Our retrospective, real-world study proved the high efficiency of paclitaxel and platinum plus BV in previously highly treated advanced TETs without life-threatening toxicity. The ORR for thymoma and thymic carcinoma were 24% and 57%; and the median PFS were 6months and 8months, respectively.To our knowledge, this is the first report evaluating the addition of BV to standardchemotherapy in TETs, although its superiority has been established in other malignanciesthrough randomized trials. [8, 9, 11] Imbimbo et al registered a phase II trial, using similar antiangiogenic agent (ramucirumab) plus paclitaxel and carboplatin for thymic malignancies, while the results have not been revealed yet.[12]
There were 21 patients with thymoma in this study, and all of them received front-line chemotherapy before this trial. However, only one patient (4.7%) showed partial response. In Lemma et al’s study, the ORR of paclitaxel-carboplatin regimen was 42.9% in thymoma.[4]Meanwhile, the ORR of anthracycline-containing regimen was approximately 73% in Lucchi et al’s report.[13] All our 21 patients had pleural disseminations, and mainly showed resistance to routine chemotherapeutic regimens.To our delight, 5 out of 21 (24%) patients experienced tumor regression when BV was added to routine chemotherapy. At the same time, an ORR of 57% was observed in our 28 TC patients with the same regimen, which was much higher than that ofthe front-line chemotherapy (25%) in this cohort, as well as the ORRs in other large-sample reports.[14–15] As for the enhancement mechanism of BV, most authors agreed that it improves drug delivery to the tumor.[16–18] In addition, due to its anti-VEGF antibody nature, BV may also inhabit tumor angiogenesis, which is critical for tumor progression. Similarly, in our current study, the improvement in ORR was obvious in both thymoma and TC (24% vs 4.7, 57% vs 25%) compared with front-line chemotherapy.
Johnson et al reported in their phase II study that 6 out of 11 patients with squamous cell lung cancer developed severe pulmonary hemorrhage (4 were fatal) after receiving BV-containing chemotherapy. [19] Thus, squamous lung cancer was excluded from the candidates of BV target therapy. In our study, however, there were 28 cases of thymic squamous cell carcinoma. Only 1 patient developed grade 2 hemoptysis, and the treatment was discontinued thereafter. We reviewed the computed tomography of this patient and found that his tumor body was adjacent to the main trachea and showed a sign of invasion. As we know, a major portion of squamous cell lung cancers are centrally located, and have a tendency to involve hillarstructure like main bronchia and vessel. When BV delivered, the necrotic cavity inside tumor is likely to form up, resulting in fatal bleeding. While the situations in thymic squamouscarcinoma and cervical cancer are different, although the pathological types are also squamous cell, the risk of severe hemorrhage is relatively low. Therefore, they should not be viewed as contraindications of BV treatment despite of the pathology.
The dose of paclitaxel in the current study (160mg/m2) was lower than that in Lemma et al’s study (225mg/m2)[4], because all our patients were heavily treated before they received the new regimen. Meanwhile, BV was prescribed at the dose of 7.5mg/kg based on the results of AVAiL study, in which similar clinical outcome was observed in either 7.5mg/kg group or 15mg/kg group. [11] These might explain the lower incidence of severe hematological toxicity and hypertension in this trial (Table 3) than that of previous studies. [8–9, 19] Whether higher dose of paclitaxel and BV could produce better outcome in TETs needs to be examined in further prospective trials.
In this study, the median PFS for thymoma was 6 months, shorter than that of 16.7 months in Lemma et al’s study,[4] possibly due to the lower response rate (24%) in our thymoma cohort. While for thymic carcinoma, the median PFS was 8 months, consistent with previous reports. [5, 15] We did not take overall survival (OS) as a primary end point because there was great heterogenis in the subsequent therapy after progression so that it is complicated to interpret OS. