Mesothelioma Treatment: Chemotherapy Agents and Drug Classes
There are a large number of chemotherapy drugs in use today. These different agents are grouped into distinct classes of chemotherapy drugs, where each separate class is defined by the biological activity of the individual drugs. Agents from most of the standard groups have been investigated for mesothelioma treatment as both single agents and in combination with other chemotherapy drugs, but the results have generally been disappointing. Recent research indicates that mesothelioma may have a built-in resistance to apoptosis, i.e., the programmed death of unhealthy cells, which would be a major factor in its resistance to treatment and a likely factor in its overall aggressiveness.
The following section is an overview of some the individual drugs that have been used to treat mesothelioma in the past. Even though pemetrexed and cisplatin are the current standard of care and have superseded many of the drugs that will be discussed, it is likely that a mesothelioma patient who is researching chemotherapy will come across some of these names, so we are providing this information to help patients learn more about the different historical agents that have used for the treatment of mesothelioma. In some cases, such as that of vinorelbinea drug we will discuss near the end of this articlethe drug represents a possible future course of treatment and is included to provide information on cutting edge research into chemotherapy, not on the historical uses of it.
Antifolates are chemotherapy drugs that inhibit the activity of folate (folic acid) during DNA synthesis, which is an essential part of cell division and replication. By inhibiting the formation of new DNA, antifolates can then restrict the growth of new cells. This is the reason for their usefulness in cancer treatment.
Antifolates are members of a larger class of chemotherapy drugs known as antimetabolites. These chemicals undermine the proper execution of specific biochemical processes because their basic structure closely resembles that of elements that are necessary to these processes, so they are metabolized in place of the proper elements. Once this occurs, however, the body cannot complete the targeted process because the antimetabolites structure prevents the process proper execution. Antifolates inhibit the activity of folate because they are structurally similar to it.
A number of antifolates have been investigated for the treatment of mesothelioma, with pemetrexed demonstrating the most effectiveness. Even prior to its introduction, however, other drugs in this class demonstrated modest response levels in mesothelioma patients. Gene expression analysis has revealed that mesothelioma cells over-express alpha folate receptors and the reigning theory among mesothelioma specialists is that antifolate agents generate a response activity in mesothelioma cells because they disrupt the process by which these folate receptors are activated.
Along with pemetrexed, raltitrexed is another antifolate which has been examined for the treatment of mesothelioma. Studies have investigated combination therapy with cisplatin and raltitrexed and these have also shown some therapeutic activity. When compared to pemetrexed + cisplatin, the raltitrexed + cisplatin regimen exhibited a similar toxicity profile, but hasnt matched the overall efficacy of the standard regimen.
Platinum agents are part of the class of chemotherapy agents known as alkylating/alkylating-like agents. This class of drug disrupts cell replication by binding with a cells DNA and undermining its structural integrity, triggering apoptosis and the removal of the cell from the replication cycle. Cisplatin was the original platinum agent developed for chemotherapy, although analogues of itcarboplatin and oxaliplatinare also in use today.
Both carboplatin and oxaliplatin have been examined as alternative platinum agents in first-line mesothelioma treatment, but they have not demonstrated the same effectiveness that cisplatin has demonstrated. However, cisplatin can be difficult to tolerate and has been associated with significant side effects in some patients, so carboplatin can be used in place of cisplatin if toxicity is a concern.
Anthracyclines are among the most commonly-used chemotherapy drugs. They are active during all phases of the cell cycle and have proven effective in the treatment of a wide variety of cancers. Because of their general usefulness, physicians had high hopes that anthracyclines would also be effective for the treatment of mesothelioma. Doxorubicin, which is marketed under the trade name Adriamycin®, is one of the most used agents in this class and was extensively tested with mesothelioma patients. It was initially thought to be quite active, but subsequent research has revealed very little clinical benefit to its use. Other anthracyclines have been used as well, but they, too, have not demonstrated much effectiveness for treatment of the disease.
Vinca alkaloids are the last major class of drugs that we will cover in our overview of chemotherapy treatments for mesothelioma. This class of drugs targets cell mitosis, which is the process of cell division where a mother cell splits into two daughter cells that are genetically identical to each other. A number of vinca alkaloids have been investigated for mesothelioma treatment, but most of them have not demonstrated any useful activity in the management of the disease. However, some recent studies have shown that vinorelbine, a newer agent in this class, is very active with mesothelioma cells.
Vinorelbine has been investigated in both single agent therapy and in combination therapy with cisplatin. It has also been studied as first-line chemotherapy and as a second-line therapy. Results from these studies have shown that that it is among the most active agents that have been deployed for mesothelioma treatment, with a response rate that is similar to that of pemetrexed. However, some of these same studies have also identified a tendency towards toxicity in a large number of patients. Most of the researchers who have reported their findings have done so with a call for more research into vinorelbines use for the treatment of the disease. Because of the treatment activity these studies have described, research into vinorelbine is likely to continue and will probably increase if future studies also demonstrate similar response rates.
The four classes of chemotherapy drugs that we have discussed here do not represent all of the chemotherapy classes that are available for cancer treatment. However, agents from these classes make up the majority of the drugs that are currently used for mesothelioma chemotherapy, or represent significant attempts in the historical treatment of the disease.
A number of newly-developed chemotherapy agents are currently involved in laboratory studies in the treatment of mesothelioma or are just beginning human trials, so the information on these pages is likely to change as results of these studies come in.
For more information related to chemotherapy and mesothelioma treatment, please read the following: