Even as the introduction of combination chemotherapy using pemetrexed and cisplatin(Alimta Therapy) was a watershed event in the history of mesothelioma treatments, research into the disease’s underlying cellular activity has shown that mesothelioma cells demonstrate a natural resistance to most forms of chemotherapy, as well as a natural resistance to apoptosis. This research has postulated that the disease’s anti-apoptotic tendency may be one of the primary reasons for its aggressiveness and its ability to resist long-term management. Therapies using pemetrexed and cisplatin have certainly achieved longer median survival times than previous therapies have achieved, but they are still not a curative solution for pleural mesothelioma or peritoneal mesothelioma. At some point in a patient’s treatment, the chemo agents begin to lose efficacy and the disease eventually overcomes the treatment’s ability to manage it. If this is due to the disease’s natural resistance to apoptosis, then understanding the biological mechanisms responsible for this resistance should offer researchers the chance to develop treatments that account for these mechanisms, which could then lead to the development of more effective therapies than are currently available.

One of the leading genetic candidates for influencing mesothelioma’s apoptotic resistance is p21, a gene that regulates certain aspects of the S phase—the synthesis phase—of the cell cycle. High levels of p21 expression have been implicated in prior research regarding anti-apoptotic behavior and it has been shown to be highly expressed in mesothelioma cell tissues and cell lines.

Researchers in Italy conducted a study where they investigated the relationship between p21 expression and mesothelioma’s resistance or susceptibility to apoptosis and cytotoxic treatment. They found that p21 was expressed within in tumor cells in response to some chemotherapy agents, which may explain why mesothelioma is so resistant to chemotherapy: even as the chemo agents are being absorbed by the cancer cells, the cells are expressing a genetic agent, p21, that increases their resistance to apoptosis, and therefore, the cytotoxic effects of chemotherapy.

The researchers found that if they could disrupt the expression of p21 in these cells then the cytotoxic effects of the chemotherapy agents they were studying were greatly enhanced. Their results were so successful that they are now calling for more research into the effects of p21 expression in mesothelioma and, specifically, the study of novel therapeutic techniques to inhibit its expression among mesothelioma cells.

Labels: chemotherapy, mesothelioma, treatments

Eli Lilly has announced that its cancer drug Alimta, when used in combination with cisplatin, has received FDA approval for the first-line treatment of “locally-advanced and metastatic non-small cell lung cancer (NSCLC), for patients with nonsquamous histology.” The FDA’s new approval is the third overall approval that Alimta has received, and the second for its use in first-line therapy. The drug is most well known for the first-line treatment of pleural mesothelioma where it—again in combination with cisplatin—represents the chemotherapy standard of care for the treatment of the disease. It has also received approvals in single-agent use for the second-line treatment of NSCLC after prior chemotherapy treatment.

Labels: chemotherapy, LungCancer, mesothelioma, treatments

The medical journal Current Treatment Options in Oncology has recently published a number of articles on the biology, diagnosis and treatment of mesothelioma. In a report published last week, we covered their article, “Diagnosis, Staging, and Surgical Treatment of Malignant Pleural Mesothelioma,” which provided an overview of the diagnostic procedures used to identify the disease, the system that has been developed to analyze the disease’s stage in an individual patient and an introduction to the surgical procedures that are used to treat pleural mesothelioma. Surgical invention is one of the key elements in the multimodal treatment of the disease, but many patients are not eligible for radical surgery because their diagnosis only came after the disease had progressed to an advanced stage. For these patients, chemotherapy represents their best chance to extend survival. In recognition of its importance to overall mesothelioma treatment, Current Treatment Options has also published an article describing the current use of chemotherapy in the treatment of the disease.

“Systemic Treatments for Mesothelioma: Standard and Novel” provides an historical overview of the chemotherapy treatments deployed before the introduction of pemetrexed, as well as a description of the current use of pemetrexed and an overview of other avenues in contemporary mesothelioma research. The article closes with a discussion of novel therapeutic agents that have been proposed for mesothelioma treatment.

Cytotoxic Chemotherapy Before Pemetrexed

The article begins with reference to a report published in the Journal of Clinical Oncology from 1988 entitled “Malignant Mesothelioma, a disease unaffected by current therapeutic maneuvers,” which noted that chemotherapy, like every other then-current cancer treatment, was simply not effective for management of the disease. Since that time, however, much has changed for the better. Even though the disease is still without a cure, current treatments have definitely led to improvements in both median survival time and symptom management.

