Dickgreber NJ, Fink TH, Latz JE, Hossain AM, Musib LC, Thomas M.

Hannover Medical School, Hannover, Germany. nicolas.dickgreber@gmx.de

Abstract

Purpose: Pemetrexed is approved as monotherapy and in combination with cisplatin. The established combination dose was identified before the addition of folic acid and vitamin B₁₂ to the treatment regimen. We evaluated the toxicity and pharmacokinetics (PK) of higher pemetrexed doses with cisplatin and vitamin supplementation.

Experimental Design: Patients with malignant pleural mesothelioma or non–small cell lung cancer received pemetrexed doses from 500 to 900 mg/m² + 75 mg/m² cisplatin once every 21 days. Folic acid and vitamin B₁₂ were administered per label recommendations.

Results: Twenty-one patients received a combined total of 84 cycles. The maximum tolerated dose was 900 mg/m² pemetrexed + 75 mg/m² cisplatin. Dose-limiting toxicities at this dose included grade 3 anemia, bronchopneumonia, and neutropenia, and 1 death from sepsis secondary to grade 4 febrile neutropenia, considered possibly related to study drugs. The recommended dose was 800 mg/m² pemetrexed + 75 mg/m² cisplatin. Pemetrexed PK were consistent across doses; pemetrexed did not seem to affect total or free platinum PK.

Conclusions: Pemetrexed with vitamin supplementation was safe and well tolerated at higher doses than the currently established 500 mg/m² + 75 mg/m² cisplatin. Based on this study, the recommended dose would be 800 mg/m² pemetrexed + 75 mg/m² cisplatin. However, recent studies showed a lack of improved efficacy for 900 or 1,000 mg/m² single-agent pemetrexed versus 500 mg/m² and a lack of PK/pharmacodynamic exposure-response relationship for the pemetrexed/cisplatin combination across pemetrexed exposures corresponding to this dose range. Based on currently available evidence, we recommend retaining the established dose.

Glossary

regimen

(rej-uh-men) a strict, regulated plan (such as diet, exercise, or other activity) designed to reach certain goals. In cancer treatment, a plan to treat cancer.

grade

The grade of a cancer reflects how abnormal it looks under the microscope. There are several grading systems for cancer, such as the Gleason score for prostate cancer. Each grading system divides cancer into those with the greatest abnormality (poorly differentiated), the least abnormality (well-differentiated), and those in between (moderately differentiated). Grading is done by the pathologist who examines the tissue from the biopsy. It is important because higher grade cancers tend to grow and spread more quickly and have a worse prognosis.

cell

the basic unit of which all living things are made. Cells replace themselves by splitting and forming new cells (mitosis). The processes that control the formation of new cells and the death of old cells are disrupted in cancer.

cancer

malignancy; a group of diseases typified by abnormal, generally out-of-control, cell growth.

anemia

(uh-neem-ee-uh) low red blood cell count.

mesothelioma

a tumor derived from mesothelial tissue, such as the peritoneum (lining the abdomen) or pleura (lining the lungs). More on mesothelioma.

pemetrexed

chemotheraputic agent that interferes with a crucial process that allows cancer cells to reproduce and spread. Specifically, pemetrexed stops the production of three enzymes that are required to feed the cancer cell. Often used in combination with cisplatin. Marketed under the name ALIMTA. See: Alimta.

Carteni G, Manegold C, Garcia GM, Siena S, Zielinski CC, Amadori D, Liu Y, Blatter J, Visseren-Grul C, Stahel R.

Cardarelli Hospital, Medical Oncology, Via Cardarelli 9, 80100 Naples, Italy. giacomo.carteni@ospedalecardarelli.it

Abstract

Aim: Peritoneal mesothelioma (PM) has rarely been studied. The Expanded Access Program (EAP) provided access to 109 patients with PM.

Methods: This was a nonrandomized, open-label study conducted in chemo-naïve or previously treated patients with PM not amenable to curative surgery. Patients received pemetrexed (PEM) 500mg/m2 alone or with cisplatin (CIS) 75mg/m2 or carboplatin (CARBO) AUC 5 every 21 days, supplemented with standard vitamin B12, folate, and dexamethasone.

