Chemotherapy Articles

Results of a Phase II Trial of Combined Chemotherapy for Patients with Diffuse Malignant Mesothelioma of the Pleura.Cancer 1999 Apr 15;85(8):1740-9

Kasseyet S, Astoul P, Boutin C

Department of Pulmonology, University Hospital la Conception, Mediterranean University Medical School, Marseille, France.

BACKGROUND: Malignant pleural mesothelioma is associated with a poor prognosis because of its resistance to treatment. 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. Fourteen patients received cisplatin, 5-fluorouracil, folinic acid, and mitomycin C with the protocol unchanged, and oral etoposide 50 mg on Days 1-21 without growth factors (1 cycle every 28 days). Histology included epithelial (in 33 cases), sacromatous (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.

---

Systemic Drug Therapy of Malignant Pleural Mesothelioma

Monaldi Arch Chest Dis 1998 Apr;53(2):236-40
Ardizzoni A, Grossi F, Pennucci MC
Istituto Nazionale per la Ricerca sul Cancro, Division of Medical Oncology I, Genova, Italy.

Malignant pleural mesothelioma (MPM) is an uncommon malignancy characterized by a rapid clinical course. Few patients are possible candidates for radical surgery. According to most reviews, radiotherapy has a limited role in the treatment of MPM. 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 on objective response to a number of chemotherapeutic agents, the impact on survival appears limited and improvement in the quality of life remains uncertain. The results of combination chemotherapy are comparable to those of single-agent chemotherapy and no major difference is detectable among the various combinations. Prospective phase II trials are recommended for the identification of new active treatments while large-scale randomized phase III trials are needed to identify the best available treatment. In addition, new standard criteria for eligibility and response assessment are required. This paper reviews the available literature on the systemic drug therapy of MPM.

---

Management of Mesothelioma By Neoadjuvant Chemotherapy, Followed by Resection and Radiation-A New Approach

George Haasler, M.D., Associate Professor, Surgery (Cardiothoracic), Medical College of Wisconsin;
Paul Ritch, M.D., Professor of Medicine (Hematology/Oncology);
J. Frank Wilson, M.D., F.A.C.R., Chairman, Radiation Oncology.

A 38-year-old man presented with progressive shortness of breath and right chest pain. He had been a non-smoker and was generally healthy. His employment history included some work as a roofer in his late teens. As an adult, he is a graphic artist. He has no known asbestos exposure.

Chest X-ray revealed a large right pleural effusion. Thoracentesis revealed mesothelial cells. Diagnostic thoracoscopy demonstrated an epithelial neoplasm consistent with mesothelioma of the epithelial type. The initial CT scan demonstrated a large tumor that involved the entire parietal pleura and appeared to extend across the midline, invading the thymic fat and the peri-esophageal region. Subcarinal lymph nodes were enlarged. We thought this tumor to be unresectable, and recommended pre-surgical treatment of the patient with chemotherapy, rather than to commit him to palliative options only. Although the usual aggressive multi-modality treatment for mesothelioma has involved initial resection followed by radiation and chemotherapy, we had seen neoadjuvant chemotherapy be helpful one other time with substantial success.

The patient underwent nine cycles of Adriamycin and Taxol chemotherapy, which he tolerated well. By that time, his tumor had decreased in size substantially to the point where his mediastinal disease appeared much more approachable. He underwent a standard pleural pneumonectomy, involving removal of the right lung, associated parietal pleura, right aspect of the pericardium and phrenic nerve, and the diaphragm. Reconstruction was carried out with a large Gortex patch tented across the lower chest to reconstruct the right hemidiaphragm. A second patch was placed along the right side of the pericardium. His postoperative course was somewhat stormy, with short-term renal failure requiring dialysis, some initial ventilatory insufficiency, and significant depression. After his discharge from the hospital, he underwent consolidative radiation therapy from which he recovered uneventfully. He has had no evidence of recurrence over one year following resection.