Before the introduction of pemetrexed in 2004 a number of different chemotherapy drugs had tried–and failed—to treat mesothelioma. Anthracyclines, such as doxorubicin, were once hailed as a promising new therapeutic avenue for the disease, but subsequent radiological analysis showed limited response rates to these agents. Even though a number of these drugs were also tried, they only offered limited value at disease control.

Along with the use of single-agent treatment regimens, combination therapies were also used, but they, too, demonstrated limited efficacy. A meta analysis was then conducted on the different chemotherapy clinical trials performed between 1965 and 2001 and this showed that the platinum agent cisplatin was the most active single drug for mesothelioma treatment. Because of this, cisplatin became the focus of a number of new treatment regimens. Along with it, other platinum agents, such as carboplatin and oxaliplatin, were also investigated for their efficacy in mesothelioma treatment.

The Antifolates

Antifolates are the most active class of chemotherapy agents that have been used to treat mesothelioma. These drugs inhibit the ability of cells to metabolize folate (folic acid), which is an essential ingredient in the process of DNA replication. Thus, an antifolate's fundamental mechanism of action is disrupting a tumor’s ability to continue to replicate. Methotrexate is one of the most common antifolates deployed for cancer treatment and studies that investigated its use for mesothelioma showed a higher response rate (37%) and a longer median survival (11 months) than many of the previous mesothelioma trials had shown. These results gave great hope to mesothelioma physicians, but it was with the introduction of pemetrexed that chemotherapy turned a corner in its effectiveness for mesothelioma treatment.

The FDA approved pemetrexed in 2004 after the largest clinical trial that had ever been conducted on a mesothelioma treatment showed clear advantages to combination therapy using pemetrexed and cisplatin than the use of cisplatin alone. Not only did this study achieve one of the highest response rates (41%) and the longest median survival time (12.1 months) when compared to other trials, study participants also reported significant increases in symptom control and quality of life issues. The combination of cisplatin and pemetrexed is now the world-wide chemotherapy standard of care for pleural mesothelioma and the investigations into its activity for peritoneal mesothelioma are also promising. In some cases, cisplatin may be replaced with carboplatin, which has demonstrated similar—though slightly less effective—response rates to cisplatin, but is associated with a less severe toxicity profile. Because of this, weak patients are sometimes given carboplatin in place of cisplatin.

Even as pemetrexed has achieved “standard of care” status, the article notes that a number of questions regarding its use remain unanswered. One of the most important of these questions has to do with onset of treatment: is it better to begin treatment at time of diagnosis, at the onset or progression of symptoms or at signs of radiological disease progression? For patients who are diagnosed in the disease’s later stages, this question is not applicable because symptoms have usually become quite difficult at that time, but for patients who are diagnosed in its early stages and with the epithelial subtype of the disease—which is associated with the best prognosis—this question is still opened. Physicians are waiting for the results of a large trial before they can answer this question with any certainty.

Another question the article brings up revolves around the optimum length of treatment: four to eight cycles of combination therapy are typically given to patients, but many people are not able to tolerate more cycles, so the question of the long-term management of the disease with chemotherapy remains open. There is some indication that pemetrexed can be given as a single agent after the full combination course has been completed, but, again, physicians are waiting for trial results before any definitive answers are given.

Another antifolate that has shown some activity in the treatment of mesothelioma is raltitrexed. It has not yet matched pemetrexed’s efficacy when combined with a platinum agent, but some research is still being conducted on this agent.

Other Active Cytotoxic Agents

Gemcitabine and vinorelbine are two other chemotherapy agents that have demonstrated some activity in the treatment of mesothelioma. Studies investigating gemcitabine in both single-agent regimens and in combination regimens with cisplatin, carboplatin and oxaliplatin have shown a wide variety of response rates. Prior studies on pemetrexed and gemcitabine have not found any synergistic effect in their combination, but they have shown increased toxicity profiles. However, investigations of this regimen do continue.

Vinorelbine is a chemotherapy drug in the class of drugs known as vinca alkaloid agents. While other vinca alkaloids have not shown much activity for mesothelioma, studies involving vinorelbine have shown some of the highest response rates besides pemetrexed. A number of recent studies have reported promising indications for its use in both first-line and second-line therapy and larger scale studies investigating its overall efficacy are currently being planned.

Novel Agents

Investigations into the biological substrates of mesothelioma genesis have identified a number of proteins that may be overexpressed by the disease. In identifying these elements, the studies opened up the possibility that highly targeted treatment agents could possibly be developed that would inhibit the growth of the malignancy at a cellular level. Some of the areas targeted for therapy include EGFR, PDGF and VEGF. Initial studies on agents targeted at these growth factors have not shown much clinical efficacy to the treatments under investigation, but the agents are still quite new and many physicians still believe that the more we understand the molecular composition of mesothelioma, the more effective our treatments of it will become.

