First-Line Chemotherapy for Malignant Pleural Mesothelioma

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1 39 First-Line Chemotherapy for Malignant Pleural Mesothelioma Pasi A. Jänne The Impact of Systemic Chemotherapy The true impact of systemic chemotherapy in mesothelioma has been difficult to evaluate because of the rarity of the disease, the paucity of randomized studies, the lack of uniform staging, heterogeneity within the pathologic subclasses of mesothelioma, the imbalance of prognostic factors, and the difficulties in assessing response to therapy using computed tomography (CT) and other radiographic imaging modalities. It presently is not clear whether chemotherapy prolongs survival in patients with mesothelioma compared to supportive care alone. The natural history of mesothelioma can be variable and thus benefits seen in clinical trials may be biased by patient selection. Some attempts to define the natural history of mesothelioma have been made. Merritt and colleagues examined 101 patients who were not candidates for aggressive surgical therapy between 1987 and Seventy of these patients received a pleurodesis, 30 had palliative radiation for chest pain, and 9 received chemotherapy as a radiation sensitizer. The median survival in this group of patients was 7 months [213 days; 95% confidence interval (CI), days]. Unfortunately, staging information is not available in these patients. A retrospective review of 332 patients with mesothelioma from Canada from 1965 to 1984, identified 176 patients who were treated with palliative care alone without any surgery, chemotherapy, or radiation therapy (1). In this group of patients the media survival was 6.8 months. Although neither of these studies was randomized, they do provide some data on the natural history of the disease in the absence of aggressive surgery or systemic chemotherapy. In contrast, the median survival of 337 patients in 11 mesothelioma clinical trials conducted by the Cancer and Leukemia Group B (CALGB) between 1984 and 1994 was also only 7 months (2). To date no randomized studies have been performed using supportive care alone as a control arm. The British Thoracic Society and the British Medical Research Council are conducting the first such randomized study (Fig. 39.1) (3). In this study, patients with malignant 593

2 594 Chapter 39 First-Line Chemotherapy for Malignant Pleural Mesothelioma The British Mesothelioma Trial: Role of Chemotherapy Best Supportive Care Malignant Pleural Mesothelioma Target accrual 840 patients; 240 per arm Randomize Best Supportive Care + MVP 4 Best Supportive Care + Vin 12 Primary end point: survival Secondary end points: QOL (EORTC QLQ & FACT-L) Figure Phase III trial evaluating the role of chemotherapy in the treatment of mesothelioma. MVP, mitomycin, vinblastine, cisplatin; Vin, vinorelbine; QOL, quality of life. mesothelioma will be randomized to receive best supportive care (BSC) alone, BSC and four cycles of mitomycin, vinblastine, and cisplatin (MVP), or BSC and 12 cycles of vinorelbine. The choice of the chemotherapy arms is based on prior phase II studies that demonstrated an improvement in quality of life in patients receiving these chemotherapy regimens (4,5). This randomized study will assess the impact of chemotherapy not only on overall survival but also on patient s quality of life, which will be assessed by either the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) C30 and LC13 or the Functional Assessment of Cancer Therapy Lung (FACT-L) questionnaire (6). The sample size for this study is 840 patients (280 per arm) with a 90% power at a significance level of.05 to detect a median survival difference of 3 months (9 vs. 12 months) in patients receiving chemotherapy (3). The estimated accrual time is 4 years and preliminary data suggest that this design is feasible (7). This is a very important study, and it should provide definitive data on the benefits of chemotherapy and on survival and quality of life for patients with malignant mesothelioma. Unfortunately, the trial is experiencing accrual difficulties. Evaluating the Impact of Chemotherapy The evaluation of the impact of therapy is also challenging in mesothelioma. In addition to survival analyses, the main methods of evaluating the benefits of chemotherapy include radiographic tumor assessment, and evaluations of symptom control and improvements in the quality of life. Radiographic assessment, even by CT, of the pleural rind is sometimes difficult, especially when the tumor rind is accompanied by a pleural effusion or when the rind thickness is less than 1cm.

