Chemotherapy involving a cisplatin doublet (raltitrexed plus cisplatin or pemetrexed plus cisplatin) is more effective than single-agent chemotherapy.
Pemetrexed in Combination with Cisplatin
This combination is an active treatment protocol for desmoplastic mesothelioma patients. It prolongs survival in comparison to cisplatin alone among individuals with advanced mesothelioma.
Results derived from a single-blinded trial, in which 456 study subjects were randomly administered cisplatin (75 mg/m2) along with either pemetrexed (500 mg/m2) or a placebo (both administered once every 3 weeks), showed that median survival was considerably longer in case of the combination therapy (12.1 as opposed to 9.3 months). The objective response rate (41 as opposed to 17 percent) and the time to progression (5.7 as opposed to 3.9 months) were also significantly higher.
Apart from the survival benefit, the combination drug regimen has also been linked with improved quality of life and enhanced symptom alleviation. As per an initial report that evaluated these secondary benefits, differences became evident between the two groups within the preliminary three cycles. These differences had acquired statistical importance by the fifteenth week. Several different parameters demonstrated the superiority of combination therapy including pain, fatigue, cough, dyspnea, anorexia, and global quality of life.
The variation in survival was most noticeable among patients who were administered folic acid and vitamin B12 supplementation during treatment. In addition, therapy-related toxicity was considerably less, and the mean number of therapy cycles (including both the combination and single agent cisplatin) was significantly greater for the supplemented group in comparison to the non-supplemented group.
As per a multivariate regression analysis involving prognostic factors derived from this trial, parameters that were indicative of overall survival included vitamin supplementation group, therapy group, white blood cell count (≥8200/microL as opposed to lower values), staging, histologic subtype, and Karnofsky performance status (90-100 as opposed to 70-80).
Also, high levels of cystathionine (>300 µmol/L versus lower values) were indicative of worse survival. High cystathionine levels were linked with increasing deficiencies of vitamins B6, B12, as well as folic acid, albeit to a lesser extent. Supplementation with vitamin B6 was not required during the treatment regimen, and it may be compelling to speculate that cumulative deficiency of B6 adversely affected survival among patients. It may be possible that supplementation with vitamin B6 would further prolong overall survival among patients who receive treatment with cisplatin and pemetrexed. However, a prospective trial would be required to answer this question.
These results have prompted the use of pemetrexed and cisplatin combination regimen along with prophylactic folic acid and vitamin B12. This regimen has become the standard treatment for individuals diagnosed with malignant pleural mesothelioma. This is applicable for patients whose disease is either unresectable or those who cannot be considered appropriate candidates for curative surgery.
Pemetrexed and Carboplatin
In order to decrease toxicity level, carboplatin has been used in place of cisplatin in combination with pemetrexed. Of the two non-randomized phase II studies, the larger one involved 102 patients who were administered carboplatin (AUC 5) plus pemetrexed (500 mg/m2), along with vitamin B12 and folic acid supplements. Objective responses were recorded among 19% of patients, with the median time to progression being 6.5 months and median survival being 12.7 months. A subsequent age-based analysis of 2 of these clinical studies demonstrated that the combination of carboplatin and pemetrexed was well tolerated. Also, this regimen showed a similar level of activity among patients ≥70 years of age, in comparison to patients who were relatively younger.
These results are similar to those associated with cisplatin-based combination chemo. If toxicity issue is to be addressed, the combination of pemetrexed and carboplatin can be used as an alternative treatment regimen for this population.
Raltitrexed and cisplatin
The combination of raltitrexed and cisplatin improves survival in comparison to cisplatin alone in patients with advanced desmoplastic mesothelioma who were not previously treated with these specific drugs. This was demonstrated in a phase III trial involving 250 patients who were randomly assigned to raltitrexed (3 mg/m2) in combination with cisplatin (80 mg/m2 – both administered every 21 days) or an equal dose of cisplatin alone.
The trial found:
- Among the 213 patients with measurable disease, the group that received combination drug therapy demonstrated a higher objective response rate (24 as opposed to 14 percent, p = 0.06).
- In all randomized patients, survival was considerably prolonged with the combination drug regimen. The median survival and one-year survival were 11.4 months and 46% respectively in comparison to 8.8 months and 40% respectively in case of single agent cisplatin.
- In a separate analysis that evaluated health-related quality of life (QOL), it was noticed that overall QOL remained impaired at baseline, but was found to be stable for patients who continued to receive treatment (including both regimens).
Other drug Combinations
In phase II studies, several other drug combinations have been evaluated. Randomized trials will be needed in order to assess the effectiveness of these regimens:
- Gemcitabine in combination with a platinum – Gemcitabine has been used in combination with carboplatin, cisplatin, and oxaliplatin. These combinations have demonstrated response rates in the range of 15-48%, with toxicity levels that are considered acceptable.
- The potential effectiveness of the gemcitabine plus cisplatin combination drug therapy was demonstrated in a phase II trial involving 106 previously untreated patients who were randomly put on the gemcitabine plus cisplatin regimen with either bevacizumab or placebo. Here, the median survival was around 15 months for both the treatment protocols. These results are consistent with those achieved with a combination of cisplatin and pemetrexed.
- Other types of cisplatin-based regimens – In phase II trials, cisplatin has also been used in combination with a variety of older chemotherapy agents such as the combination of fluorouracil, mitomycin, plus etoposide; the combination of methotrexate plus vinblastine; and anthracyclines (doxorubicin, epirubicin). Results derived from these studies have not shown any advantage in comparison to combinations involving cisplatin with either gemcitabine or pemetrexed.
While only limited data is available, second-line chemotherapy can be useful for individuals diagnosed with malignant pleural mesothelioma. In the second-line environment, the most extensive data is for pemetrexed, either used alone or in combination with cisplatin. Gemcitabine, anthracyclines and vinorelbine are some of the other drugs that have been used.
In an analysis of phase III EMPHACIS trial that involved comparison of pemetrexed plus cisplatin and cisplatin alone, it was noticed that second-line (post study) chemotherapy significantly influenced extended survival. That chemotherapy offered a survival benefit was indicated in a retrospective multiple regression analysis involving patient risk factors.
More information on the utility of second-line chemotherapy has been derived from a multicenter trial involving 243 previously untreated patients who were randomly assigned to best supportive care or pemetrexed. Pemetrexed demonstrated significant increase in the median progression-free survival (3.6 versus 1.5 months), time to progression (3.7 versus 1.5 months) and time to treatment failure (3.6 versus 1.5 months).
However, the median survival with pemetrexed was only 8.4 months as compared to 9.7 months achieved with best supportive care. It is possible that an overall survival benefit may have remained obscured because 52% of patients assigned to best supportive care were administered systemic chemotherapy once it was evident that the disease had progressed.
Adjuvant and neoadjuvant chemotherapy
Preliminary results show evidence of a potential benefit associated with adjuvant chemotherapy administered after surgery in case of resected (limited-stage) mesothelioma patients and neoadjuvant or induction chemotherapy in case of patients with probable resectable disease.