed by conformal radiation with or without chemotherapy for malignant pleural mesothelioma. J Thorac Cardiovasc Surg 2002;124(6): Ahamad A, et al. 100% local control of malignant pleural mesothelioma after extrapleural pneumonectomy followed by intensity modulated radiotherapy (IMRT) to the chest. Int J Radiat Oncol Biol Phys 2003;in press. 25. Forster KM, et al. Intensity-modulated radiation therapy following extrapleural pneumonectomy for the treatment of malignant mesothelioma: clinical implementation. Int J Radiat Oncol Biol Phys 2003;in press. 26. Boutin C, Rey F, Viallat JR. Prevention of malignant seeding after invasive diagnostic procedures in patients with pleural mesothelioma. A randomized trial of local radiotherapy. Chest 1995;108(3): Law MR, Hodson ME, Turner-Warwick M. Malignant mesothelioma of the pleura: clinical aspects and symptomatic treatment. Eur J Respir Dis 1984; 65(3): Brenner J, et al. Malignant mesothelioma of the pleura: review of 123 patients. Cancer 1982;49(11): Adams VI, Unni KK. Diffuse malignant mesothelioma of pleura: diagnostic criteria based on an autopsy study. Am J Clin Pathol 1984;82(1): Sterman DH, Kaiser LR, Albelda SM. Advances in the treatment of malignant pleural mesothelioma. Chest 1999;116(2):

12 31. de Graaf-Strukowska L, et al. Factors influencing the outcome of radiotherapy in malignant mesothelioma of the pleura a single-institution experience with 189 patients. Int J Radiat Oncol Biol Phys 1999;43(3): Gordon W Jr, et al. Radiation therapy in the management of patients with mesothelioma. Int J Radiat Oncol Biol Phys 1982;8(1): Davis SR, Tan L, Ball DL. Radiotherapy in the treatment of malignant mesothelioma of the pleura, with special reference to its use in palliation. Australas Radiol 1994;38(3): Brenner J, et al. Malignant peritoneal mesothelioma: review of 25 patients. Am J Gastroenterol 1981;75(4): R.P. Smith and S.M. Hahn 627