3 Patients with pleural mesothelioma are also often symptomatic. They present with chest pain, shortness of breath, dyspnea, weight loss, and night sweats, among other symptoms. The impact of chemotherapy on the symptoms of mesothelioma is poorly characterized. Very few studies exist in which quality of life has been evaluated as a result of chemotherapy. Steele and colleagues (4) performed a phase II study using vinorelbine in patients with chemotherapy-naive malignant mesothelioma. This study also used the Rotterdam Symptom Checklist to assess quality of life. The partial radiographic response rate was 24%, but 48% of patients reported improvements in respiratory symptoms and 76% in psychosocial functioning. Importantly, quality of life improvements were not limited to patients achieving radiographic benefits but were also observed in patients without radiographic tumor regression. Nowak and colleagues (8) performed a phase II multicenter study of cisplatin/gemcitabine in chemotherapy-naive patients with mesothelioma. The partial response rate to therapy was 17% (Table 39.1). Quality of life was assessed by the EORTC QLQ-C30 questionnaire and pulmonary function was assessed by measuring forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV 1 ) (6). In patients who responded to chemotherapy there was a significant change in FVC over baseline (p =.002). There was no change in nonresponding patients. Patients who had stable disease as their best response to therapy were not examined as a separate group. Similarly, quality of life improved significantly in the responding compared to nonresponding (partial response and stable disease) patients ( p =.006). Quality of life was also assessed in the phase III trial of cisplatin/pemetrexed versus cisplatin using a modified Lung Cancer Symptom Scale (LCSS) for patients with mesothelioma (9,10). Significant improvements in quality of life were seen as early as week 12 in cough, dyspnea, and pain, favoring those who received cisplatin/pemetrexed (10). By week 18 all measures of quality of life were statistically significant in favor of patients who received cisplatin/pemetrexed. This study also examined changes in vital capacity during chemotherapy treatment (11). There was a statistically significant improvement in vital capacity (p =.034 at cycle 4 and p =.002 at cycle 6) favoring patients receiving cisplatin/pemetrexed (12). Changes in pulmonary function tests (PFTs), slow vital capacity (SVC), FVC, and FEV 1 were also examined in relationship to radiographic response to chemotherapy (13). Patients who achieved a radiographic response to chemotherapy had a significant improvement in PFTs when compared to those with disease progression. However, patients with stable disease as their best radiographic response also had a statistically significant improvement in SVC, FVC, and FEV 1 compared to patients with disease progression (13). These studies underscore the importance of including the assessments of quality of life and pulmonary function, in addition to survival end points, in future chemotherapy studies of mesothelioma. Additional studies should also help confirm whether quality of life benefits are limited to just those with radiographic regressions or are also observed in patients with stable disease as a result of treatment. P.A. Jänne 595

