Mesothelioma chemotherapy

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27.01 Chemotherapy Overview

Tri-modal therapy, surgery, chemotherapy, and radiation is recommended for patients with early epethelial mesothelioma. For others, chemotherapy will be an important option. Here, we look at what types of chemotherapy we be used alone and in the tri-modal therapy. The results are similar to non-small cell lung cancer, with platinum-based chemotherapy probably the norm, and now used with the drug Taxol. Chemotherapy can extend life and, reduce disease-related symptoms, though it usually does not provide a cure.
The percentage of partial responses with chemotherapy (reduction of tumor volume by 50%) in clinical trials ranges from 20-35%, with a few studies above and below that range. A review from 1998 noted that various drugs are tested:

“To our knowledge, no chemotherapeutic regimen has emerged as a standard of care. A review of the literature reveals that small activity against this disease has been shown by the anthracyclines, platinum compounds, and alkyllating agents, whereas higher activity has been reported with the antimetabolites. Dose-escalated chemotherapeutics regimens may offer an advantage, whereas combination chemotherapy has not shown any benefit over single-agent therapy. Favorable responses have been reported with the administration of intrapleural biological response modifiers. Further trials and the investigation of new agents in the treatment of this disease are necessary.”

Another article states:

The role of chemotherapy in the management of pleural mesothelioma still remains uncertain. The available data indicate that although 10-20% of patients are known to achieve an objective response to a number of chemotherapeutic agents, the impact on survival appears limited and improvement in the quality of life remains uncertain. Ardizonni, (1)

Some studies have shown an increase in survival associated with chemotherapy:

The influence of treatment on clinical outcome in pleural mesothelioma (PM) is uncertain. We studied 83 patients with PM treated at our institution to evaluate the impact of treatment modality on survival, Methods. Medical records of 83 patients with PM treated between 1978 and 1994 were reviewed. The following data were tabulated for each patient; age, sex, date of diagnosis, history of asbestos exposure, smoking history, method of diagnosis, histologic subtype, type of treatment and survival from diagnosis. Four treatment groups were analyzed; chemotherapy (C), surgery (S), combined modality (CM i.e. S + C with or without radiation therapy) and supportive care alone (SC). Survival curves were calculated and adjustment made for age.... Seventy-one males and 12 females with a mean age of 67 years were analyzed. Seventy-five percent were smokers and 74% reported definite or probable asbestos exposure. Treatment groups did not vary according to smoking or asbestos history. The CM group and SC groups contained similar proportions of patients with epithelial tumors (54% v 56%). Median survival for patients in the CM (combined modality) group was 23.9 months versus 4.5 months among those receiving SC (supportive care) (p < 0.01). Huncharak (2)

While an impact of chemotherapy is seen, some have interpreted the study as supporting combined modalities, surgery and chemotherapy, and not chemotherapy alone. Another study we look at showed chemotherapy and immunotherapy lengthening survival in some patients.
27.1 PLATINUM-BASED CHEMOTHERAPY COMBINATIONS
Cisplatin is a widely used chemotherapy drug which has demonstrated effectiveness with non-small cell lung cancer, and other types of cancer. Cisplatin combinations have shown consistent responses, though Cisplatin is associated with nausea and stomach discomfort. Use of newer drugs to relieve stomach discomfort, and substitution of Carboplatin, a similar platinum drug with fewer side effects but similar effectiveness, may reduce the problems associated with the drug. Precisely what should be used with Cisplatin remains unclear, as other chemotherapy drugs, immunotherapy, newer forms of gene therapy, are all being tried.
27.11 Side Effects
Unfortunately Cisplatin’s strength is also its weakness; its capacity to stop the division of cells may also create problems in some areas of the body where such division is a part of normal functioning. Cells in the stomach frequently divide as part of digestion, and Cisplatin has been associated with nausea and even episodic vomiting. However, one third of the patients had an episode of nausea or vomiting. Many patients will want to risk such side effects for the chance to extend life, but some may not, and side effects with Cisplatin combinations must be discussed with your oncologist.
Many of the combination therapies limit Cisplatin because of its potency. In the future, Carboplatin, a similar drug with few side effects, may be substituted, as it is with other forms of lung cancer.
27.12 Cisplatin and Irinotecan
A Japanese clinical trial combined Cisplatin with Irinotecan. The abstract states:
“The purpose of this study was to assess the efficacy and toxicity of a combination of cisplatin and irinotecan (CPT-11) in the treatment of patients with malignant pleural mesothelioma.... METHODS: Fifteen previously untreated patients with malignant pleural mesothelioma were treated with cisplatin (60 mg/m2 on Day 1) and CPT-11 (60 mg/m2 on Days 1, 8, and 15) administered intravenously and followed by a 1-week rest period... RESULTS: All patients were valuable for response and toxicity. Four partial responses (response rate of 26.7%) with a median response duration of 25.9 weeks and 2 regressions of valuable disease (overall response rate of 40%) were observed.” Nakano (Note the term response rate usually is defined as reduction in tumor size by at least 50%).

