Systemic Treatment of Malignant Pleural Mesothelioma

Chemotherapy

First-line Chemotherapy

Chemotherapy represents the main treatment option for the majority of patients with MPM, even in the absence of a formal demonstration of its superiority over best supportive care. The only randomized study that investigated active symptoms control versus active symptoms control plus vinorelbine or mitomycin–vinblastine–cisplatin failed to demonstrate a survival benefit for the two chemotherapy arms compared with active symptoms control, with a median OS of 8.5 and 7.6 months, respectively. When analyzed by the type of chemotherapy, patients who received single-agent vinorelbine had a prolonged OS (9.4 months), but the study was not powered to detect such a difference and, therefore, it can only be inferred that the addition of an active drug, such as vinorelbine, may improve survival.^[19]

Whether chemotherapy should be started at diagnosis or at the time of disease progression has not been investigated, despite this being a relevant issue owing to the palliative intent of the systemic treatment in this disease. A small randomized study showed a trend for improved survival and a more extended period of symptom control in those patients receiving chemotherapy at diagnosis, rather than at the time of symptomatic progression.^[20] However, in the above-mentioned study, a combination of mitomycin C, vinblastine and cisplatin was tested and it should be considered that this regimen is currently suboptimal for its clinical efficacy; these results would need to be validated in larger studies with the most active available chemotherapy regimens. These data only suggest that chemotherapy may improve patient outcomes.

In a meta-analysis including all Phase II studies conducted in MPM from 1965 to 2001, cisplatin was found to be the most active single agent and it became the reference for combination chemotherapy regimens.^[21] Cisplatin and antifolate-based combination chemotherapy is the only treatment with demonstrated survival advantage in randomized clinical trials, and it should be adopted as first-line chemotherapy in all MPM patients considered candidates for medical treatment.

In the EMPHACIS trial, 456 chemotherapy-naive patients were randomly assigned to receive cisplatin at 75 mg/m² plus either pemetrexed (500 mg/m²) or placebo every 3 weeks. The combination of cisplatin plus pemetrexed statistically improved OS over cisplatin alone, with a median OS of 12.1 versus 9.3 months. Response rate (RR) and time to progression (TTP) also favored the combination (41 vs 17% and 5.7 versus 3.9 months, respectively).^[22] The combination chemotherapy was also associated with an improvement in quality of life and symptoms control. The observed difference in these secondary end points became evident within the first three cycles and remained statistically significant by week 15.^[23] Differences in survival were greater in patients who received folic acid and vitamin B12 supplementation, and supplemented patients experienced less treatment-related toxicities and received a greater median number of cycles.^[24] Based on these findings cisplatin and pemetrexed with folic acid and vitamin B12 supplementation became the worldwide standard first-line regimen for patients with MPM who are candidates for systemic treatment.

Because of the cumulative nonhematological toxicities associated with cisplatin use, carboplatin has also been investigated in combination with pemetrexed. In the larger of two Phase II studies, 102 patients were treated with carboplatin AUC 5 followed by pemetrexed at 500 mg/m² with folic acid and B12 vitamin supplementation, reporting a RR of 19%, a TTP of 6.5 months and a median OS of 12.7 months.^[25] The other study included 76 patients and reported a RR of 25% with a TTP of 8 months and a median OS of 14 months.^[26] In a retrospective analysis of these two studies, the combination of carboplatin and pemetrexed had a similar outcome in younger patients compared with those >70 years, with the exception of a greater hematological toxicity in the older patient subgroup.^[27] Results from a large expanded-access program including 1704 chemotherapy-naive MPM patients demonstrated a lower RR for carboplatin plus pemetrexed compared with cisplatin plus pemetrexed (26 vs 21%), but a similar TTP (6.9 vs 7 months) and 1-year survival rate (63 vs 64%).^[28] Although not supported directly by a randomized comparison, carboplatin in combination with pemetrexed may be considered a valid alternative option in elderly patients with comorbidities when cisplatin toxicity is of major concern.

In a randomized Phase III trial promoted by the European Organization for the Research and Treatment of Cancer and the National Cancer Institute of Canada, 250 patients were randomized to receive 80 mg/m² cisplatin with 3 mg/m² raltitrexed (a thymidylate synthase [TS] inhibitor) or cisplatin alone, with both regimens administered every 3 weeks.^[29] In 213 patients with measurable disease, the combination of cisplatin and raltitrexed achieved a RR of 24 versus 11% with a median OS of 11.4 versus 8.8 months and a 1-year survival rate of 46 versus 40%. These differences were of borderline statistical significance, probably because the study was underpowered. A separate analysis on quality of life pointed out that dyspnea improved with cytotoxic treatment and that this effect was statistically significant in those patients who received the combination.^[30] Raltitrexed is currently licensed for the treatment of MPM in Europe and Canada, but not commercially available in the USA.