Results: Response rates (95% CI) for PEM, PEM/CIS, and PEM/CARBO were 12.5% (3.5, 29.0), 20.0% (7.7, 38.6), and 24.1% (10.3, 43.5), respectively. Median survival for PEM was 10.3 months. One-year survival rates for PEM/CIS and PEM were 57.4% (95% CI: 10.3, 100) and 41.5% (95% CI: 4.6, 78.4), respectively, and were not available for PEM/CARBO. Anemia was the most common serious adverse event (6.4%). Neutropenia (34.6%) was the most frequent CTC grade 3 or 4 toxicity reported.

Concluding statement: PEM with or without a platinum agent was both active and well tolerated in patients with peritoneal mesothelioma.

Keywords: Peritoneal mesothelioma, Pemetrexed, Platinum, Cisplatin, Carboplatin, Compassionate-use program, Expanded Access Program (EAP).

Glossary

oncology

(on-call-o-jee) the branch of medicine concerned with the diagnosis and treatment of cancer.

grade

The grade of a cancer reflects how abnormal it looks under the microscope. There are several grading systems for cancer, such as the Gleason score for prostate cancer. Each grading system divides cancer into those with the greatest abnormality (poorly differentiated), the least abnormality (well-differentiated), and those in between (moderately differentiated). Grading is done by the pathologist who examines the tissue from the biopsy. It is important because higher grade cancers tend to grow and spread more quickly and have a worse prognosis.

cancer

malignancy; a group of diseases typified by abnormal, generally out-of-control, cell growth.

anemia

(uh-neem-ee-uh) low red blood cell count.

mesothelioma

a tumor derived from mesothelial tissue, such as the peritoneum (lining the abdomen) or pleura (lining the lungs). More on mesothelioma.

peritoneal

(pair-uh-tuh-nee-al) the serous membrane that lines the cavity of the abdomen. (More on Peritoneal Mesothelioma.)

pemetrexed

chemotheraputic agent that interferes with a crucial process that allows cancer cells to reproduce and spread. Specifically, pemetrexed stops the production of three enzymes that are required to feed the cancer cell. Often used in combination with cisplatin. Marketed under the name ALIMTA. See: Alimta.

Berghmans T.

Département des Soins Intensifs et Oncologie Thoracique, Institut Jules-Bordet (Centre des Tumeurs de l’Université Libre de Bruxelles), 1 Rue Héger-Bordet, Brussels, Belgium. thierry.berghmanns@bordet.be

Abstract

Malignant pleural mesothelioma is a rare tumour of poor prognosis. Available therapeutics have restricted efficacy. Pleuro-pneumonectomy is the only treatment with curative intent but it could be offered to a limited and well selected group of patients. The role of radiotherapy is palliative and its preventive role on malignant seeding after invasive procedures is controversial. There are few active cytotoxic drugs in this disease. Currently, based on two randomised trials, the most efficacious chemotherapy regimen consists in a combination of cisplatin and an antifolate agent, pemetrexed or raltitrexed.

Keywords: Mesothelioma, Surgery, Radiotherapy, Chemotherapy

Glossary

regimen

(rej-uh-men) a strict, regulated plan (such as diet, exercise, or other activity) designed to reach certain goals. In cancer treatment, a plan to treat cancer.

prognosis

(prog-no-sis) a prediction of the course of disease; the outlook for the cure of the patient. For example, women with breast cancer that was detected early and who received prompt treatment have a good prognosis.

cytotoxic

(site-o-tox-ik) toxic to cells; cell-killing.

