Clin J Gastroenterol (2012) 5:373–376 DOI 10.1007/s12328-012-0334-1
CASE REPORT
Advanced diffuse malignant peritoneal mesothelioma responding to palliative chemotherapy Koji Nakashima • Haruhiko Inatsu • Kazuo Kitamura • Tomomi Hikosaka Shinri Hoshiko • Shinya Ashiduka
•
Received: 17 February 2012 / Accepted: 23 September 2012 / Published online: 17 October 2012 Ó Springer Japan 2012
Abstract A 64-year-old man diagnosed with advanced malignant peritoneal mesothelioma by laparoscopic biopsy was treated with systemic chemotherapy. The patient underwent first-line chemotherapy with pemetrexed plus cisplatin for 11 months, then second-line chemotherapy with gemcitabine plus vinorelbine for 6 months, and thirdline chemotherapy with CPT-11 for 4 months. After thirdline chemotherapy failed, he received palliative treatment. Although the tumor continued to grow, and he died 24 months after initiation of treatment, chemotherapy prolonged the survival time and improved his quality of life. Keywords Malignant peritoneal mesothelioma Diffuse type Chemotherapy Pemetrexed Cisplatin
Introduction Malignant peritoneal mesothelioma (MPM) is a rare and highly aggressive tumor. Surgical resection is possible in a minority of patients, and palliative chemotherapy is necessary in most. Although initial chemotherapy of MPM has been established [1], there is no established treatment of MPM. Therefore, effective chemotherapy is needed for the treatment of these patients. We present a report of a patient with MPM who received an initial course of treatment with pemetrexed plus cisplatin.
K. Nakashima (&) H. Inatsu K. Kitamura T. Hikosaka S. Hoshiko S. Ashiduka First Department of Internal Medicine, Faculty of Medicine, University of Miyazaki Hospital, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan e-mail: [email protected]
Case report A 64-year-old man with a 12-year history of exposure to asbestos suffered from abdominal pain and was admitted to the hospital near his home. Upper and lower endoscopic findings were normal; however, positron emission tomography–computed tomography (PET–CT) showed abnormal accumulation in the upper left abdomen (Fig. 1). Although the primary tumor was unclear, peritoneal dissemination was suspected at first. Laparoscopic biopsy was performed for the purpose of diagnosis. In operative findings, multiple small nodules were shown on the surfaces of the omentum, peritoneum, and mesenterium. Biopsied specimens showed a proliferation of polygonal cells with bizarre nuclei forming epithelioid mesothelioma (Fig. 2). In immunohistochemistry, polygonal cells were positive for carletinin and anti-cytokeratin antibody (AE1/AE3). From these results, MPM, of the epithelioid type, was diagnosed. The patient was transferred to our hospital for chemotherapy. Pain in the left and right upper abdomen was observed in physical findings. Laboratory data on admission are shown in Table 1. Serum tumor markers and hyaluronic acid were within normal ranges. Abdominal contrast-enhanced CT scans showed a slightly high-density area in the peritoneum (Fig. 3), while chest CT scans showed no abnormal findings in the lung field and pleura. The patient received combination chemotherapy with pemetrexed (PEM) plus cisplatin (CDDP). PEM 500 mg/m2 and CDDP 75 mg/m2 were administered on day 1 of a 21-day cycle. After starting chemotherapy, the patient’s abdominal pain decreased. After the 3rd cycle of PEM plus CDDP, serum creatinine levels increased to 1.5 mg/dl. We needed to reduce the dosage of CDDP. After 3 months, abnormal accumulation had disappeared on PET–CT (Fig. 4). Although the dosage of CDDP finally required about a 30 % reduction, 12 cycles of PEM plus CDDP were administered. After 11 months,
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374
PET–CT showed a new mass in the left upper abdominal cavity (Fig. 5). The patient received second-line combination chemotherapy with gemcitabine (GEM) plus vinorelbine (VNR). GEM 1000 mg/m2 and VNR 25 mg/m2 were administered on days 1 and 8 of a 21-day cycle. Although the mass was stable disease (SD) on abdominal CT, after 6 months from starting second-line chemotherapy CT revealed an increase of the left upper abdominal mass and new abdominal dissemination. The patient received third-line chemotherapy with CPT-11 for 4 months. After third-line chemotherapy failed, he received palliative treatment and experienced progression of the disease. He died 24 months after the start of first-line chemotherapy.