The optimal length of first-line treatment remains an unanswered question. Nearly 60% of supplemented patients in the EMPHACIS study received six courses of therapy and a few continued beyond. A small nonrandomized Dutch feasibility study on maintenance pemetrexed after six courses of pemetrexed-containing regimens demonstrated that maintenance treatment is nontoxic, well tolerated and associated with some improvement in TTP and OS.^[31] It is of some clinical relevance that, among patients with stable disease at the start of the maintenance phase with pemetrexed, 23% of them subsequently achieved a partial response (PR). A large prospective CALGB randomized study is currently ongoing to more definitively address this question on maintenance.^[202] While waiting for these results, treatment duration should be individualized based on the clinician's judgment and patient preference.

Single-agent gemcitabine showed limited activity in different small Phase II studies, with a RR ranging from 0 to 31%.^[32] Gemcitabine has been combined with cisplatin, carboplatin and oxaliplatin, with a RR ranging from 12 to 40%, median TTP of 6–7 months and median OS of 13–15 months.^[33–35] Other platinum-based combinations have been evaluated in the first-line setting, with the combination of cisplatin and anthracyclines yielding a RR ranging from 19 to 46% and a median OS of 12–13 months.^[36,37] Owing to the lack of Phase III evidence, the first-line use of these combinations is not supported.

For patients unfit for platinum-based doublets, single-agent chemotherapy represents a treatment option. The activity of front-line use of single-agent pemetrexed has been tested in a Phase II study with or without vitamin supplementation.^[38] A total of 64 patients were enrolled and single-agent pemetrexed resulted in a RR of 14% with a median OS of approximately 11 months. Forty-three patients received vitamin supplementation, and had a better treatment tolerability and a median OS of 13 months compared with 8 months for nonsupplemented patients. Vinca alkaloids showed single-agent activity, and in a Phase II study including 29 chemotherapy-naive patients administered with vinorelbine 30 mg/m² weekly resulted in a RR of 24% and median OS of 10.6 months, with improvement of quality of life and pulmonary symptoms reported in 41% of the patients.^[39]

Anthracyclines have only shown negligible activity with RR ranging from 0 to 20% and, owing to the unfavorable toxicity profile compared with other cytotoxic agents, such as antifolates, this class of drugs has only a very marginal role in the systemic treatment of MPM.^[40]

Results from selected Phase II and III studies of single-agent and combination chemotherapy trials in first-line treatment of MPM are summarized in Table 1.

Second-line Chemotherapy

Almost every patient with MPM progresses after first-line treatment, even if there was an initial response to treatment. At progression, many patients still maintain a good performance status with preserved organ function, and thus are eligible for second-line therapy. An analysis of the Phase III EMPHACIS study identified poststudy second-line chemotherapy as a significant predictor for prolonged survival (hazard ratio: 0.56; 95% CI: 0.44–0.72), even though this finding has been influenced by a sort of selection bias in favor of patients able to receive further chemotherapy.^[41] Several agents have been tested in this context, but currently there is no specifically approved second-line regimen for MPM, which remains the most appropriate disease setting to test the efficacy of new agents and strategies.

The most extensive data set is available for pemetrexed used either alone or in combination with platinum compounds. In the second-line setting, the only randomized Phase III study performed compared single-agent pemetrexed with best supportive care in 243 previously treated and pemetrexed-naive patients. Pemetrexed significantly improved the disease control rate (DCR) (59 vs 19%) and median progression-free survival (3.6 vs 1.5 months), although it failed to show any advantage in quality of life and OS benefit. It should be carefully considered that 52% of patients in the best-supportive-care arm received poststudy chemotherapy and this may have jeopardized a potential survival benefit.^[42] Furthermore, the activity of second-line pemetrexed-based chemotherapy in pemetrexed-naive patients has been confirmed in an expanded-access program. An initial analysis in 153 evaluable patients showed an overall RR of 33% for the combination of cisplatin and pemetrexed and 5.5% for pemetrexed alone, with a DCR of 69 and 47%, respectively. Median OS was 7.6 months for pemetrexed plus cisplatin and 4.1 months for pemetrexed alone.^[43] In a further analysis of the same expanded-access program, on 396 pretreated patients who received single-agent pemetrexed, the RR was 12% with a median TTP of 4.9 months.^[44] Overall these data indicate that for patients with advanced MPM who did not receive pemetrexed as part of the first-line treatment, second-line pemetrexed, alone or in combination with platinum compounds, represents a reasonable treatment option.