DES

abbreviation for diethylstilbestrola (die-eth-l-steh-BES-ter-ol),  synthetic form of estrogen.

chemotherapy

(key-mo-THER-uh-pee) treatment with drugs to destroy cancer cells. Chemotherapy is often used with surgery or radiation to treat cancer when the cancer has spread, when it has come back (recurred), or when there is a strong chance that it could recur.

mesothelioma

a tumor derived from mesothelial tissue, such as the peritoneum (lining the abdomen) or pleura (lining the lungs). More on mesothelioma.

pemetrexed

chemotheraputic agent that interferes with a crucial process that allows cancer cells to reproduce and spread. Specifically, pemetrexed stops the production of three enzymes that are required to feed the cancer cell. Often used in combination with cisplatin. Marketed under the name ALIMTA. See: Alimta.

Lee CW, Murray N, Anderson H, Rao SC, Bishop W.

BC Cancer Agency – Fraser Valley Centre, 13750 96th Avenue, Surrey, British Columbia, Canada V3V 1Z2. clee@bccancer.bc.ca

Abstract

Cisplatin plus pemetrexed has been standard systemic therapy for malignant pleural mesothelioma (MPM) since the landmark randomized trial reported in 2003. However, the combination of cisplatin and gemcitabine was incorporated into clinical practice following publication of promising phase II trial results in 1999. The impact of these platinum-based regimens is assessed in this review of practice in the province of British Columbia. All cases of MPM diagnosed from 1999 to 2005 were identified in a provincial registry using ICD-O codes. The clinical records of individuals referred to the BC Cancer Agency were reviewed, and those treated with a platinum analog plus gemcitabine or pemetrexed as first-line therapy were included in survival analyses. During the selected period, 81 patients were treated first-line with a platinum analog plus gemcitabine (n=40) or pemetrexed (n=41). Characteristics of the entire cohort include: age at diagnosis, mean 65 years (median 66, range 43-84); gender, male 70 (86%); laterality of disease, right-sided 51 (63%); histology, epithelioid or not otherwise specified 69 (85%). Median survival was 10 months (95% confidence interval, 7.7-12.3), with 1- and 2-year survival rates 0.42 and 0.21, respectively. Survival did not appear to be influenced by the chemotherapy agent used. Survival outcomes with chemotherapy for MPM in the province are comparable to what is reported in the literature. No difference is seen combining platinum analogs with gemcitabine or pemetrexed. Platinum-based doublets might represent a therapeutic ceiling for cytotoxic chemotherapy in MPM.

Glossary

therapy

any of the measures taken to treat a disease. Unproven therapy is any therapy that has not been scientifically tested and approved. Use of an unproven therapy instead of standard (proven) therapy is called alternative therapy. Some alternative therapies have dangerous or even life-threatening side effects. For others, the main danger is that a patient may lose the opportunity to benefit from standard therapy. Complementary therapy, on the other hand, refers to therapies used in addition to standard therapy. Some complementary therapies may help relieve certain symptoms of cancer, relieve side effects of standard cancer therapy, or improve a patient's sense of well-being. The ACS recommends that patients considering use of any alternative or complementary therapy discuss this with their health care team.

systemic therapy

treatment that reaches and affects cells throughout the body; for example, chemotherapy.

diagnosis

identifying a disease by its signs or symptoms, and by using imaging procedures and laboratory findings. The earlier a diagnosis of cancer is made, the better the chance for long-term survival.

cytotoxic

(site-o-tox-ik) toxic to cells; cell-killing.

chemotherapy

(key-mo-THER-uh-pee) treatment with drugs to destroy cancer cells. Chemotherapy is often used with surgery or radiation to treat cancer when the cancer has spread, when it has come back (recurred), or when there is a strong chance that it could recur.

cancer

malignancy; a group of diseases typified by abnormal, generally out-of-control, cell growth.

mesothelioma

a tumor derived from mesothelial tissue, such as the peritoneum (lining the abdomen) or pleura (lining the lungs). More on mesothelioma.

pemetrexed

chemotheraputic agent that interferes with a crucial process that allows cancer cells to reproduce and spread. Specifically, pemetrexed stops the production of three enzymes that are required to feed the cancer cell. Often used in combination with cisplatin. Marketed under the name ALIMTA. See: Alimta.

Li L, Razak AR, Hughes A.