Discussion Malignant mesothelioma (MM) is a rare and highly aggressive tumor arising from the mesothelial cells of the
Fig. 1 Positron emission tomography–computed tomography (PET–CT). Abnormal accumulation of upper left abdomen was detected (SUV max 15.1)
Clin J Gastroenterol (2012) 5:373–376
pleura, peritoneum, pericardium, or tunica vaginalis testes. Pathogenesis of MM is strongly associated with occupational asbestos exposure. The peritoneum is the second most frequent site of origin of MM, following the pleura [2]. In the United States, MPM accounts for about 10 % of all cases of mesothelioma [3]. In Japan, 105 cases of MM were investigated, and MPM accounted for 7 cases (6.7 %) [4]. From these data, MPM is considered a very rare tumor. It is classified as a diffuse or localized type. Localized MPM usually has a good prognosis following complete surgical excision, whereas diffuse MPM is aggressive and rapidly spreads within the abdominal cavity. In diffuse MPM, there are no specific signs or symptoms. Abdominal distention and pain are the most and second most frequent initial symptoms, present in 56–82 % and 27–58 % of patients, respectively [5, 6]. In our case, abdominal pain was the initial symptom. Serological studies and CT scans were useless, whereas laparoscopic biopsy was useful. In operative findings and histological studies (hematoxylin– eosin and immunohistochemical staining), diffuse type MPM, of the epithelioid type, was diagnosed. In unresectable malignant pleural mesothelioma, combination therapy with pemetrexed (PEM) plus cisplatin (CDDP) has been established as standard first-line chemotherapy [1]. On the other hand, MPM is uncommon and most clinical trials are small, and there is no established treatment of diffuse-type MPM. Although randomized trials have not been conducted, two open-label studies suggest the value of combination therapy with PEM plus CDDP in patients with MPM [7, 8]. In one of these studies, 98 patients with MPM received PEM alone or PEM plus CDDP, and 73 patients (43 previously treated, 28 chemotherapy-naive, and 2 not classified) were evaluated. In previously treated patients, response rate (RR) and median survival time (MST) was 23.3 % and 13.1 months, respectively. In chemotherapy-naive patients, RR was 25 % (MST had not been reached) [7]. For this reason,
Fig. 2 Biopsied specimen of a nodule on the omentum. This specimen shows a proliferation of polygonal cells with bizarre nuclei formed in part in epithelioid fashion
123
Clin J Gastroenterol (2012) 5:373–376 Table 1 Laboratory data on admission
375
Hematology
Blood chemistry
Serology
WBC
7000/ll
TP
7.41 g/dl
CRP
0.23 mg/dl
Neut
58.3 %
Alb
4.07 g/dl
CEA
1.7 ng/dl
Lymph Mono
32.2 % 5.3 %
AST ALT
20 IU/l 14 IU/l
CA19-9 Hyaluronic acid
10.4 U/dl 21 ng/ml
Eosin
3.8 %
LDH
216 IU/l
Baso
0.4 %
T-bil
0.3 mg/dl
Coagulation PT-INR
0.88
RBC
453 9 104/ll
BUN
11.6 mg/dl
APTT
28.5 s
Hb
13.9 g/dl
Cre
0.77 mg/dl
Hct
41.8 %
Na
144 mEq/l
Plt
31.7 9 104/ll
K
3.8 mEq/l
Cl
109 mEq/l
Fig. 3 Abdominal contrast-enhanced CT scan. The white arrows show a slightly high density of the peritoneum
Fig. 4 PET–CT. Abnormal accumulation disappeared after 3 months starting of initial chemotherapy
PEM plus CDDP was selected as first-line chemotherapy in our patient. Although randomized trials have not been conducted, other combination regimens, especially PEM plus carboplatin or gemcitabine (GEM) plus PEM, may show effective anti-tumor activities. Carboplatin is often substituted