While this is still short-term information, this young man has done extremely well to date. Mesothelioma is a very unusual tumor to begin with, but in young people is even more rare. It usually presents in one of two histologic variants, or some combination- epithelial or mesenchymal. Patients with epithelial variants of these tumors are more likely to respond to treatments with reasonable prognosis. This history of asbestos exposure may be very distant, or even absent. While some of the best results that have been reported are those with radical surgery followed by chemotherapy and radiation therapy, this approach of neoadjuvant chemotherapy appears to have some promise for tumors that initially appear unresectable, especially with newer agents that may have increased activity against these tumors. The options for what to do depend significantly upon a patient's overall clinical state. For those in whom complete resection is not possible, palliative pleurectomy without pneumonectomy may nevertheless allow control of the pleural effusion and a marked reduction of the amount of tumor. In some instances, pleurectomy has been shown to extend survival. While always a challenging tumor, and one which often presents in debilitated patients, it is important to be aware of changes in both the palliative and potentially curative options for this disease.

---

Newer Chemotherapy Options

Gemcitabine

At the American Society of Clinical Oncology (ASCO) conference in 1998, Bischoff and colleagues, from Germany, reported a 31% response rate of single-agent gemcitabine in a small group of patients (n = 23) with MPM. An additional 40% of the patients were said to have experienced significant symptomatic improvement of their disease. The median and 1-year survival rates were not reported. It should be noted that the majority of the patient in this trial had epithelial histology (which confers a more favorable prognosis) and were in an early stage of disease.

Despite the impressive activity seen in this trial, published single-agent studies have failed to demonstrate any substantial antitumor activity of gemcitabine in mesothelioma. A Cancer and Leukemia Group B (CALGB) multicenter trial had no responders among the 17 patients studied.[11] Another multicenter study conducted in Europe demonstrated a response rate of only 7%.[12]

While results of single-agent gemcitabine are discouraging, combination trials may prove to be more beneficial. Based on preclinical evidence that the combination of gemcitabine and cisplatin demonstrated additive antitumor activity, Byrne and colleagues,[13] in Australia, initiated a phase 2 study examining the combination in patients with advanced MM. They studied 21 patients, 18 of whom had stage 3-4 disease.

The overall response rate was 47.6%, with a median duration of response of 25 weeks. The estimated 1-year survival was 41% and the treatment was well tolerated. The same group subsequently conducted a multi-institutional study that has been reported in abstract form.[14] At the time of reporting, there were 53 eligible patients. Twelve of 46 assessable patients (26%) showed a partial response. The results of further trials, planned by the Southwest Oncology Group and the European Organization for the Research and Treatment of Cancer (EORTC)-Lung Cancer Cooperative Group are eagerly awaited.

Pemetrexed

Another interesting new chemotherapy agent that has been studied in MM is pemetrexed (multitargeted antifolate [pemetrexed]). Pemetrexed is a novel chemotherapy agent that inhibits several folate-dependent enzymes, including thymidylate synthase (TS, the enzyme target of 5-flourouracil [5-FU] following its metabolic activation), dihydrofolate reductase (the enzyme target of methotrexate), and glycinamide ribonucleotide formyltransferase. Pemetrexed is a more potent inhibitor of TS than of the other enzymes. However, in vitro studies demonstrating activity of pemetrexed against cancer cell lines resistant to 5-FU and raltitrexed because of TS amplification suggest that its cytotoxicity may be mediated through these enzymes as well.

Several administration schedules of pemetrexed have been studied in phase 1 trials: daily for 5 days, every 3 weeks; weekly for 4 weeks, every 6 weeks; and every 21 days. The maximum tolerated doses (MTDs) with these 3 schedules were 4 mg/m2/day, 40 mg/m2/week, and 600 mg/m2 every 3 weeks, respectively. The main dose-limiting toxicity (DLT) seen in these phase 1 studies was neutropenia.