4 596 Chapter 39 First-Line Chemotherapy for Malignant Pleural Mesothelioma Table Combination chemotherapy studies in mesothelioma Median No. of Response rate survival Agent(s) patients (95% CI) (95% CI) Reference Anthracycline based Doxorubicin/Ifosfamide 24 32% (13 51%) 7 (NA) 57. Doxorubicin/Ifosfamide 17 13% (2 38%) 7.8 (NA) 58. Doxorubicin/cisplatin/cylophosphamide 23 30% (19 36%) 13.8 (NA) 59. Doxorubicin/5azacytidine 36 22% (NA) 13 (NA) 60. Doxorubicin/cisplatin/mitomycin c 24 21% (7 42%) NA 61. Doxorubicin/cyclophosphamide 36 11% (6 21%) 6.7 (NA) 62. Doxorubicin/cylophosphamide/DTIC 40 13% (6 21%) 5.5 (NA) 62. Doxorubicin/IFN a 25 16% (8 30%) 11 (3 19) 63. Platinum based Cisplatin/DHAC 36 14% (5 36%) 6.4 ( ) 64. Cisplatin/irinotecan 15 27% (8 55%) 6.5 (NA) 65. Cisplatin/vinblastine 20 25% (NA) NA 66. Cisplatin/doxorubicin 35 14% (5 30%) 8.8 (NA) 67. Cisplatin/doxorubicin 26 25% (10 47%) 10 (NA) 68. Cisplatin/doxorubicin/IFN a 37 29% (15 47%) 9.3 (NA) 69. Cisplatin/mitomycin c 35 26% (12 43%) 7.7 (NA) 67. Cisplatin/etoposide 27 12% (NA) NA 70. Cisplatin/mitomycin c/ifn a 20 10% (NA) 15 (NA) 71. Cisplatin/mitomycin c/ifn a 43 23% (11 36%) 11.5 ( ) 72. Cisplatin/IFN a 26 36% (20 60%) 12 (NA) 73. Cisplatin/IFN a 30 27% (NA) NA 74. Cisplatin/mitomycin c/etoposide/5fu 45 38% (24 53%) 16 ( ) 75. Cisplatin/mitomycin c/vinblastine 39 20% (NA) 6 (NA) 55. Cisplatin/gemcitabine 21 48% (26 69%) 9.5 (NA) 29. Cisplatin/gemcitabine 53 33% (20 46%) 11.2 (NA) 88. Cisplatin/gemcitabine 32 16% (1 31%) 9.6 (8 12) 30. Carboplatin/gemcitabine 50 26% (15 40%) 15.2 (NA) 31. Cisplatin/paclitaxel 18 6% (0 24%) 12 (NA) 76. Carboplatin/IFNa 15 7% (0 20%) 5.8 (NA) 77. Carboplatin/pemetrexed 27 32% (NA) 14.8 (NA) 78. Oxaliplatin/raltitrexed 55 20% (11 31%) 7.2 ( ) 79. Oxaliplatin/vinorelbine 17 12% (NA) NA 80. Oxaliplatin/gemcitabine 25 40% (21 61%) 13 (NA) 81. CI, confidence interval; NA, not available; DTIC, dimethyltriazeno imidazole carboxamide; 5-FU, 5-fluorouracil; IFN, interferon; DHAC, dihydro-azacytidine. Single-Agent Chemotherapy Virtually every chemotherapy agent has been evaluated in patients with mesothelioma. The response rates to single-agent therapy have been variable, and only a few agents have demonstrated consistent response rates of 10% to 20%. The most efficacious single chemotherapy agents for mesothelioma are the anthracyclines, the antimetabolites, and the platinum analogues (Table 39.2). Agents with little to no antitumor activity include the taxanes, topoisomerase inhibitors, and vinca alkaloids apart from vinorelbine (14 18). Of the anthracyclines, doxorubicin was one of the first agents to be tested in mesothelioma. The Eastern Cooperative Oncology Group (ECOG) performed a retrospective review of its experience with doxorubicin and chemotherapy regimens containing doxorubicin. The

5 response rate was 14%, including two complete responses, with a median survival of 7.5 months (19). However, subsequent studies failed to demonstrate similar antitumor activity of doxorubicin (20). Analogues of doxorubicin and liposomal formulations have also been examined and to date, appear to offer no additional benefit (Table 39.2). The response rates and median survivals have been quite variable, ranging from 0 to 43% and 4.4 to 17 months, respectively (Table 39.2). The largest single study of doxorubicin to date was a phase III trial comparing doxorubicin to ranpirnase (Onconase; Alfacell Corp., Bloomfield, NJ), an antitumor ribonuclease, in patients with mesothelioma (Table 39.3). Preliminary findings from the study have been presented; in the intention-to-treat population, the median survival for patients who received doxorubicin was 8.2 months (21). Single-agent cisplatin and carboplatin have also been investigated in at least four studies. The response rates are low (but consistent at 7% to 16%) and the median survivals range from 5 to 8 months. Cisplatin was the reference arm of the phase III trial comparing cisplatin to cisplatin/pemetrexed (Table 39.3) (12). In that study the median survival of patients treated on the cisplatin arm was 9.3 months (12). Thus for single-agent doxorubicin and cisplatin, these