Fig. 5 PET–CT. The new mass in the left upper intra-abdomen was detected 11 months after starting initial chemotherapy (white arrow)
for cisplatin, particularly in elderly patients. Two phase II trials of malignant pleural mesothelioma [9, 10] and openlabel studies of MPM suggested a similar level of effect for PEM plus carboplatin as PEM plus CDDP. On the other hand, one phase II trial of MPM suggested the efficacy of GEM plus PEM. GEM plus PEM was administered to 20
123
376
Clin J Gastroenterol (2012) 5:373–376
patients as first-line chemotherapy. RR and MST was 15 % and 27 months, respectively [11]. In patients who cannot tolerate CDDP, PEM plus carboplatin or GEM plus PEM may be used as alternative treatment. Because first-line chemotherapy is not established in MPM, the role of second-line chemotherapy is not proven. However, in malignant pleural mesothelioma, the secondline chemotherapy of patients who were previously treated with PEM plus CDDP or CDDP alone showed significantly prolonged survival [12]. In a small phase II study of malignant pleural mesothelioma, GEM plus vinorelbine (VNR) was administered to 30 patients who had previously been treated with PEM-based chemotherapy as second-line chemotherapy. RR, median time to progression, and MST was 10 %, 2.8 months, and 10.9 months, respectively [13]. According to these data on malignant pleural mesothelioma, GEM plus VNR was selected as second-line chemotherapy in our patient. On the other hand, although a phase II study of CPT-11 alone showed no anti-tumor effect at first line chemotherapy [14], another phase II study of CPT-11 plus cisplatin with or without mitomycin C suggest that CPT-11 may have activity in malignant pleural mesothelioma [15]. Because the effect of third-line chemotherapy is not yet established in malignant pleural mesothelioma, we presumed the activity of CPT-11 and used it in third-line chemotherapy. In conclusion, PEM plus CDDP showed improvement of abdominal pain and disappearance of peritoneal abnormal accumulation on PET–CT. We consider that palliative chemotherapy had good disease control and prolonged the survival time. Because a number of combination chemotherapies may be effective in advanced MPM, randomized trials of these regimens should be performed. Conflict of interest
No author has any conflict of interest.
References 1. Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol. 2003;21:2636.
123
2. Antman KH. Current concepts: malignant mesothelioma. N Engl J Med. 1980;303:200–2. 3. Rodrı´guez D, Cheung MC, Housri N, Koniaris LG. Malignant abdominal mesothelioma: defining the role of surgery. J Surg Oncol. 2009;99:51–7. 4. Fujimoto N, Aoe K, Gemba K, Kato K, Yamazaki K, Kishimoto T. Clinical investigation of malignant mesothelioma in Japan. J Cancer Res Clin Oncol. 2010;136:1755–9. 5. Antman KH. Clinical presentation and natural history of benign and malignant mesothelioma. Semin Oncol. 1981;8:313–20. 6. Sugarbaker PH, Welch LS, Mohamed F, Glehen O. A review of peritoneal mesothelioma at the Washington Cancer Institute. Surg Oncol Clin N Am. 2003;12:605–21. 7. Ja¨nne PA, Wozniak AJ, Belani CP, Keohan ML, Ross HJ, Polikoff JA, et al. Open-label study of pemetrexed alone or in combination with cisplatin for the treatment of patients with peritoneal mesothelioma: outcomes of an expanded access program. Clin Lung Cancer. 