A number of other agents besides the ones mentioned in this article are also under investigation, although definitive results for many of these studies will not be available for years. Even as the disease’s still-poor response rate to most treatments is frustrating when seen against the background of great successes that have been achieved in the management of other cancers, the number of studies under active investigation for mesothelioma is an indication that treatments are improving and that hope for the development of future treatments is well-placed.

Labels: chemotherapy, mesothelioma, treatments

The MD Anderson Cancer Center in Houston, TX is currently recruiting participants for their ongoing chemotherapy study entitled Phase I Trial of Cisplatin, Pemetrexed, and Imatinib Mesylate in Unresectable or Metastatic Malignant Mesothelioma.

As a Phase I trial, the study's primary endpoint is the determination of the maximum tolerated dose for a chemotherapy regimen using pemetrexed, cisplatin and imatinib for mesothelioma patients. Along with this objective, the study has designated a number of secondary endpoints as well, including the exploration of the biologic effects of this regimen on tumor tissue and on surrogate serum markers and an assessment of the therapy's overall rate of response. Other secondary endpoints have been defined as well and can be viewed at the trial's home page on www.clinicaltrials.gov.

Patients will have to meet a number of specific requirements for enrollment in the study. These requirements include a number of positive indications that must be met, as well as a number of exclusion criteria that will disallow the patient from enrolling in the study if he or she satisfies any of them. If the patient meets these criteria and his or her initial workup is positive, the patient will then be enrolled in the study and will start on imatinib right away. A week after this, the patient will then commence the first of six cycles of cisplatin and pemetrexed administration. Each of these cycles will last 28 days. Every four weeks physical examinations will be given and then CT or MRI will be given every eight weeks to measure tumor response. After these 6 cycles, the patient will stop cisplatin and pemetrexed, but will continue the imatinib for up to a month. When treatment is completed, the patient will have his or her end-of-study visit, where a final set of tests and scans will be conducted.

This study is being conducted by Anne S. Tsao, MD, at the MD Anderson Cancer Center in Houston, TX. The contact information is the following:

Anne S. Tsao, MD
U.T.M.D. Anderson Cancer Center
Houston, Texas 77030
713-792-6363

Cisplatin, Pemetrexed, and Imatinib Mesylate in Malignant Mesothelioma

Labels: chemotherapy, mesothelioma

In July of this year, The Lancet published an article describing the results of a study that compared the efficacy of a chemotherapy regimen utilizing mitomycin, vinblastine and cisplatin (MVP) or vinorelbine to a treatment regimen featuring best supportive care and active symptom control for patients with mesothelioma. The study showed that neither the MVP regimen nor the vinorelbine regimen showed any statistically significant improvement in extending patient life over the symptom control regimen. However, the authors concluded that vinorelbine deserves more study because there was some evidence to indicate a possible survival benefit to the treatment, even though it did not achieve statistical significance.

The latest edition of The Lancet has published a letter criticizing that study and its conclusions, as well as a reply by the authors of the original study. The letter attacked the design of the study and the pathology analysis conducted during it, as well as the authors’ conclusion that the use of vinorelbine to treat pleural mesothelioma deserved more research. The letter noted that while active symptom control and vinorelbine were more tolerable than pemetrexed (Alimta), the latter is still the only chemotherapy agent to demonstrate statistically significant improvements in median survival times for mesothelioma patients, so patients who can tolerate it should be treated with pemetrexed.

In their reply, the authors’ defend their study and their conclusion that vinorelbine warrants more research. They state that the recommendation to continue research on vinorelbine is warranted by their demonstration of some survival benefit, even though their results were not conclusive and were not presented as such. The authors state that a two month survival benefit in some of the patients treated with the chemo agent alone justifies the call for more research, especially considering how so few therapies have shown any benefit for the treatment of mesothelioma. They conclude that the future of mesothelioma diagnoses and treatment regimens is the identification of specific biomarkers and the development of truly targeted therapies.

Labels: chemotherapy, mesothelioma, treatments

The development of more effective treatment options for patients with mesothelioma remains the most pressing issue facing physicians and researchers who work with the disease. Pleural mesothelioma is the most common form of the disease, so the majority of research programs that are conducted for the study of mesothelioma are devoted to the study of its pleural form. However, nearly 20% of all mesothelioma diagnoses are for peritoneal mesothelioma, where the malignancy attacks the peritoneum, which is the lining of the abdominal cavity. Because of this situation, even less is known about effective therapies for peritoneal mesothelioma than is known about general mesothelioma treatments. Large scale studies have been impossible to perform for patients with this variety of disease, so the major ways in which information has been shared among physicians has been through case reports made in journal articles. Even though these reports cannot replace the validity of results achieved with large scale studies, they are still able to share important information about the treatment of the malignancy and of the experience that individual physicians have had with individual mesothelioma patients.