Department of Medical Oncology, Northern Centre for Cancer Treatment (NCCT), Westgate Road, Newcastle upon Tyne NE4 6BE, United Kingdom.

Abstract

Background: Malignant pleural mesothelioma is an aggressive cancer. Chemotherapy with cisplatin and pemetrexed can improve overall survival but has a toxic profile. Substitution of cisplatin with carboplatin may avoid some potential side-effects. Therefore, we undertook a retrospective review to assess the effectiveness and tolerability of carboplatin and pemetrexed in patients with malignant pleural mesothelioma in clinical practice.

Methods: Patients with malignant pleural mesothelioma who had been treated with carboplatin and pemetrexed were retrospectively identified from pharmacy databases. The endpoints were disease control rate, time to treatment failure, clinical improvement rate and overall survival. We also evaluated any significant haematological and non-haematological toxicities.

Results: A total of 49 patients were identified. Of 45 evaluable cases, the disease control rate was achieved in 34 patients (69%, 95% CI 55–82, intention to treat analysis). The clinical response rate was achieved in 34 out of 49 patients (69%, 95% CI 55–82). The median time to treatment failure was 4.6 months (95% CI 3.4–5.8) and median overall survival was 14 months (95% CI 9.5–18.5). Grade 3/4 haematological toxicities were observed in 7 patients (14.3%). Grade 3/4 non-haematological toxicities were seen in 12 patients (24.5%). No toxic deaths were recorded.

Conclusion: The combination of carboplatin and pemetrexed may be a viable option in the treatment of malignant pleural mesothelioma.

Keywords: Pleural; Mesothelioma; Pemetrexed; Carboplatin; Chemotherapy; Disease control; Retrospective; Survival

Abbreviations: CI, confidence interval; MPM, malignant pleural mesothelioma; IMIG, International Mesothelioma Interest Group; AUC, area under the curve; i.v., intravenous; DCR, disease control rate; CT, computed tomography; TTF, time to treatment failure; OS, overall survival

Glossary

oncology

(on-call-o-jee) the branch of medicine concerned with the diagnosis and treatment of cancer.

grade

The grade of a cancer reflects how abnormal it looks under the microscope. There are several grading systems for cancer, such as the Gleason score for prostate cancer. Each grading system divides cancer into those with the greatest abnormality (poorly differentiated), the least abnormality (well-differentiated), and those in between (moderately differentiated). Grading is done by the pathologist who examines the tissue from the biopsy. It is important because higher grade cancers tend to grow and spread more quickly and have a worse prognosis.

chemotherapy

(key-mo-THER-uh-pee) treatment with drugs to destroy cancer cells. Chemotherapy is often used with surgery or radiation to treat cancer when the cancer has spread, when it has come back (recurred), or when there is a strong chance that it could recur.

cancer

malignancy; a group of diseases typified by abnormal, generally out-of-control, cell growth.

mesothelioma

a tumor derived from mesothelial tissue, such as the peritoneum (lining the abdomen) or pleura (lining the lungs). More on mesothelioma.

pemetrexed

chemotheraputic agent that interferes with a crucial process that allows cancer cells to reproduce and spread. Specifically, pemetrexed stops the production of three enzymes that are required to feed the cancer cell. Often used in combination with cisplatin. Marketed under the name ALIMTA. See: Alimta.

Hesdorffer ME, Chabot J, DeRosa C, Taub R.

Mesothelioma Applied Research Foundation, Santa Barbara, CA, USA. mhesdorer@curemeso.org

Abstract

Opinion statement: Malignant peritoneal mesothelioma (MPM) is an aggressive neoplasm that rapidly spreads within the confines of the abdominal cavity to involve most accessible peritoneal and omental surfaces. Current treatment options are unsatisfactory, and new approaches are needed. Recent publications have reported improved survival with an intensive loco-regional treatment strategy including cytoreductive surgery (CRS) along with hyperthermic intraperitoneal chemotherapy (HIPEC). We have noted at our institution prolonged survival in selected patients after intensive multimodality treatment. Our most recently reported trial included initial laparatomy with omentectomy, resection of peritoneal implants, and placement of bilateral peritoneal Portacath; repeated courses of intraperitoneal chemotherapy with doxorubicin, cisplatin, and interferon gamma; second-look laparotomy; and intraoperative hyperthermic perfusion with mitomycin and cisplatin, followed by whole abdominal radiation. To date there have been no universally accepted treatments for MPM. Unless referred to a specialty center, patients are routinely treated with pemetrexed and cisplatin which has been shown to increase survival in pleural mesothelioma.