two phase III studies establish a benchmark with a median survival range of 8 to 9 months. A meta-analysis of 83 clinical studies of chemotherapy in the treatment of mesothelioma, conducted between 1983 and 2001, has also recently been performed (22). Cisplatin was identified as the most active single-agent treatment with response rate of 23.2% (95% CI, %) for cisplatin-containing regimens compared with 11.6 % (95% CI, %; p <.001) for non-cisplatin-containing regimens. Cisplatin is also the reference arm of an ongoing phase III trial comparing cisplatin to the combination of cisplatin and raltitrexed. The other class of agents with consistent antitumor activity are the antimetabolites including the antifolates and nucleoside analogues (Table 39.2). The response rates range from 5% to 37% (apart from one study of gemcitabine with a 0% response rate) and the median survivals also range from 4.7 to 11 months (Table 39.2). The antifolates appear to be one of the most active group of agents in the treatment of mesothelioma (Table 39.2). The mechanism(s) behind these observations have not been completely elucidated. Antifolates can be transported into tumor cells through the alpha folate receptor, the reduced folate carrier, and via a newly identified pemetrexed transporter (23 25). This latter transporter, yet to be identified, is a high-affinity and specific pemetrexed transport mechanism found on mesothelioma cell lines. Future studies need to be performed to further characterize this mechanism, but these observations may in part explain the sensitivity of mesotheliomas to pemetrexed. An alternative, although not mutually exclusive, hypothesis is the presence of a common genetic deletion in mesotheliomas. A homozygous deletion of 5 -deoxy-5 methylthioadenosine phosphorylase (MTAP) located on chromosome 9p21 has been observed in approximately 70% of mesotheliomas. 26 Tumor cell lines that are MTAP deficient are more dependent on de novo purine biosynthesis and in vitro more sensitive to the effects of antifolates compared to those containing a wild type MTAP gene. 27,28 Thus P.A. Jänne 597

6 598 Chapter 39 First-Line Chemotherapy for Malignant Pleural Mesothelioma Table Selected single agent chemotherapy studies in mesothelioma No. of Response rate Median survival Agent patients (95% CI) (95% CI) Reference Anthracyclines Doxorubicin 15 0% NA 20. Mitoxantrone % (0 13%) 4.4 (NA) 32. Mitoxantrone 30 7% (NA) NA 33. Epirubicin 63 15% ( %) 9.2 (NA) 34. Epirubicin 23 5% (NA) 7.5 (NA) 35. Pirarubicin % (NA) 10 (NA) 36. Detorubicin 35 43% (NA) 17 (NA) 37. Menogaril 22 5% (0 23%) NA 38. Liposomal doxorubicin 32 6% (0 20%) 13 (NA) 39. Liposomal doxorubicin 24 0% 8.5 (NA) 40. Liposomal daunorubicin 11 0% 6.1 (NA) 41. Platinums Cisplatin 25 13% (4 31%) 5 (NA) 42. Cisplatin 35 14% (NA) 7.5 (NA) 43. Carboplatin 31 16% (5.4 34%) 8 (NA) 44. Carboplatin 41 7% (2 21%) 7.1 (NA) 45. Antimetabolites-Antifolates Methotrexate 63 37% (NA) 11 (NA) 46. Trimetrexate 17 12% (2 33%) 5.0 ( ) 47. Trimetrexate 34 12% (7 29%) 8.9 ( ) 47. Edatrexate 20 25% (9 49%) 9.6 (NA) 48. Edatrexate + leucovorin 40 16% (6 31%) 6.6 (NA) 48. Di-Deazafolic acid 18 5% ( %) NA Fluorouracil 20 5% (NA) 5 (NA) dihydro azacytadine 41 17% (7 32%) 6.7 ( ) 51. Raltitrexed 24 21% (7 42%) 7 ( ) 52. Pemetrexed 64 14% (7 25%) 10.7 ( ) 53. Antimetabolites-Others Gemcitabine 17 0% 4.7 ( ) 54. Gemcitabine 27 7% (1 24%) 8 (5 12) 55. Gemcitabine 16 31% (NA) NA 56. Others Vinorelbine 29 24% (10 44%) 10.6 (NA) 44. Table Phase III studies in malignant mesothelioma No. of Response Median Agent(s) patients rate survival Reference Ranpirnase 84 NA 7.7 (NA) 21 Doxorubicin 70 NA 8.2 (NA) Cisplatin % (NA) 9.3 (NA) 12 Cisplatin/pemetrexed % (NA) 12.1 (NA)* * p <.05.