27.13 Cisplatin and Interferon

Immunotherapy and gene therapy are frequently used to fight mesothelioma. In a phase 1 study of 13 patients with mesothelioma, four patients had a partial response, and one a complete response. A phase 1 trial is designed to determine tolerable doses as well as assess response. Some anemia and renal or kidney problems were noted from the therapy, but overall the study showed promise with phase 2 trials expected. Porohit (10)
27.14 Cisplatin, Etopiside and 5 Fluourouracil
A recent French study examined Cisplatin, Etoposide and 5-fluourouracil, a combination previously used with other forms of lung cancer:
The authors conducted a Phase II trial in which two drugs (etoposide and 5-fluorouracil) were added to the Cancer and Leukemia Group B cisplatin-mitomycin regimen in an effort to define a more effective chemotherapy. METHODS: Forty-five patients with confirmed Stage II malignant pleural mesothelioma were prospectively enrolled in the study. Thirty-one patients received cisplatin 60 mg/m2 on Day 1, 5-fluorouracil 600 mg on Days 1-4, folinic acid 100 mg/m2 on Days 1-4, mitomycin C 10 mg/m2 on Day 3, and etoposide 100 mg/m2 i.v. on Days 1-3, with prophylactic hematopoietic growth factors.... Histology included epithelial (in 33 cases), sarcomatous (in 6), mixed (in 3), and unspecified type (in 3).RESULTS: Two hundred eleven cycles were administered. Treatment was well tolerated and the major toxicity was hematologic: anemia in 30% of cases, neutropenia in 24%, and 2 probable cases of mitomycin-induced pneumonitis. The objective response rate was 38% (17 of 45 were partial responses), and the median response duration was 12 months. The median survival time was 16 months. There were no differences in response or survival between the 31 patients treated with growth factors and the 14 patients treated without them. Survival was slightly better for responders than for nonresponders who had stable disease or progression (20 vs. 10 months, P < 0.05). CONCLUSIONS: This four-drug combination was effective, with a notably high response rate, acceptable toxicity, and good adherence to protocol doses. The impact on survival was limited.”

27.15 Cisplatin and Gemcitibine
Gemcitabine is a newer chemotherapy drug used to treat lung cancer. Its side effects are generally limited. Gemcibatine has been tried alone:

Gemcitabine is broadly active in a variety of solid tumors, including malignant mesothelioma. In vitro, gemcitabine demonstrates activity against mesothelioma cell lines. The role of single-agent gemcitabine in patients with mesothelioma is unclear, since three phase II trials treated a total of 60 patients and achieved response rates of 0%, 7%, and 31% Kindler (10)

Another study reported an unusually high partial response rate of 47% using Cisplatin and Gemcitabine. (Byrne 5). However, one third of the patients had an episode of nausea or vomiting. Another study reported more modest results with 4 of 25 patients having partial responses. The average time for the disease to progress was 6 months with median survival measured at 9.6 months, perhaps only a modest increase over nonintervention and non-chemotherapy based treatment.
27.3 NEW CHEMOTHERAPY DRUGS

27.31 Pemetrexed (Alimta)

A phase I study of pemetrexed in combination with cisplatin showed a remarkable response rate of approximately 50% in patients with the epithelial subtype of MPM.Mangegold (4) “Pemetrexed is a new antifolate which inhibits many reactions that are essential for cell proliferation. Another writer suggests that anti-metabolites combined with either Cisplatin or Carboplatin will be the preferred treatment:

“Antifolates such as methotrexate are among the most active compounds in mesothelioma, albeit based only on phase II data. Recently two antifolate-based combinations with apparently higher efficacy than older regimens have emerged:the pemetrexed/cisplatin regimen and the raltitrexed/oxaliplatin regimen. In two phase I trials with pemetrexed combined with either cisplatin or carboplatin responses occurred in five of 11 and nine of 29 patients, respectively. In a phase I trial of raltitrexed/oxaliplatin, six of 17 patients (35%) with mesothelioma achieved a partial response. In a phase II trial of raltitrexed/oxaliplatin, 14 objective responses were confirmed in 72 patients (25%) with malignant pleural mesothelioma.”