Glossary

resection

surgery to remove part or all of an organ or other structure.

oncology

(on-call-o-jee) the branch of medicine concerned with the diagnosis and treatment of cancer.

neoplasm

(nee-o-plas-um) an abnormal growth (tumor) that starts from a single altered cell; a neoplasm may be benign or malignant. Cancer is a malignant neoplasm.

interferon

(in-ter-fear-on) a protein produced by cells. Interferon helps regulate the body's immune system, boosting activity when a threat, such as a virus, is found. Scientists have learned that interferon helps fight against cancer, so it is used to treat some types of cancer.

chemotherapy

(key-mo-THER-uh-pee) treatment with drugs to destroy cancer cells. Chemotherapy is often used with surgery or radiation to treat cancer when the cancer has spread, when it has come back (recurred), or when there is a strong chance that it could recur.

bilateral

(bi-lat-er-ul) on both sides of the body; for example, bilateral breast cancer is cancer in both breasts.

mesothelioma

a tumor derived from mesothelial tissue, such as the peritoneum (lining the abdomen) or pleura (lining the lungs). More on mesothelioma.

peritoneal

(pair-uh-tuh-nee-al) the serous membrane that lines the cavity of the abdomen. (More on Peritoneal Mesothelioma.)

pemetrexed

chemotheraputic agent that interferes with a crucial process that allows cancer cells to reproduce and spread. Specifically, pemetrexed stops the production of three enzymes that are required to feed the cancer cell. Often used in combination with cisplatin. Marketed under the name ALIMTA. See: Alimta.

intraperitoneal chemotherapy

(IPC) a form of regional chemotherapy; the flooding of the abdominal cavity with chemotheraputic drugs to target the cancer cells directly. It is sometimes heated to improve absorption of the anticancer drugs by the cancerous cells and because heat itself can kill cancer cells.

Felip E, Rosell R.

Vall d’Hebron University Hospital Barcelona, Spain.

Abstract

NSCLC accounts for 80% of all cases of lung cancer, which is the leading cause of cancer mortality. The majority of NSCLC patients present with advanced, unresectable disease, which remains incurable. In advanced disease, chemotherapy with platinum (cisplatin or carboplatin) in combination with a third-generation cytotoxic drug (vinorelbine, gemcitabine, paclitaxel, or docetaxel) can provide a modest improvement in survival without impairing quality of life. In chemotherapy-naïve, advanced, non-squamous NSCLC patients, the combination of bevacizumab with chemotherapy was shown to produce better outcomes than chemotherapy alone. Response rates of 20%-40% can now be expected, with a median survival of 8-11 months and a 1-year survival rate of 30%-40%. In second-line treatment, docetaxel has shown superiority to best supportive care in terms of survival and quality of life. A pooled analysis comparing docetaxel administered weekly versus 3-weekly found similar survival rates between the schedules and a non-significant reduction in febrile neutropenia for the weekly regimen. Pemetrexed, a multitargeted antifolate agent, has shown clear activity in several tumors, including mesothelioma and NSCLC. In a phase III trial, second-line treatment with pemetrexed demonstrated overall survival comparable to docetaxel, with a more manageable toxicity profile.