One such article has recently been published in the journal Surgical Laparoscopy, Endoscopy & Percutaneous Techniques. In it, the authors describe their experience treating a 49 year-old woman with pleural mesothelioma and peritoneal mesothelioma who presented with a painful ascites that was not responsive to any of the therapies attempted to treat it. Because of this, they treated the woman with a procedure known as laparoscopic hyperthermic intraperitoneal chemotherapy (LHIPEC). The journal article describes the women’s presentation and their successful treatment of her malignant ascites.

Mesothelioma, Ascites and LHIPEC

Ascites is a condition where fluid has built-up within the abdominal cavity. It is common to a number of disorders and is associated with a number of painful symptoms, such as dyspnea, abdominal pain and nausea. When the ascites are caused by an underlying malignancy, such as peritoneal mesothelioma or colon cancer, other symptoms may include reduced mortality and malnutrition. Many of the traditional treatments for ascites, such as paracentesis or some form of shunting to move the fluid into a different area, are not often associated with successful symptom management. Because of this, alternative therapies are being researched on a number of fronts.

The authors note that one of these therapies, laparoscopic hyperthermic intraperitoneal chemotherapy (LHIPEC), has achieved a 100% success rate in recently-published, retrospective studies involving the treatment of ascites. LHIPEC is a variant of traditionally-delivered heated intraperitoneal chemotherapy, but the chemo agents are delivered through laparoscopic entry techniques instead of a traditional laparotomy, which refers to a potentially large surgical incision that is made to facilitate open access to the abdomen. Because the use of laparoscopic techniques are associated with enhanced recovery time, LHIPEC is considered a potential option in cases where palliation is the primary concern.

Case Study

The authors describe the case of a 49 year-old woman who presented with “debilitating ascites” after pleural mesothelioma had spread to her abdomen. She initially received treatment for pleural mesothelioma in 2003 involving pleural decortication and adjuvant chemotherapy using pemetrexed and carboplatin. In 2006, CT scans showed a relapse of pleural mesothelioma, the spread of the disease to her peritoneum and the development of ascites. She was treated with further chemotherapy but integrated PET/CT showed gross spread of the disease and her mesothelioma symptoms continued to restrict her quality of life. Because of this, she underwent LHIPEC in January of 2007. Cisplatin and doxorubicin were the agents delivered.

After the operation, the patient was watched for 24 hours. During this initial period she developed a grade 4 hyponatremia, which is an abnormally low level of sodium in one’s blood, but this was treated upon discovery and soon corrected. She began taking food on the second post-op day, had the drains removed on the fourth day and was discharged on the seventh day after the surgery.

The procedure was a great success. The patient experienced noticeable improvements in symptom relief within a day of surgery, including a “complete remission of dyspnea and abdominal distension.” Her follow-up scans showed no signs the ascites were returning. She died six months after the procedure, but from a pulmonary embolism unrelated to her mesothelioma.

Conclusion

The authors feel that LHIPEC could be an important therapeutic option for the palliative treatment of malignant ascites. It seems to be well-tolerated and other recent studies have also shown its effectiveness for palliative purposes. The authors state that their article is only the second one to describe its use for the treatment of peritoneal mesothelioma and they call for more research into the use of LHIPEC. They also note that along with the symptom control they achieved—which the procedure was initially conducted for—their patient also demonstrated some therapeutic response to LHIPEC as post-op imaging scans showed a much lesser extent of ascites than before the procedure.

It is much too early to conclude that LHIPEC should be a regular option for the treatment of mesothelioma, but the results of this case report certainly point to the need for more research into the various forms of mesothelioma.

Labels: chemotherapy, mesothelioma, peritonealmesothelioma, treatments

The current standard of care for the treatment of mesothelioma is combination chemotherapy using pemetrexed (Alimta) and cisplatin. The US FDA first approved this therapy in 2004, soon after the results of a large-scale, Phase III clinical trial were published that showed statistically significant improvements in median survival and time-to-progression for patients with pleural mesothelioma. Subsequent trials confirmed the clinical benefits this study found and the intervening years have seen approvals of the therapy from every other major nation’s health care regulatory agency. However, this treatment is still not a curative solution for mesothelioma, so research into improving its efficacy, along with additional research into the combination of these agents with other modalities of treatment, continues on a number of other fronts.