In a Phase II study including 63 pretreated MPM patients, single-agent weekly vinorelbine at 30 mg/m² for 6 weeks yielded a RR of 16% and median OS of 9.6 months.^[45]

In a small Phase II study, 30 patients, after failure of first-line pemetrexed-based chemotherapy, received gemcitabine at 1000 mg/m² and vinorelbine at 25 mg/m² on days 1 and 8 every 3 weeks, obtaining a RR of 10% with a TTP of 2.8 months and median OS of 10.9 months.^[46]

In another small Phase II study including 45 patients, gemcitabine at 750 mg/m² and epirubicin at 70 mg/m² on day 1, every 21 days, produced objective tumor shrinkage in 13% of the cases and, a median OS of 9.7 months was documented.^[47]

Patient rechallenge with pemetrexed is another area of clinical interest. Recently, it has been reported that retreatment with pemetrexed (either alone or in combination with platinum compounds) in patients already exposed to the same agent is a valuable option with a good tolerability profile. A DCR of 48% was documented in 31 patients with a median PFS of 3.8 months and median OS of 10.5 months. Notably, patients with a PFS time duration following first-line treatment exceeding 12 months had a PFS time after retreatment of 5.5 months, whereas patients with a shorter PFS at first line had a median retreatment PFS of 2.5 months. Although this is a small series, these results suggest that rechallenge with pemetrexed is a viable option and that this strategy could be considered in patients with prolonged tumor control after first-line pemetrexed.^[48] In a recently reported multicenter survey of second-line chemotherapy in MPM, although with the limitations of a retrospective analysis with potential selection biases, second-line chemotherapy showed a clinical activity with an overall DCR of 52%. The subgroup of patients retreated with pemetrexed-based second-line chemotherapy achieved a significantly longer PFS and OS, and higher DCR than patients treated with second-line regimens not containing pemetrexed.^[49] These findings are consistent with those previously reported in small retrospective series.^[50,51] Selected trials of second-line chemotherapy are summarized in Table 2.

Individualized Chemotherapy

The improvement of treatment selection on the basis of individual tumor characteristics, imaging technologies and biomarkers represents a relevant challenge in the treatment of MPM. The main aim is the identification of factors that can help in selecting patients with a greater probability of receiving a benefit from a specific treatment. A retrospective study has demonstrated a significant correlation between the level of immunohistochemistry positivity for TS expression and both TTP and OS in MPM patients treated with pemetrexed, with a lower TS expression being a predictor for a better outcome.^[52] Conversely, no apparent correlation has been shown between the expression of folate receptor-α (a protein that allows the drug to enter the cells) and pemetrexed activity.^[53] The standardization of diagnostic techniques for TS assessment and its validation in prospective studies may contribute towards defining, in routine clinical practice, the role of TS as a biomarker for the personalization of pemetrexed therapy in MPM. The expression of the ERCC1 gene in tumor tissue has been shown to be predictive for platinum activity in several tumor types.^[54] In MPM, no correlation was detected between ERCC1 expression level and cisplatin activity, while high ERCC1 expression levels predict for a longer OS regardless of treatment.^[52]

Table 1. Selected Phase II and III studies of combination and single-agent chemotherapy trials as first-line therapies.
Chemotherapy	Phase	Patients (n)	RR (%)	Median PFS (months)	Median OS (months)	Ref.
Chemotherapy vs ASC alone	III	409	12.0	5.6 vs 5.1	8.5 vs 7.6	[17]
Cisplatin + pemetrexed vs cisplatin	III	456	41.3 vs 16.7	5.7 vs 3.9	12.1 vs 9.3	[20]
Cisplatin + pemetrexed vs Carboplatin + pemetrexed	EAP EAP	843 861	26.3 21.7	7.0 6.9	63% (1 year) 64% (1 year)	[26]
Cisplatin + raltitrexed vs cisplatin	III	250	23.6 vs 13.6	5.3 vs 4.0	11.4 vs 8.8	[27]
Pemetrexed	II	64	14.1	4.7	10.7	[36]
Vinorelbine	II	29	24.0	Not available	10.6	[37]

Table 2. Selected studies of second-line chemotherapy.
Regimen	Phase	Patients (n)	RR (%)	PFS (months)	Median OS (months)	Ref.
Pemetrexed vs BSC	III	243	DC 59.0 vs 19.0	3.6 vs 1.5	8.4	[40]
Vinorelbine	II	63	16.0	Not available	9.6	[43]
Vinorelbine + gemcitabine	II	30	10.0	2.8	10.9	[44]
Gemcitabine + epirubicin	II	23	13.0	6.3	9.3	[45]
Cisplatin + pemetrexed Pemetrexed	EAP	96 91	32.0 5.0	Not available	7.6 4.1	[41]
Pemetrexed	EAP (pretreated)	396	12.1	6.0	Not available	[42]

Table 3. Selected studies on target agents in mesothelioma.
Novel agent	Phase	Patients (n)	Median PFS (months)	Median OS (months)	Ref.
Gefitinib	II	43	2.6	6.8	[58]
Erlotinib	II	63	2.0	10.0	[59]
Bevacizumab + CG vs CG	II	115	6.9 vs 6.0	15.6 vs 14.7	[66]
Vatalanib	II	47	4.1	10.0	[67]
Sorafenib	II	51	3.7	10.7	[72]
Sunitinib	II	23	3.5	5.9	[74]
Valproic acid + doxorubicin	II	45	2.5	6.7	[89]
NGR–hTNF	II	57	2.8	12.1	[90]

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