2005;7:40–6. 8. Carteni G, Manegold C, Garcia GM, Siena S, Zielinski CC, Amadori D, et al. Malignant peritoneal mesothelioma—results from the International Expanded Access Program using pemetrexed alone or in combination with a platinum agent. Lung Cancer. 2009;64:211–8. 9. Ceresoli GL, Zucali PA, Favaretto AG, Grossi F, Bidoli P, Del Conte G, et al. Phase II study of pemetrexed plus carboplatin in malignant pleural mesothelioma. J Clin Oncol. 2006;24:1443–8. 10. Castagneto B, Botta M, Aitini E, Spigno F, Degiovanni D, Alabiso O, et al. Phase II study of pemetrexed in combination with carboplatin in patients with malignant pleural mesothelioma (MPM). Ann Oncol. 2008;19:370–3. 11. Simon GR, Verschraegen CF, Ja¨nne PA, Langer CJ, Dowlati A, Gadgeel SM, et al. Pemetrexed plus gemcitabine as first line chemotherapy for patients with peritoneal mesothelioma: final report of a phase II trial. J Clin Oncol. 2008;26:3567–72. 12. Manegold C, Symanowski J, Gatzemeier U, Reck M, von Pawel J, Kortsik C, et al. Second line (post-study) chemotherapy received by patients treated in the phase III trial of pemetrexed plus cisplatin versus cisplatin alone in malignant pleural mesothelioma. Ann Oncol. 2005;16:923–7. 13. Zucali PA, Ceresoli GL, Garassino I, De Vincenzo F, Cavina R, Campagnoli E, et al. Gemcitabine and vinorelbine in pemetrexedpretreated patients with malignant pleural mesothelioma. Cancer. 2008;112:1555–61. 14. Kindler HL, Herndon JE, Zhang C, Cancer and Leukemia Group B. Irinotecan for malignant mesothelioma A phase II trial by the Cancer and Leukemia Group B. Lung Cancer. 2005;48:423–8. 15. Fennell DA, Steele JP, Shamash J, Evans MT, Wells P, Sheaff MT, et al. Efficacy and safety of first- or second-line irinotecan, cisplatin, and mitomycin in mesothelioma. Cancer. 2007;109: 93–9.
CASE REPORT
Advanced diffuse malignant peritoneal mesothelioma responding to palliative chemotherapy Koji Nakashima • Haruhiko Inatsu • Kazuo Kitamura • Tomomi Hikosaka Shinri Hoshiko • Shinya Ashiduka
•
Received: 17 February 2012 / Accepted: 23 September 2012 / Published online: 17 October 2012 Ó Springer Japan 2012
Abstract A 64-year-old man diagnosed with advanced malignant peritoneal mesothelioma by laparoscopic biopsy was treated with systemic chemotherapy. The patient underwent first-line chemotherapy with pemetrexed plus cisplatin for 11 months, then second-line chemotherapy with gemcitabine plus vinorelbine for 6 months, and thirdline chemotherapy with CPT-11 for 4 months. After thirdline chemotherapy failed, he received palliative treatment. Although the tumor continued to grow, and he died 24 months after initiation of treatment, chemotherapy prolonged the survival time and improved his quality of life. Keywords Malignant peritoneal mesothelioma Diffuse type Chemotherapy Pemetrexed Cisplatin
Introduction Malignant peritoneal mesothelioma (MPM) is a rare and highly aggressive tumor. Surgical resection is possible in a minority of patients, and palliative chemotherapy is necessary in most. Although initial chemotherapy of MPM has been established [1], there is no established treatment of MPM. Therefore, effective chemotherapy is needed for the treatment of these patients. We present a report of a patient with MPM who received an initial course of treatment with pemetrexed plus cisplatin.