7 P.A. Jänne 599 mesotheliomas containing homozygous MTAP deletions may be more sensitive to antifolates. This hypothesis needs to be validated in clinical studies of antifolates. Combination Chemotherapy Many combination chemotherapy studies have been performed, but only a few have evaluated the benefits of combination chemotherapy compared to single-agent chemotherapy. The two most common combinations include either doxorubicin or platinum (cisplatin, carboplatin, and oxaliplatin) (Table 39.1). In general, the response rates are higher for both doxorubicin- (11 32% for combination vs. 0 14% for single-agent) and platinum- (6 48% for combination vs. 7 16% for single-agents) containing combinations than those observed with single-agent therapy (Tables 39.1 and 39.2). However, the median survivals are not clearly superior for the combination studies. A meta-analysis evaluating chemotherapy for malignant mesothelioma demonstrated that combinations containing both cisplatin and doxorubicin were associated with the highest response rate (28.5%; 95% CI, %) (22). In this same analysis combination studies were associated with a significantly better response rate compared to singleagent studies (22.6% vs. 11.6%; p <.001) (22). The combination of cisplatin or carboplatin and gemcitabine is commonly used in the treatment of patients with malignant mesothelioma. Three phase II studies of cisplatin/gemcitabine have been published to date (Table 39.1). Two of the studies examined giving cisplatin 100mg/m 2 on day 1 with gemcitabine at 1000mg/m 2 on days 1, 8, and 15 of a 28-day cycle (8,26). With this schedule, the day 15 gemcitabine dose was reduced or omitted in 58% (126/219) of patients with a mean relative dose intensity of 75% (8). The response rates and median survivals in these studies were 48% and 9.5 months and 33% and 11.2 months, respectively (Table 39.1) (8,26). The study by van Haarst and colleagues (27) used a 21-day schedule with cisplatin 80mg/m 2 on day 1 and gemcitabine 1250mg/m 2 on days 1 and 8. Most patients received their planned chemotherapy and mean relative dose intensity of gemcitabine was 94%. The response rate was slightly lower with this schedule (16%), but the median survival was comparable (9.6 months; Table 39.1). A single study of carboplatin/gemcitabine has also been performed (28). In this study, 50 patients were treated with carboplatin [area under the curve (AUC) = 5] on day 1 and gemcitabine 1000mg/m 2 on days 1, 8, and 15. Similar to the 28-day cisplatin/gemcitabine combination schedules, the day 15 gemcitabine was reduced or omitted in 44% of patients. The response rate and median survival in this study were 26% (95% CI, 15 40%) and 15.2 months, respectively. These studies demonstrate consistent antitumor activity of the cisplatin/ carboplatin and gemcitabine combinations and hence, represent a combination chemotherapy option for patients with mesothelioma. Other platinum-based phase II studies, including oxaliplatin-based combination studies, have also been performed (Table 39.1). Non

8 600 Chapter 39 First-Line Chemotherapy for Malignant Pleural Mesothelioma platinum-based combination chemotherapy regimens, including gemcitabine and pemetrexed, are presently being evaluated. The largest combination chemotherapy study to date in mesothelioma is the phase III study comparing single-agent cisplatin to the combination of cisplatin and pemetrexed (Table 39.3) (11). This study, representing the first large randomized study comparing combination chemotherapy to single-agent therapy, randomized 456 patients, 228 to receive either cisplatin or cisplatin/pemetrexed, with survival as the primary end point. Patients receiving the combination of cisplatin/ pemetrexed had both a better response rate (41% vs. 17%) and median survival [12.1 vs. 9.3; p <.020; log rank (Fig. 