The major results of our study were: (1) Partial remission (PR) was unlikely (6.9%) when oxaliplatin/gemcitabine was used as chemotherapy in multiple pretreated, pemetrexed-resistent patients with MPM. (2) However, disease control could be achieved in 44.8%, when at least three cycles of chemotherapy could be applicated. (3) The combination therapy was well tolerated and no WHO grade 4-toxicities occurred in our patients.
The diagnosis of malignant pleural mesothelioma (MPM) is still associated with a poor prognosis. The 5-year survival rates are less than 1% and median survival has been reported to be as low as 8 to 12 months for therapy-naïve patients [3
]. The introduction of pemetrexed/platin-based chemotherapy has improved therapeutic options in the treatment of MPM. However, no chemotherapy regime could so far demonstrate a significant efficacy in patients with relapsed MPM after pemetrexed/platin-based treatment [10
Vogelzang and co-workers showed an evident benefit of a pemetrexed/cisplatin-based chemotherapy for the treatment of MPM with a response rate of 41.3% in contrast to 16.7% response in the control group with cisplatin-monotherapy [19
]. A decade ago, a review by this group figured response rates of MPM to different chemotherapy-regimes regularly as low as 10 to 20%, with only single, unconfirmed studies indicating possible higher response rates [1
]. The more recent review by Ellis and associates concluded, that among other chemotherapeutics for MPM, older studies with gemcitabine monotherapy revealed response rates from 0 up to 31% [10
]. Schütte and his colleagues were the first to describe results of the oxaliplatin/gemcitabine combination for the first line chemotherapy of MPM. In their multicenter phase II study, objective responses were measured as follows: partial response in 40% (10/25 patients), stable disease in 24% (6/25 patients), and progressive disease in 36% (9/25 patients). Median TTP and OS were 7 and 13 months, respectively.
Since pemetrexed based therapy has become first line treatment for MPM, we report in our observational study the efficacy and safety of the previously described oxaliplatin/gemcitabine protocol for further therapy in pemetrexed/platin pretreated patients. Our rationale for selecting these two agents was first, the favourable response rate in first line therapy for MPM demonstrated by Schütte and co-workers [17
], and second, the acceptable toxicity-profile and thus possible clinical benefits [11
All 29 patients included in our study had advanced MPM with a median interval from primary diagnosis to begin of study treatment of 53 weeks (8 – 185 weeks) and 1 to 4 preceding chemotherapies (including the pemetrexed/platin combination). The median OS (beginning from primary diagnosis) was 72 weeks (31 – 243 weeks) and the median survival after beginning of study treatment 24 weeks (5 – 97 weeks), respectively. The median TTP was 9 weeks (3 – 68 weeks). PFS and TTF were both 12 weeks (3 – 50 weeks). Partial remission (PR) was expectably low (6.9%), but overall disease control for at least three cycles of chemotherapy could be achieved in 44.8%.
Generally, evidence is lacking for second line chemotherapy in relapsing MPM in literature. A most recently published paper by Jassem and his group compared the outcome of pemetrexed in second line treatment with best supportive care (BSC) in previously treated patients. In this trial median survival after enrolment was 14.5 months in the pemetrexed plus BSC group vs. 9.7 months in the BSC group (p = 0.74). TTP, PFS and TTF differed significantly in both groups, favouring the pemetrexed group [20
In a post-study analysis, Vogelzang and co-workers determined the benefit of a second-line chemotherapy in a subgroup of patients treated with pemetrexed/cisplatin or cisplatin. They found a prolonged survival following a second line chemotherapy. However, whether this effect could be attributed to the second line chemotherapy or the prolonged survival caused by the natural history of the tumour could not be demonstrated with statistical significance. Agents used for second line chemotherapy included gemcitabine, vinorelbine, doxorubicin, and epirubicin in mono- or combination therapy [21
Porta and colleagues investigated the anti-tumour activity of raltitrexed and oxaliplatin given as a second line regime in a series of 14 patients. The study was prematurely discontinued because no response according to the given endpoints response rate, TTP and OS was observed [22
]. In contrast, Fizazi and his group observed a median survival of 44 weeks from the start of treatment and a median survival of 226 weeks from the primary diagnosis in 15 patients receiving a second line chemotherapy with the same regime of raltitrexed and oxaliplatin [23
The toxicities of the combination oxaliplatin/gemcitabine as well as of the monotherapy with oxaliplatin were very acceptable in our study – in accordance with the low toxicities reported in the first line therapy [17
]. In general, chemotherapy was tolerated well by all patients. Mild haematologic toxicities were common but not associated with complications or even life-threatening events. Solely peripheral neuropathy, fatigue and mild renal impairment were observed.
This study has limitations due to its observational design and heterogeneity of the patients included. However, no standard therapy has been established as second line or beyond and a structured observational approach may help to foster the understanding of efficacy and safety in this clinical setting. Second, we reported all patients receiving oxaliplatin/gemcitabine therapy at any stage of the disease. This method may reduce applicability of your results in terms of efficacy as a second line therapy, but results in more confident results regard drug safety. Third, the comparison of your results with other second line studies in MPM is difficult because patients' characteristics, employed chemotherapy regimens, methods of response evaluation, and the time from primary diagnosis to start of second line chemotherapy do vary widely.