An article describing the history of pemetrexed use, from its earliest Phase I studies to the 2004 Phase III study that led to its approval, has been published in the journal Therapeutics and Clinical Risk Management. The authors provide a full literature review of these various trials and they describe pemetrexed’s mechanism of action and the initial studies that investigated its use, as well as a detailed description of the study design and results of the Phase III study that led to pemetrexed’s approval.

The following is a partial summary of that article, “Review of Pemetrexed in Combination with Cisplatin for the Treatment of Malignant Pleural Mesothelioma.”

Cisplatin and Pemetrexed

Cisplatin is a chemotherapy drug in the class of drugs known as platinum agents. Cisplatin was first introduced in 1978 and its efficacy for the treatment of a number of cancers has been shown time and time again. Pemetrexed is an antimetabolite chemotherapy agent, whose efficacy arises from its ability to inhibit folate (folic acid) from being metabolized.

Phase I and Phase II Clinical Trials

A number of different chemotherapy agents have been used to treat mesothelioma, but the results have been disappointing. Preclinical studies of cisplatin and pemetrexed showed efficacy for the treatment of non-small cell lung cancer, so researchers considered it possibly beneficial for mesothelioma treatment. In a Phase I evaluation, a number of patients with various cancers, including pleural mesothelioma, were given pemetrexed in combination with cisplatin. This trial investigated dosage recommendations and their relationship with treatment toxicities. The study concluded with a recommendation of 600 mg/m² of pemetrexed and 75 mg/m² of cisplatin and a call for more research.

A Phase II study of the combination chemotherapy was not conducted with mesothelioma patients, but was conducted for untreated patients with Stage IIIB or IV non-small cell lung cancer. In this trial, pemetrexed levels were reduced to 500 mg/m² and cisplatin levels remained the same. Overall response was 45% and the treatment was well-tolerated, so a Phase III trial was planned for mesothelioma patients.

EMPHACIS III Clinical Trial and FDA Approval

The Evaluation of Mesothelioma in a Phase III Trial of Pemetrexed with Cisplatin (EMPHACIS) enrolled 448 chemonaive patients into a trial that randomized patients into one of two groups: a group that received pemetrexed + cisplatin and a group that received cisplatin alone. Administrations were given every 21 days. When B12 and folic acid deficiency were discovered as common side effects, vitamin supplementation administrations were added to the trial design. This was the largest study of mesothelioma patents ever attempted.

The initial study results showed a median survival time for the combination arm at 12.1 months, compared to 9.3 months for the cisplatin only group. Although not statistically significant, subgroup analysis of the patient cohort showed that patients who received both the combination therapy and vitamin supplements had a 13.3 month median survival vs. 10.0 months for the cisplatin + vitamin crowd. Final results of the study were released in 2005, with a 12.8 month median survival noted for the combination therapy patients vs. only 9 months for the cisplatin-alone patients. These results also demonstrated improvements in pulmonary function tests.

This study led to the FDA’s approval of pemetrexed and cisplatin in 2004. The FDA could not fully confirm all of the results of the EMPHACIS trial, but they could confirm that this treatment arm was more effective than previous trials had been. The FDA’s dose recommendation also incorporated the recommendation for vitamin supplements, as well as the use of dexamethasone to prevent pemetrexed-caused rashes.

International Approval and Quality of Life Issues

The FDA was the first major regulatory agency to approve pemetrexed + cisplatin for the treatment of pleural mesothelioma. Since that time, most other national healthcare agencies have also approved its use. As was alluded to in our description of the Phase III trial, pemetrexed’s efficacy is not simply based on increased survival time, but is also based on real improvements in patient quality of life. A number of studies have shown statistically significant improvements in disease-related dyspnea, pain and cough.

Other Studies and Combinations

Even as this combination has proven the most effective chemotherapy treatment in clinical trials, research into other pemetrexed-based combinations also continues. In place of cisplatin, carboplatin is sometimes used because it typically has a more favorable toxicity profile. Overall response rates and efficacy tend to be higher with cisplatin, but carboplatin has demonstrated easier tolerability for many patients. However, Phase III trials have not been conducted for this combination.

Labels: chemotherapy, mesothelioma, treatments

Italian biotechnology company MolMed has recently announced that ARENEGYR, its experimental anti-cancer drug that is being investigated for the treatment of mesothelioma and a number of other cancers, has been granted orphan drug status from the US FDA. This announcement follows on a similar designation given by the EU’s pharmaceutical regulatory agency in June. Orphan drug status is available to investigational treatment agents that focus on uncommon and/or rare diseases, specifically defined as pathologies that affect less than 5 in 10,000 people, and it confers a number of benefits to the manufacturer to reward their research.