39.2)] (11). The combination was also associated with better lung function and subjective quality of life. This study establishes the superiority of the benefits of combination cisplatin-based chemotherapy compared to cisplatin alone. A similar phase III study comparing cisplatin to cisplatin and raltitrexed is ongoing. There are many active combination chemotherapy regimens. It is not clear at this time whether one is superior to the other, and definitive proof would require additional phase III studies. However, given the limited numbers of patients with mesothelioma and the potential small incremental benefits in survival such results might yield (compare, for example, the many phase III studies of doublet chemotherapies in non small-cell lung cancer), such studies should be avoided. The choice of chemotherapy regimens for the treating oncologist and the patient with mesothelioma will ultimately depend on the availability of the drugs, their side-effect profiles, cost, and convenience of administration. Figure Kaplan-Meier estimates of overall survival for all patients treated with cisplatin/pemetrexed vs. cisplatin alone.

9 P.A. Jänne 601 Conclusions and Future Directions Progress has been made in the treatment of mesothelioma with chemotherapy and mesothelioma is no longer a chemotherapy-resistant disease. Anthracyclines, platinum agents, and antimetabolites have demonstrated consistent, albeit low level, single-agent antitumor activity. Combination platinum-based chemotherapies are associated with a higher response rate and are commonly used in clinical practice. However, questions remain unanswered, including the survival benefits of chemotherapy. The rarity of the disease has limited the size of many of the clinical trials, and only one phase III clinical trial has been completed. The combination of cisplatin and pemetrexed is likely to set a new standard for chemotherapy in mesothelioma. Efforts should now focus on combination studies (such as with a molecular agent) with cisplatin/pemetrexed, integration of active chemotherapy combinations into multimodality approaches, use of novel therapeutic agents such as receptor tyrosine kinase inhibitors, and second-line studies. Summary Most patients with malignant mesothelioma are candidates for systemic chemotherapy during the course of their disease, but no standard regimen has been established. Several phase II single-agent and combination chemotherapy studies have been performed over the past two decades. Although the true impact of chemotherapy in mesothelioma remains to be determined, agents with consistent antitumor activity include the platinum agents and the antifolates. Phase II studies of combination chemotherapy are associated with higher response rates but not necessarily longer median survivals. Recent data from a large randomized phase III clinical trial established the superiority of cisplatin/pemetrexed compared to cisplatin alone. Data from this and other ongoing studies will help establish standard chemotherapy regimens for mesothelioma and provide a basis for combination studies with molecular agents and incorporation of these regimens into multimodality treatment approaches. References 1. Ruffie P, Feld R, Minkin S, et al. Diffuse malignant mesothelioma of the pleura in Ontario and Quebec: a retrospective study of 332 patients. J Clin Oncol 1989;7: Herndon JE, Green MR, Chahinian AP, et al. Factors predictive of survival among 337 patients with mesothelioma treated between 1984 and 1994 by the Cancer and Leukemia Group B. Chest 1998;113: Girling DJ, Muers MF, Qian W, et al. Multicenter randomized controlled trial of the management of unresectable malignant mesothelioma proposed by the British Thoracic Society and the British Medical Research Council. Semin Oncol 2002;29:

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