Other toxicities included thrombocytopenia, mucositis, diarrhea, fatigue, anorexia, nausea, vomiting, skin rash, and liver enzyme elevations. Dexamethasone was given prophylactically to patients who developed skin rashes for 3 days prior to subsequent doses, and the rash was improved or prevented. The recommended dose for phase 2 studies was established at 600 mg/m2 every 21 days.

Pharmacokinetics parameters were examined in 20 patients at the 600 mg/m2 every 21 days dose level.[15] The mean maximum concentration was 137 mcg/mL and the mean elimination half-life (t1/2) was 3.1 hours. The clearance and volume of distribution were 40 mL/min/m2 and 7 L/m2, respectively. The elimination of pemetrexed is primarily renal, with greater than 80% of the dose recovered in the urine during the first 24 hours after dosing. The clearance of pemetrexed correlated with the creatinine clearance, and, thus, it appeared to decrease with age.

Pemetrexed Single-Agent Studies

Single-agent phase 2 studies have demonstrated activity with pemetrexed in nonsmall-cell lung cancer, advanced breast cancer, head and neck cancer, bladder cancer, colorectal cancer, and cervical cancer. The DLT of single-agent pemetrexed in these phase 2 trials was neutropenia, with grade 3 or 4 toxicity occurring in about 50% of patients.

Grade 1-2 elevations in liver enzymes were common, occurring in 60% to 70% of patients, but were transient, returning to baseline values before the next cycle. Skin rashes were also common and sometimes severe, characterized by a diffuse erythematous maculopapular rash with a predominantly truncal distribution. This toxicity was ameliorated with the use of prophylactic corticosteroids prior to subsequent cycles.

Niyikiza and colleagues[18] examined the relationship between nutritional status and toxicities with pemetrexed in a multivariate statistical analysis of combined study data from 246 patients. The initial results were presented at the European Society for Medical Oncology meeting in 1998. They showed a correlation between elevated baseline plasma homocysteine levels (a marker for poor folate and B12 status) and development of life-threatening hematologic (neutropenia and thrombocytopenia) and nonhematologic (mucositis and diarrhea) toxicities.

An update of these data was presented at the ASCO conference in May 2001.[19] An additional 78 patients were evaluated, and these patients received vitamin supplementation in the form of folic acid (350-1000 mcg per day) and vitamin B12 (1000 mcg intramuscularly every 9 weeks). The incidence of grade 3 and 4 toxicities was significantly reduced in the patients who received vitamin supplementation compared with control patients who did not. Drug-related deaths did not occur in the supplemented group.

At the mesothelioma symposium in April, Dr. Axel Hanauske briefly presented results from a recently completed phase 2 study in mesothelioma. In this study, 62 patients with advanced mesothelioma, the majority of which had epithelial histology and were stage 4, were treated with pemetrexed. The preliminary overall response rate was 14.5%, with a median duration of response of 10.8+ months, median time to progression of 5.4 months, and median survival of 10.7 months.

Vitamin supplementation was added to the treatment protocol of some patients during the trial. Responses were 1/17 (6%) in those patients who did not receive vitamin supplementation, 3/5 (60%) in those who started vitamin supplementation part way through the trial, and 5/40 (13%) in those who received vitamin supplementation throughout the trial. The principle toxicity was neutropenia (grade 3-4 approximately 27%), which occurred with a lower incidence in patients receiving vitamin supplementation. Other toxicities included febrile neutropenia (4.8%), fatigue (grade 3, 8.7%), anorexia (5.9%), and nausea (4.8%).

Pemetrexed Combination Studies

A number of recent studies have examined the use of pemetrexed in combination with other chemotherapy agents.

Adjei and colleagues,[20] from the Mayo Clinic, studied the combination of pemetrexed and gemcitabine in patients with advanced solid tumors and found the combination to be well tolerated and broadly active. Of the 2 patients with mesothelioma that were enrolled in this study, 1 had a partial response.