Malignant pleural mesothelioma remains a very difficult disease to treat effectively. Even though contemporary multimodal treatment protocols have increased median survival time, the disease is still not curable, so research into more effective therapeutics continues on a number of fronts. ARENEGYR represents one of the most promising avenues of contemporary research. It is a vascular targeting agent that selectively targets and binds with a tumor’s blood vessels. Its mechanism of action is governed by two major elements: NGR, a “tumor homing peptide” that allows this binding to occur, and TNF, a cytokine known for its ability to trigger apoptosis, which is the principal mechanism for ARENEGYR’s antitumor activity.

Along with its proposed use for mesothelioma treatment, ARENEGYR is being investigated in single agent therapy for the treatment of colorectal cancer, hepatocellular carcinoma and small-cell lung cancer. Molmed is also exploring ARENEGYR in combination with cisplatin for mesothelioma treatment and with Xelox for colorectal cancer.

Labels: chemotherapy, mesothelioma, pleuralmesothelioma, treatments

Even as improvements in the therapies available for mesothelioma patients have been made in recent years, the disease remains without cure. Most patients are ineligible for curative surgeries, so investigations into improving the efficacy of chemotherapy are among the most common research programs in contemporary mesothelioma treatment studies. Combination chemotherapy using pemetrexed and cisplatin (Alimta therapy) is considered first-line chemotherapy because it has demonstrated the most effective improvement in median time of survival when compared to every other chemotherapy regimen that has been tried. However, at some point during treatment, the disease always takes the upper hand and the chemo’s attempt to control the mesothelioma becomes more and more ineffective, until the drugs are no longer able to restrict the disease at all. When this happens in other cancers, one of the standard responses is for an oncologist to attempt another course of chemotherapy using different agents. This type of treatment regimen is known as second-line chemotherapy. Unfortunately, research has not yet identified an effective second-line chemotherapy regimen for pleural mesothelioma. Even as research into it continues, most results have been disappointing.

A group of renowned mesothelioma specialists has recently released the results of a study they conducted in hopes of identifying an effective second-line chemotherapy for pleural mesothelioma. Their study investigated the use of erlotinib plus bevacizumab for this purpose and their results have recently appeared in the journal Cancer.

This article is a summary of their findings.

Overview of the Study

A number of different agents and treatment regimens have been studied for the second-line use of chemotherapy in pleural mesothelioma patients. No standard has been identified though, so research into this question continues in hospitals around the world. Much of this research is being conducted based on our growing understanding of the biological foundations of the disease.

Some studies have demonstrated that vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) are important co-factors in the growth and spread of mesothelioma, so the authors of the present study investigated whether agents that inhibit these growth factors would be effective for treatment of the disease. Erlotinib is an inhibitor of EGFR, while bevacizumab inhibits VEGF. Combination therapy using these agents has been shown to have clinical efficacy as second-line treatment for non-small cell lung cancer and the physicians were hopeful that it would demonstrate similar efficacy for pleural mesothelioma.

The treatment plan under study called for the daily administration of 150 mg of erlotinib and for the administration of 15 mg/kg of bevacizumab on Day 1 of a 21-day cycle. Patients would be assessed for individual reactions to the treatment at each administration, while tumor assessment would be conducted through CT every two cycles.

Results

A total of 24 patients were included in the final study. As in most mesothelioma-related studies, the majority of those studied were older Caucasian men. There were 15 men and 9 women, with an average age of 62.5 years. 23 of the patients were white and one was Hispanic. 8 of the patients began the study with a performance status of 0 and 16 began it with PS of 1. The authors report on a number of other breakdowns and classifications as well.

The overall results of the treatment were disappointing. This chemotherapy regimen was not nearly nearly as effective for mesothelioma patients as it was for patients with non-small cell lung cancer. There were no complete or partial responses, but temporary stable disease was achieved in 12 patients. The other 12 patients had had progressive disease throughout the study. Of the 12 patients who demonstrated stable disease, 7 (of 8) were from the group with the best performance status (0) and 10 (of 16) presented with epithelial mesothelioma, the form of the disease with the best prognosis.

The patient cohort demonstrated a median time-to-progression of 2.2. months and a median survival time of 5.8 months. When studied at 6- month and 12- month intervals, the time-to-progression percentages were 29% and 6%, respectively, and the survival rate percentages were 46% and 24%, respectively.

Conclusion

Because of mesothelioma’s unique behavior pattern, chemotherapy remains the most commonly deployed treatment modality and this situation is unlikely to change in the near future. Advancements in the available therapies have already led to increased survival time, but more research is needed before medicine truly turns the corner on its ability to effectively treatment pleural mesothelioma. Even though this study did not demonstrate any clinical efficacy, other studies have identified alternative agents as possible treatment candidates and results from those investigations are eagerly awaited by doctors and patients alike.