K. Nakashima (&) H. Inatsu K. Kitamura T. Hikosaka S. Hoshiko S. Ashiduka First Department of Internal Medicine, Faculty of Medicine, University of Miyazaki Hospital, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan e-mail: [email protected]
Case report A 64-year-old man with a 12-year history of exposure to asbestos suffered from abdominal pain and was admitted to the hospital near his home. Upper and lower endoscopic findings were normal; however, positron emission tomography–computed tomography (PET–CT) showed abnormal accumulation in the upper left abdomen (Fig. 1). Although the primary tumor was unclear, peritoneal dissemination was suspected at first. Laparoscopic biopsy was performed for the purpose of diagnosis. In operative findings, multiple small nodules were shown on the surfaces of the omentum, peritoneum, and mesenterium. Biopsied specimens showed a proliferation of polygonal cells with bizarre nuclei forming epithelioid mesothelioma (Fig. 2). In immunohistochemistry, polygonal cells were positive for carletinin and anti-cytokeratin antibody (AE1/AE3). From these results, MPM, of the epithelioid type, was diagnosed. The patient was transferred to our hospital for chemotherapy. Pain in the left and right upper abdomen was observed in physical findings. Laboratory data on admission are shown in Table 1. Serum tumor markers and hyaluronic acid were within normal ranges. Abdominal contrast-enhanced CT scans showed a slightly high-density area in the peritoneum (Fig. 3), while chest CT scans showed no abnormal findings in the lung field and pleura. The patient received combination chemotherapy with pemetrexed (PEM) plus cisplatin (CDDP). PEM 500 mg/m2 and CDDP 75 mg/m2 were administered on day 1 of a 21-day cycle. After starting chemotherapy, the patient’s abdominal pain decreased. After the 3rd cycle of PEM plus CDDP, serum creatinine levels increased to 1.5 mg/dl. We needed to reduce the dosage of CDDP. After 3 months, abnormal accumulation had disappeared on PET–CT (Fig. 4). Although the dosage of CDDP finally required about a 30 % reduction, 12 cycles of PEM plus CDDP were administered. After 11 months,
123
374
PET–CT showed a new mass in the left upper abdominal cavity (Fig. 5). The patient received second-line combination chemotherapy with gemcitabine (GEM) plus vinorelbine (VNR). GEM 1000 mg/m2 and VNR 25 mg/m2 were administered on days 1 and 8 of a 21-day cycle. Although the mass was stable disease (SD) on abdominal CT, after 6 months from starting second-line chemotherapy CT revealed an increase of the left upper abdominal mass and new abdominal dissemination. The patient received third-line chemotherapy with CPT-11 for 4 months. After third-line chemotherapy failed, he received palliative treatment and experienced progression of the disease. He died 24 months after the start of first-line chemotherapy.
Discussion Malignant mesothelioma (MM) is a rare and highly aggressive tumor arising from the mesothelial cells of the
Fig. 1 Positron emission tomography–computed tomography (PET–CT). Abnormal accumulation of upper left abdomen was detected (SUV max 15.1)
Clin J Gastroenterol (2012) 5:373–376
pleura, peritoneum, pericardium, or tunica vaginalis testes. Pathogenesis of MM is strongly associated with occupational asbestos exposure. The peritoneum is the second most frequent site of origin of MM, following the pleura [2]. In the United States, MPM accounts for about 10 % of all cases of mesothelioma [3]. In Japan, 105 cases of MM were investigated, and MPM accounted for 7 cases (6.7 %) [4]. From these data, MPM is considered a very rare tumor. It is classified as a diffuse or localized type. Localized MPM usually has a good prognosis following complete surgical excision, whereas diffuse MPM is aggressive and rapidly spreads within the abdominal cavity. In diffuse MPM, there are no specific signs or symptoms. Abdominal distention and pain are the most and second most frequent initial symptoms, present in 56–82 % and 27–58 % of patients, respectively [5, 6]. In our case, abdominal pain was the initial symptom. Serological studies and CT scans were useless, whereas laparoscopic biopsy was useful. In operative findings and histological studies (hematoxylin– eosin and immunohistochemical staining), diffuse type MPM, of the epithelioid type, was diagnosed. In unresectable