Precisely why these drugs are particularly effective remains to be established.
27.311 Side Effects
Some side effects are seen with this drug. A study of non-small cell cancer showed grade 3 or 4 neutropenia was seen in 25 patients (42%).

“The early studies of pemetrexed showed that the important dose-limiting toxicities were myelosuppression, mucositis, and diarrhea, all of which are common with any antimetabolite. Subsequent studies described in this article will show that these toxicities can be significantly reduced by the use of vitamin supplementation with folate and B(12), and that pemetrexed has considerable activity in non-small cell lung cancer and mesothelioma. Clark (8).

27.312 Availability under Expanded Use Program

A July 23, 2002 press release reported:

“The U.S. Food and Drug Administration (FDA) has agreed to allow the drug manufacturer‚ Eli Lilly‚ to make Alimta® (pemetrexed) available on a “compassionate or expanded use basis” to patients with malignant pleural mesothelioma before it becomes commercially available. This means that mesothelioma patients who have not yet received treatment may be eligible to receive Alimta® free of charge before the FDA review process is completed.”

27.32 Oxaliplatin and Raltitraxed

“In a phase I study, the combination of oxaliplatin and raltitrexed was shown to be active against malignant pleural mesothelioma Four partial responses, 1 regression of disease (objective response rate, 45%; 95% CI, 15.6-74.4%), 4 stable diseases and 2 progressions of disease were observed. An improvement in disease-related symptoms was recorded in all responders and in 2 patients with stable disease. Toxicity was mild, with no toxic-related death and only 1 episode of grade 4 neurotoxicity. CONCLUSIONS: We consider the combination promising and worthy of further studies.” Maisano (5)

27.33 Intrapleural Administration of Chemotherapy

For most tumors including non-small cell, the drug is given either orally or intravenously. However, a new form of treatment where the drug is applied directly to the tumor has been utilized with mesothelioma with some success.
several investigators have studied direct intrapleural delivery of chemotherapy with the rationale of achieving high local drug concentrations while minimizing systemic toxicity. Intrapleural delivery requires the presence of a patent pleural space, which limits the candidate pool to those with earlier stages of disease, because the pleural space is often obliterated in advanced mesothelioma.