Labels: chemotherapy, mesothelioma, pleuralmesothelioma, treatments

U.S. News and World Report has recently written about a clinical trial for an experimental mesothelioma treatment that is being conducted at the Mesothelioma Center at New York-Presbyterian Hospital and Columbia University Medical Center. The trial is investigating the combined use of chemotherapy and radiation in the treatment of pleural mesothelioma, which is a departure from the standard therapies that normally specify some form of curative surgery. Patients who are enrolled in the trial will receive multiple cycles of a chemotherapy regimen consisting of either cisplatin and doxorubicin or cisplatin and pemetrexed (Alimta). The latter chemotherapy regimen is the current standard of care in chemotherapy for mesothelioma. All of these patients will receive radiation that is targeted directly at the pleural tissue on the lung.

Although the treatment regimen does not specify curative surgery, it will be available for patients who elect to undergo it. Patients can choose between extrapleural pneumonectomy and pleurectomy/decortication.

The trial is investigating whether this regimen will demonstrate any improvements in overall patient outcome than do the standard therapies.

The Mesothelioma Center at New York-Presbyterian Hospital and Columbia University Medical Center is the only cancer center in the country to offer this therapy.

Labels: chemotherapy, mesothelioma, radiation, treatments

The chemotherapeutic treatment of mesothelioma is one of the major arms of contemporary mesothelioma research. A wide variety of investigations into new agents and treatment regimens are currently being conducted in hospitals and laboratories around the world. Even as the last few years have seen major advancements in the effectiveness of a number of mesothelioma treatments, the reality of the situation is that mesothelioma is still without cure. As impressive and welcome as the extension in median survival times are for patients and their families, physicians know that more work is required before the treatment of pleural mesothelioma and peritoneal mesothelioma will be seen within the same framework of successful therapies that other cancers are now seen within.

One of the newer chemotherapy agents that is increasingly being studied for the treatment of mesothelioma is vinorelbine, which is a member of the class of chemotherapy drugs known as vinca alkaloid agents. These drugs disrupt the mitosis phase in the cell cycle. Previous vinca agents were not active in the treatment of mesothelioma, but a number of recent studies have indicated that vinorelbine is not only active in the treatment of mesothelioma, but may be among the most active in terms of overall response rate.

To further investigate the efficacy of vinorelbine, researchers from Denmark conducted a study on its use with that of cisplatin as first-line chemotherapy in the treatment of pleural mesothelioma. They have recently published their results in the journal British Journal of Cancer.

Overview of the Study

The combination of vinorelbine and cisplatin has shown activity in the treatment of the non-small cell lung cancer, so the researchers were interested if the combination would be similarly active for pleural mesothelioma. Platinum agents, such as cisplatin, have already been shown to be active in the treatment of mesothelioma and are a part of the major chemotherapy standard of care for pleural mesothelioma, which is combination therapy using pemetrexed (Alimta) and cisplatin (or carboplatin).

To conduct their study, the researchers enrolled patients with histologically-proven pleural mesothelioma, who were not eligible for surgery and had not previously completed a chemotherapy regimen, among other requirements. The treatment dictated cisplatin every four weeks, with standard antiemetic therapy, and weekly vinorelbine administrations. The patients were monitored on a number of fronts for treatment response, as well as side effects and toxicity.

Results

A total of 54 patients were treated with the vinorelbine + cisplatin regimen. There were 46 males and 8 females. The breakdown of the histological subtypes of the disease were as follows: 40 patients presented with epithelial mesothelioma, 5 with sarcomatous mesothelioma and 9 presented with biphasic mesothelioma. Most of the patients were Stage III or Stage IV patients and the median age was 63 years old.

Of the full patient class, there were 14 partial responses and 2 complete responses, for an overall response rate of almost 30%. Of the 40 cases of epithelial mesothelioma, 13 patients demonstrated some response, while two patients with the sarcomatous subtype had a response and one with the biphasic response. Four of the eight women showed some response to treatment, while only 12 of the 46 men showed a response. The median survival time was 16.8 months, with a one-year survival figure of 61% and a two-year figure of 31%.

However, the authors note that a number of patients experienced significant side effects or some form of toxicity event. Even as the response rate of the procedure was more active as compared to some other treatments, the side effects experienced by the patients were also greater than those who’ve been studied with other regimens—including pemetrexed/cisplatin combination therapy.