malignant pleural mesothelioma, combination therapy with pemetrexed (PEM) plus cisplatin (CDDP) has been established as standard first-line chemotherapy [1]. On the other hand, MPM is uncommon and most clinical trials are small, and there is no established treatment of diffuse-type MPM. Although randomized trials have not been conducted, two open-label studies suggest the value of combination therapy with PEM plus CDDP in patients with MPM [7, 8]. In one of these studies, 98 patients with MPM received PEM alone or PEM plus CDDP, and 73 patients (43 previously treated, 28 chemotherapy-naive, and 2 not classified) were evaluated. In previously treated patients, response rate (RR) and median survival time (MST) was 23.3 % and 13.1 months, respectively. In chemotherapy-naive patients, RR was 25 % (MST had not been reached) [7]. For this reason,
Fig. 2 Biopsied specimen of a nodule on the omentum. This specimen shows a proliferation of polygonal cells with bizarre nuclei formed in part in epithelioid fashion
123
Clin J Gastroenterol (2012) 5:373–376 Table 1 Laboratory data on admission
375
Hematology
Blood chemistry
Serology
WBC
7000/ll
TP
7.41 g/dl
CRP
0.23 mg/dl
Neut
58.3 %
Alb
4.07 g/dl
CEA
1.7 ng/dl
Lymph Mono
32.2 % 5.3 %
AST ALT
20 IU/l 14 IU/l
CA19-9 Hyaluronic acid
10.4 U/dl 21 ng/ml
Eosin
3.8 %
LDH
216 IU/l
Baso
0.4 %
T-bil
0.3 mg/dl
Coagulation PT-INR
0.88
RBC
453 9 104/ll
BUN
11.6 mg/dl
APTT
28.5 s
Hb
13.9 g/dl
Cre
0.77 mg/dl
Hct
41.8 %
Na
144 mEq/l
Plt
31.7 9 104/ll
K
3.8 mEq/l
Cl
109 mEq/l
Fig. 3 Abdominal contrast-enhanced CT scan. The white arrows show a slightly high density of the peritoneum
Fig. 4 PET–CT. Abnormal accumulation disappeared after 3 months starting of initial chemotherapy
PEM plus CDDP was selected as first-line chemotherapy in our patient. Although randomized trials have not been conducted, other combination regimens, especially PEM plus carboplatin or gemcitabine (GEM) plus PEM, may show effective anti-tumor activities. Carboplatin is often substituted
Fig. 5 PET–CT. The new mass in the left upper intra-abdomen was detected 11 months after starting initial chemotherapy (white arrow)
for cisplatin, particularly in elderly patients. Two phase II trials of malignant pleural mesothelioma [9, 10] and openlabel studies of MPM suggested a similar level of effect for PEM plus carboplatin as PEM plus CDDP. On the other hand, one phase II trial of MPM suggested the efficacy of GEM plus PEM. GEM plus PEM was administered to 20
123
376
Clin J Gastroenterol (2012) 5:373–376
patients as first-line chemotherapy. RR and MST was 15 % and 27 months, respectively [11]. In patients who cannot tolerate CDDP, PEM plus carboplatin or GEM plus PEM may be used as alternative treatment. Because first-line chemotherapy is not established in MPM, the role of second-line chemotherapy is not proven. However, in malignant pleural mesothelioma, the secondline chemotherapy of patients who were previously treated with PEM plus CDDP or CDDP alone showed significantly prolonged survival [12]. In a small phase II study of malignant pleural mesothelioma, GEM plus vinorelbine (VNR) was administered to 30 patients who had previously been treated with PEM-based chemotherapy as second-line chemotherapy. RR, median time to progression, and MST was 10 %, 2.8 months, and 10.9 months, respectively [13]. According to these data on malignant pleural mesothelioma, GEM plus VNR was selected as second-line chemotherapy in our patient. On the other hand, although a phase II study of CPT-11 alone showed no anti-tumor effect at first line chemotherapy [14], another phase II study of CPT-11 plus cisplatin with or without mitomycin C suggest that CPT-11 may have activity in malignant pleural mesothelioma [15]. Because the effect of third-line chemotherapy is not yet established in malignant pleural mesothelioma, we presumed the activity of CPT-11 and used it in third-line chemotherapy. In conclusion, PEM plus CDDP showed improvement of abdominal pain and disappearance of peritoneal abnormal accumulation on PET–CT. We consider that palliative chemotherapy had good disease control and prolonged the survival time. Because a number of combination chemotherapies may be effective in advanced MPM, randomized trials of these regimens should be performed. Conflict of interest
No author has any conflict of interest.