Keywords: pemetrexed, second-line therapy, NSCLC

Glossary

therapy

any of the measures taken to treat a disease. Unproven therapy is any therapy that has not been scientifically tested and approved. Use of an unproven therapy instead of standard (proven) therapy is called alternative therapy. Some alternative therapies have dangerous or even life-threatening side effects. For others, the main danger is that a patient may lose the opportunity to benefit from standard therapy. Complementary therapy, on the other hand, refers to therapies used in addition to standard therapy. Some complementary therapies may help relieve certain symptoms of cancer, relieve side effects of standard cancer therapy, or improve a patient's sense of well-being. The ACS recommends that patients considering use of any alternative or complementary therapy discuss this with their health care team.

survival rate

the percentage of survivors with no trace of disease within a certain period of time after diagnosis or treatment. For cancer, a 5-year survival rate is often given. This does not mean that people can't live more than five years, or that those who live for 5 years are necessarily permanently cured.

regimen

(rej-uh-men) a strict, regulated plan (such as diet, exercise, or other activity) designed to reach certain goals. In cancer treatment, a plan to treat cancer.

mortality

a measure of the rate of death from a disease within a given population.

cytotoxic

(site-o-tox-ik) toxic to cells; cell-killing.

chemotherapy

(key-mo-THER-uh-pee) treatment with drugs to destroy cancer cells. Chemotherapy is often used with surgery or radiation to treat cancer when the cancer has spread, when it has come back (recurred), or when there is a strong chance that it could recur.

cancer

malignancy; a group of diseases typified by abnormal, generally out-of-control, cell growth.

mesothelioma

a tumor derived from mesothelial tissue, such as the peritoneum (lining the abdomen) or pleura (lining the lungs). More on mesothelioma.

pemetrexed

chemotheraputic agent that interferes with a crucial process that allows cancer cells to reproduce and spread. Specifically, pemetrexed stops the production of three enzymes that are required to feed the cancer cell. Often used in combination with cisplatin. Marketed under the name ALIMTA. See: Alimta.

Cioffredi LA, Jänne PA, Jackman DM.

Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.

Abstract

Peritoneal mesothelioma is a rare and often aggressive malignancy, mostly affecting asbestos exposed adults. We present four pediatric peritoneal cases treated with a cisplatin-based doublet regimen, the standard of care in the systemic therapy of adult mesothelioma. Treatment was well tolerated, and three of these patients have achieved long-term survival. The fathers of three of the patients worked in the construction industry and may have been the source of indirect asbestos exposure.

Keywords: chemotherapy, pediatric oncology, solid tumors

Glossary

therapy

any of the measures taken to treat a disease. Unproven therapy is any therapy that has not been scientifically tested and approved. Use of an unproven therapy instead of standard (proven) therapy is called alternative therapy. Some alternative therapies have dangerous or even life-threatening side effects. For others, the main danger is that a patient may lose the opportunity to benefit from standard therapy. Complementary therapy, on the other hand, refers to therapies used in addition to standard therapy. Some complementary therapies may help relieve certain symptoms of cancer, relieve side effects of standard cancer therapy, or improve a patient's sense of well-being. The ACS recommends that patients considering use of any alternative or complementary therapy discuss this with their health care team.

systemic therapy

treatment that reaches and affects cells throughout the body; for example, chemotherapy.

regimen

(rej-uh-men) a strict, regulated plan (such as diet, exercise, or other activity) designed to reach certain goals. In cancer treatment, a plan to treat cancer.

oncology

(on-call-o-jee) the branch of medicine concerned with the diagnosis and treatment of cancer.

chemotherapy

(key-mo-THER-uh-pee) treatment with drugs to destroy cancer cells. Chemotherapy is often used with surgery or radiation to treat cancer when the cancer has spread, when it has come back (recurred), or when there is a strong chance that it could recur.

cancer

malignancy; a group of diseases typified by abnormal, generally out-of-control, cell growth.

mesothelioma

a tumor derived from mesothelial tissue, such as the peritoneum (lining the abdomen) or pleura (lining the lungs). More on mesothelioma.

peritoneal

(pair-uh-tuh-nee-al) the serous membrane that lines the cavity of the abdomen. (More on Peritoneal Mesothelioma.)