Conclusion

The response rate figures show that the vinorelbine + cisplatin regimen is among the most active in the treatment of pleural mesothelioma. However, the authors state they are unable to recommend the treatment course for a number of important reasons. Even though their study demonstrated the efficacy of the regimen, they feel that precise comparisons between previous studies are not possible do to differences in the patients enrolled and the methodologies used to compare responses. Along with the high percentage of side effects associated with the therapy, they also feel that the weekly administration of vinorelbine makes it impractical to recommend this particular regimen of treatment.

However, the authors are hopeful regarding the future use of the treatment and state that improvements in the delivery mechanisms of vinorelbine, as well as other improvements in the overall treatment regimen, may be helpful in overcoming these issues. They also state that vinorelbine + cisplatin would be an excellent candidate in the use of induction chemotherapy before surgery.

Labels: chemotherapy, cisplatin, mesothelioma, treatments, vinorelbine

Chemotherapy is one of the most important treatment modalities for patients with mesothelioma. Due to the late stage at which the disease is normally diagnosed, many patients will not be eligible for surgery so chemotherapy is likely to be the only curative therapy that is available to them. For patients who are eligible for cytoreductive surgery, such as pleurectomy/decortication or extrapleural pneumonectomy, chemotherapy is likely to used as part of a multimodal treatment protocol. Recent advances in the effectiveness of the available chemotherapy agents have definitely led to improved survival times for some patients, but these successes are mitigated by the fact that the disease is still without cure. Because of this disappointing situation, a significant portion of contemporary mesothelioma research is directed at improving the efficacy of available mesothelioma treatments.

Some of these research programs involve the study of alternative chemotherapy regimens. Even as pemetrexed + cisplatin (Alimta Therapy) has been a real advancement in mesothelioma treatment, additional agents and delivery mechanisms are available from the treatment of other cancers and researchers from around the world are engaged with the application of these methods to mesothelioma. Researchers from Japan have recently published an article that describes their use of a custom-developed heated perfusion technique for the treatment of pleural mesothelioma.

This article is an overview of their method and a summary of their findings.

Overview of the Study

The article describes the authors’ use of intrapleural perfusion hyperthermo-chemotherapy (IPHC) for patients with pleural mesothelioma. Perfusion chemotherapy is an alternative to the standard intravenous delivery mechanism, where the chemotherapy drugs are administered to a particular area of the body instead of being injected into the blood stream. In the case of intrapleural perfusion, the chemotherapy is delivered directly to the pleural surfaces. The drugs are heated to enhance the absorption process, as research has shown that it is easier for tumors to absorb a drug when it is heated to a certain temperature.

The authors report that they had previously had good results when using this technique on patients with pleuritis carcinomatosa, so they decided to investigate its use for pleural mesothelioma. They enrolled six patients into their study, three men and three women. Of these 6 patients, five presented with epitheloid mesothelioma and one presented with the biphasic subtype. Five patients were staged as Stage III and one was declared Stage IV. Because of the small size of the study, the authors state that they were not investigating overall treatment efficacy, but were in fact studying the apoptotic effect the therapy had on the patients who were treated with it.

The procedure was accomplished with patients under general anesthesia. The authors used video-assisted thoracic surgery (VATS) to examine the patients and to perform a biopsy. Before the perfusion was begun, they removed tumor cells from a pleural effusion. When the perfusion was completed, tumor cells were immediately removed from the effusion, and then again at 24 hours and 48 hours post-perfusion. This was done so the authors could prepare an Apoptosis Index (A.I.), which would establish what effect, if any, the treatment had on the pleural mesothelioma.

Results

The authors found that the IPHC treatment demonstrated a significant apoptotic effect on each patient’s mesothelioma cells. The Apoptotic Index describes the percentage of cells within the sample that were undergoing apoptosis when analyzed. The AI of the untreated cells was 3.8% ± 2.0%, while the post-perfusion indices were as follows: immediately-following, 22.8% ± 5.1%, at 24 hours following, 63.8% ± 8.2%, and at 48 hours following, 47.8% ± 6.09%. These are clear indications of the treatment’s noteworthy effects.

Even though the authors were not directly studying treatment efficacy, when they looked at median survival time for these patients, they found figures much higher than normal: 30 months MST vs. the standard 8-12 months.

Conclusion

Recent research has shown that one of the factors that makes mesothelioma so difficult to treat is its natural resistance to apoptosis, so the results these authors are reporting are quite exciting indeed. Even if they were not specifically studying treatment efficacy, the extended survival times demonstrated in this study are also quite impressive. A sample size of six is definitely too small to draw any conclusions from, but the authors feel that the successful rests of their study of pleural mesothelioma are worthy of a larger study.

Labels: chemotherapy, mesothelioma