Thodtmann and colleagues,[21] in Belgium, conducted a phase 1 study of pemetrexed and cisplatin in patients with advanced solid tumors and found that an every-21-days schedule (both drugs on day 1) was well tolerated and clinically active. Of note, 11 patients with pleural mesothelioma were enrolled onto this study, and 5 of them had a partial response. Two phase 2 studies of this combination have been reported in previously untreated nonsmall-cell lung cancer patients.[22,23] These studies showed promising activity with the pemetrexed/cisplatin combination in that disease.

At the ASCO conference in May 2001, Hilary Calvert,[24] from Newcastle upon Tyne, United Kingdom, presented preliminary phase 1 results of pemetrexed in combination with carboplatin in patients with advanced solid tumors. Both agents were given every 21 days in a dose-escalating fashion. At the time of the report, 22 patients, all with MM, were enrolled. The MTD had not been reached. Grade 3 and 4 toxicities were mainly myelosuppression (neutropenia 69%, leukopenia 44%, and thrombocytopenia 38%). The overall response rate was 29% and clinical improvement was seen in 70% of patients. Vitamin supplementation was not used in this trial.

Prompted by the promising activity seen in MM phase 1 studies of the cisplatin/pemetrexed combination, a large phase 3 trial has recently been conducted comparing cisplatin/pemetrexed vs cisplatin alone. This trial, which is the largest randomized trial to date in this disease, enrolled 430 patients. Accrual was completed in April and interim results are expected to be available shortly.

Dr. Hanauske reported at the mesothelioma symposium that the initial 75 patients in each arm received pemetrexed without vitamin supplementation; however, an unexpectedly high death on study rate (7%) was noted. This prompted the initiation of folic acid and B12 supplementation and the death on study rate dropped to less than 1%. The results of this study are eagerly awaited.

Other Chemotherapy Agents for the Treatment of Mesothelioma

A number of other newer combinations of chemotherapy, including oxaliplatin/raltitrexed and cisplatin/irinotecan, have been examined in small trials with promising activity. Whether confirmatory studies will establish a standard regimen remains to be seen.

Despite the promise of these newer chemotherapy agents, chemotherapy has so far failed to affect the survival of this disease. This has led to the development and testing of a number of additional agents with novel mechanisms of action.

Source: Medscape

---

Chemotherapy for Malignant Mesothelioma

Historical Perspective

A number of agents have been employed for the treatment of MPM, and their results will be briefly reviewed here. For a more detailed discussion of chemotherapy trials in patients with MPM, the reader is referred to articles by Vogelzang as well as others.

Single-Agent Therapy

Several agents have demonstrated modest single-agent activity in the treatment of MPM. Doxorubicin, probably the most extensively studied agent, has a response rate in the 15% range. Other anthracyclines, such as detorubicin, pirarubicin, and epirubicin, have also been studied with similar results.

Cisplatin has been studied in a number of trials and seems to have an approximately 14% response rate.[5,8] One small study of very high dose-intensity cisplatin (80 mg/m2/week) demonstrated a 36% response rate; however, the duration of response was short (2-8 months).[9]

Other agents that have shown activity with a 10% to 20% response rate include carboplatin, mitomycin, cyclophosphamide, and ifosfamide. Early studies with high-dose methotrexate were reported in 1972 with response rates of 35% to 44%. However, no confirmatory studies have been published.

Combination Chemotherapy With Traditional Agents

Because of the lack of efficacy of single-agent chemotherapy regimes (response rates less than 20%), several combination regimens have been examined for the treatment of patients with MPM.

Doxorubicin has been combined with several agents, including cyclophosphamide and ifosfamide, but response rates were similar to single-agent doxorubicin. The combination of doxorubicin with cisplatin has shown marginal increases in response rate over single-agent therapy, but no survival advantage. A 44% response rate was seen with the 4-drug regimen of doxorubicin, cisplatin, mitoxantrone, and bleomycin, but this study has never been confirmed.

Despite many trials with numerous regimens, none of these combination chemotherapy regimens have consistently yielded response rates higher than those seen in single-agent studies. The development and testing of newer agents for the treatment of MPM are clearly needed.

Source: Medscape