Janson V, Andersson B, Behnam-Motlagh P, Engström KG, Henriksson R, Grankvist K.

Department of Medical Biosciences, Clinical Chemistry, Umeå University, Sweden. veronica.janson@medbio.umu.se

Abstract

Aims: Resistance mechanisms are important limiting factors in the treatment of solid malignancies with cis-diamminedichloroplatinum(II) (cisplatin). To gain further understanding of the effects of acquired cisplatin-resistance, we compared a human malignant pleural mesothelioma cell line (p31) to a sub-line (p31res1.2) with acquired cisplatin-resistance.

Methods and Results: The role of Na(+),K(+),2Cl(-)-cotransport (NKCC1) activity in cisplatin-induced morphological changes and acquired cisplatin-resistance was investigated in a time-resolved manner. Acquisition of cisplatin-resistance resulted in markedly reduced NKCC1 activity, absence of cisplatin-induced early membrane blebbing, and increased basal caspase-3 activity. At equitoxic cisplatin concentrations, P31res1.2 cells had a faster activation of caspase-3 than P31 cells, but the end-stage cytotoxicity and number of cells with DNA fragmentation was similar. Bumetanide inhibition of NKCC1 activity in P31 cells repressed cisplatin-induced early-phase membrane blebbing but did not increase P31 cell resistance to cisplatin.

Conclusions: Together, these results suggest that active NKCC1 was necessary for cisplatin-induced early membrane blebbing of P31 cells, but not for cisplatin-resistance. Thus, acquisition of cisplatin-resistance can affect mechanisms that have profound effects on cisplatin-induced morphological changes but are not necessary for the subsequent progression to apoptosis.

Glossary

DNA

(dee-ok-see-ri-bo-new-CLAY-ic) abbreviation for deoxyribonucleic acid. DNA holds genetic information on cell growth, division, and function.

cell

the basic unit of which all living things are made. Cells replace themselves by splitting and forming new cells (mitosis). The processes that control the formation of new cells and the death of old cells are disrupted in cancer.

mesothelioma

a tumor derived from mesothelial tissue, such as the peritoneum (lining the abdomen) or pleura (lining the lungs). More on mesothelioma.

apoptosis

a type of cell death in which the cell basically commits suicide; scientists believe some types of cancer may originate from an interruption of this programmed cell death, allowing cells to grow out of control.

Kindler HL.

Section of Hematology/Oncology, University of Chicago, Chicago, IL 60637, USA. hkindler@medicine.bsd.uchicago.edu

Abstract

Systemic therapy is the only treatment option for the majority of mesothelioma patients, for whom age, co-morbid medical illnesses, non-epithelial histology, and locally advanced disease often preclude surgery. For many years, chemotherapy had a minimal impact on the natural history of this cancer, engendering considerable nihilism. Countless drugs were evaluated, most of which achieved response rates below 20% and median survival of <1 year. Several factors have hampered the evaluation of systemic regimens in patients with mesothelioma. The disease is uncommon, affecting only about 2500 Americans annually. Thus, most clinical trials are small, and randomized studies are challenging to accrue. There is significant heterogeneity within the patient populations of these small trials, for several reasons. Since all of the staging systems for mesothelioma are surgically based, it is almost impossible to accurately determine the stage of a patient who has not been resected. Patients
with very early stage disease may be lumped together with far more advanced patients in the same study. The disease itself is heterogenous, with many different prognostic factors, most notably three pathologic subtypes—epithelial, sarcomatoid, and biphasic—that have different natural histories, and varying responses to treatment. Finally, response assessment is problematic, since pleural-based lesions are difficult to measure accurately and reproducibly. Assessment criteria often vary between trials, making some cross-trial comparisons difficult to interpret. Despite these limitations, in recent years, there has been a surge of optimism regarding systemic treatment of this disease. Several cytotoxic agents have been shown to generate reproducible responses, improve quality of life, or prolong survival in mesothelioma. Drugs with single-agent activity include pemetrexed, raltitrexed, vinorelbine, and vinflunine. The addition of pemetrexed or raltitrexed to cisplatin prolongs survival.
The addition of cisplatin to pemetrexed, raltitrexed, gemcitabine, irinotecan, or vinorelbine improves response rate. The combination of pemetrexed plus cisplatin is considered the benchmark front-line regimen for this disease, based on a phase III trial in 456 patients that yielded a response rate of 41% and a median survival of 12.1 months. Vitamin supplementation with folic acid is essential to decrease toxicity, though recent data suggests that there may be an optimum dose of folic acid that should be administered; higher doses may diminish the effectiveness of pemetrexed. There are also several unresolved questions about the duration and timing of treatment with pemetrexed that are the subject of planned clinical trials. It is essential to recognize that the improvements observed with the pemetrexed/cisplatin combination, though real, are still modest. Other active drugs or drug combinations may be more appropriate for specific individuals, and further research is still needed
to improve upon these results. Since the majority of mesotheliomas in the United States occur in the elderly, non-cisplatin-containing pemetrexed combinations may be more appropriate for some patients. Now that effective agents have been developed for initial treatment, several classical cytotoxic drugs and many novel agents are being evaluated in the second-line setting. These include drugs targeted against the epidermal growth factor, platelet-derived growth factor, vascular endothelial growth factor, src kinase, histone deacetylase, the proteasome, and mesothelin. Given the progress made in recent years, there is reason to believe that more effective treatments will continue to be developed.