References
1. Ardizzoni, Systemic Drug Therapy of Malignant Pleural Mesothelioma, Monaldi Arch Chest Dis, 1998 Apr, 53:2, 236-40.
2. Huncharak, Treatment and survival in diffuse malignant pleural mesothelioma; a study of 83 cases from the Massachusetts General Hospital, Anticancer Res 1996 May-Jun;16(3A):1265-8
4. Ho, Malignant pleural Mesothelioma.Cancer Treat Res 2001;105:327-73
5. Maisano, Oxaliplatin and raltitrexed in the treatment of inoperable malignant pleural mesothelioma: results of a pilot study, Tumori 2001 Nov-Dec;87(6):391-3
6. Clark, Phase II trial of pemetrexed disodium (ALIMTA, LY231514) in chemotherapy-naive patients with advanced non-small-cell lung cancer, Ann Oncol 2002 May;13(5):737-41
7. Rusch, A phase II trial of surgical resection and adjuvant high-dose hemithoracic radiation for malignant pleural mesothelioma, J Thorac Cardiovasc Surg 2001 Oct;122(4):788-95
8. Holsti, Altered fractionation of hemithorax irradiation for pleural mesothelioma and failure patterns after treatment. Acta Oncol 1997;36(4):397-405
9. Stenman, Advances in the Treatment of Malignant Pleural Mesothelioma, Chest. 1999;116:504-520)
10. Kindler, The role of gemcitabine in the treatment of malignant mesothelioma, Semin Oncol 2002 Feb;29(1):70-6
11. Magnegold Pemetrexed for diffuse malignant pleural mesothelioma
Semin Oncol 2002 Apr;29(2 Suppl 5):30-5
12. Byrne, Cisplatin and gemcitabine treatment for malignant mesothelioma: a phase II study, J Clin Oncol 1999 Jan;17(1):25-30
13. Fisazzi, The emerging role of antifolates in the treatment of malignant pleural mesothelioma, Semin Oncol 2002 Feb;29(1):77-81
14. Bunn, Incorporation of pemetrexed (Alimta) into the treatment of non-small cell lung cancer (thoracic tumors), Semin Oncol 2002 Jun;29(3 Suppl 9):17-22
15 Butchart, Contemporary Management of Malignant Pleural Mesothelioma, Oncologist, Vol 4, No 6, 488-500, December 1999.
16. Sugarbaker, Resection Margins, extra pleural nodal status, and cell type determine postoperative long term survival in trimodality therapy of malignant pleural mesothelioma: results in 183 cases. J. Thoracic Cardiovascular Surgery 1999, Jan, 117:1, 54,65.
17. Aziz, The management of malignant pleural mesothelioma; single centre experience in 10 years, Eur. J. Cardiothorac Surg 2002 Aug;22(2):298-305
16. Melluni, Treatment of malignant pleural mesothelioma, Minerva Chir 2001 Jun;56(3):243-50
18. Jaklitchs, Treatment of Malignant Mesothelioma, World J Surg 25:210-217 (2001)
19. Takahashi, Extrapleural pneumonectomy for diffuse malignant pleural mesothelioma. A treatment option in selected cases? Jpn J Thorac Cardiovasc Surg 2001 Feb;49(2):89-93
20. Takagi, Surgical approach to pleural diffuse mesothelioma in Japan, Lung Cancer 2001 Jan;31(1):57-65

REFERENCES

1. Butchart, Contemporary Management of Malignant Pleural Mesothelioma, Oncologist, Vol 4, No 6, 488-500, December 1999.

2. Sugarbaker, Resection Margins, extra pleural nodal status, and cell type determine postoperative long term survival in trimodality therapy of Malignant Pleural Mesothelioma: results in 183 cases, J. Thoracic Cardiovascular Surgery 1999, Jan, 117:1, 54,65.

3. Aziz, The management of malignant pleural mesothelioma; single centre experience in 10 years, Eur. J. Cardiothorac Surg 2002 Aug;22(2):298-305.

3. Melluni, Treatment of malignant pleural mesothelioma, Minerva Chir 2001 Jun;56(3):243-50.

4. Jaklitchs, Treatment of Malignant Mesothelioma, World J Surg 25:210-217 (2001).

5. Takahashi, Extrapleural pneumonectomy for diffuse malignant pleural mesothelioma. A treatment option in selected cases? Jpn J Thorac Cardiovasc Surg 2001 Feb;49(2):89-93.

6. Takagi, Surgical approach to pleural diffuse mesothelioma in Japan, Lung Cancer 2001 Jan;31(1):57-65.

7. Serrisoli, Therapeutic outcome according to histologic subtype in 121 patients with malignant pleural mesothelioma, Lung Cancer 2001 Nov;34(2):279-87.

8. Martin, Palliative surgical debulking in malignant mesothelioma. Predictors of survival and symptom control, Eur J Cardiothorac Surg 2001 Dec;20(6):1117-21.

9. Rusch, A phase II trial of surgical resection and adjuvant high-dose hemithoracic radiation for malignant pleural mesothelioma, J Thorac Cardiovasc Surg 2001 Oct;122(4):788-95.

11. Neumesister, Prognosis, staging and therapy of malignant pleural mesothelioma, Med Klin 2002 Aug 15;97(8):459-71.

12. Hahn, Photodynamic therapy for mesothelioma, Treat Curr Treat Options Oncol 2001 Oct;2(5):375-83.

"Lung Cancer & Mesothelioma" provides a wealth of relevant and useful information including; how various types of cancer are formed, medical trials, available treatments and medications, insight and discussion regarding the emotional burden of cancer upon the patient and their families and ways by which to manage grief. I believe this book will provide an invaluable resource for anyone who has or who is caring for someone with cancer. Lorraine Kember is the Author of "Lean on Me - Cancer through a Carer's Eyes", Written from her experience of caring for her husband, who had asbestos related pleural mesothelioma

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