References 1. Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol. 2003;21:2636.
123
2. Antman KH. Current concepts: malignant mesothelioma. N Engl J Med. 1980;303:200–2. 3. Rodrı´guez D, Cheung MC, Housri N, Koniaris LG. Malignant abdominal mesothelioma: defining the role of surgery. J Surg Oncol. 2009;99:51–7. 4. Fujimoto N, Aoe K, Gemba K, Kato K, Yamazaki K, Kishimoto T. Clinical investigation of malignant mesothelioma in Japan. J Cancer Res Clin Oncol. 2010;136:1755–9. 5. Antman KH. Clinical presentation and natural history of benign and malignant mesothelioma. Semin Oncol. 1981;8:313–20. 6. Sugarbaker PH, Welch LS, Mohamed F, Glehen O. A review of peritoneal mesothelioma at the Washington Cancer Institute. Surg Oncol Clin N Am. 2003;12:605–21. 7. Ja¨nne PA, Wozniak AJ, Belani CP, Keohan ML, Ross HJ, Polikoff JA, et al. Open-label study of pemetrexed alone or in combination with cisplatin for the treatment of patients with peritoneal mesothelioma: outcomes of an expanded access program. Clin Lung Cancer. 2005;7:40–6. 8. Carteni G, Manegold C, Garcia GM, Siena S, Zielinski CC, Amadori D, et al. Malignant peritoneal mesothelioma—results from the International Expanded Access Program using pemetrexed alone or in combination with a platinum agent. Lung Cancer. 2009;64:211–8. 9. Ceresoli GL, Zucali PA, Favaretto AG, Grossi F, Bidoli P, Del Conte G, et al. Phase II study of pemetrexed plus carboplatin in malignant pleural mesothelioma. J Clin Oncol. 2006;24:1443–8. 10. Castagneto B, Botta M, Aitini E, Spigno F, Degiovanni D, Alabiso O, et al. Phase II study of pemetrexed in combination with carboplatin in patients with malignant pleural mesothelioma (MPM). Ann Oncol. 2008;19:370–3. 11. Simon GR, Verschraegen CF, Ja¨nne PA, Langer CJ, Dowlati A, Gadgeel SM, et al. Pemetrexed plus gemcitabine as first line chemotherapy for patients with peritoneal mesothelioma: final report of a phase II trial. J Clin Oncol. 2008;26:3567–72. 12. Manegold C, Symanowski J, Gatzemeier U, Reck M, von Pawel J, Kortsik C, et al. Second line (post-study) chemotherapy received by patients treated in the phase III trial of pemetrexed plus cisplatin versus cisplatin alone in malignant pleural mesothelioma. Ann Oncol. 2005;16:923–7. 13. Zucali PA, Ceresoli GL, Garassino I, De Vincenzo F, Cavina R, Campagnoli E, et al. Gemcitabine and vinorelbine in pemetrexedpretreated patients with malignant pleural mesothelioma. Cancer. 2008;112:1555–61. 14. Kindler HL, Herndon JE, Zhang C, Cancer and Leukemia Group B. Irinotecan for malignant mesothelioma A phase II trial by the Cancer and Leukemia Group B. Lung Cancer. 2005;48:423–8. 15. Fennell DA, Steele JP, Shamash J, Evans MT, Wells P, Sheaff MT, et al. Efficacy and safety of first- or second-line irinotecan, cisplatin, and mitomycin in mesothelioma. Cancer. 2007;109: 93–9.