Glossary

therapy

any of the measures taken to treat a disease. Unproven therapy is any therapy that has not been scientifically tested and approved. Use of an unproven therapy instead of standard (proven) therapy is called alternative therapy. Some alternative therapies have dangerous or even life-threatening side effects. For others, the main danger is that a patient may lose the opportunity to benefit from standard therapy. Complementary therapy, on the other hand, refers to therapies used in addition to standard therapy. Some complementary therapies may help relieve certain symptoms of cancer, relieve side effects of standard cancer therapy, or improve a patient's sense of well-being. The ACS recommends that patients considering use of any alternative or complementary therapy discuss this with their health care team.

systemic therapy

treatment that reaches and affects cells throughout the body; for example, chemotherapy.

staging

the process of finding out whether cancer has spread and if so, how far. There is more than one system for staging. The TNM system, described below, is one used often. The TNM system for staging gives three key pieces of information: T refers to the size of the Tumor N describes how far the cancer has spread to nearby Nodes M shows whether the cancer has spread (Metastasized) to other organs of the body Letters or numbers after the T, N, and M give more details about each of these factors. To make this information somewhat clearer, the TNM descriptions can be grouped together into a simpler set of stages, labeled with Roman numerals. In general, the lower the number, the less the cancer has spread. A higher number means a more serious cancer.

regimen

(rej-uh-men) a strict, regulated plan (such as diet, exercise, or other activity) designed to reach certain goals. In cancer treatment, a plan to treat cancer.

platelet

a part of the blood that helps it "stick together" (clot) to promote healing after an injury. Chemotherapy can cause a drop in the platelet count--a condition called thrombocytopenia.

oncology

(on-call-o-jee) the branch of medicine concerned with the diagnosis and treatment of cancer.

cytotoxic

(site-o-tox-ik) toxic to cells; cell-killing.

chemotherapy

(key-mo-THER-uh-pee) treatment with drugs to destroy cancer cells. Chemotherapy is often used with surgery or radiation to treat cancer when the cancer has spread, when it has come back (recurred), or when there is a strong chance that it could recur.

cancer

malignancy; a group of diseases typified by abnormal, generally out-of-control, cell growth.

mesothelioma

a tumor derived from mesothelial tissue, such as the peritoneum (lining the abdomen) or pleura (lining the lungs). More on mesothelioma.

pemetrexed

chemotheraputic agent that interferes with a crucial process that allows cancer cells to reproduce and spread. Specifically, pemetrexed stops the production of three enzymes that are required to feed the cancer cell. Often used in combination with cisplatin. Marketed under the name ALIMTA. See: Alimta.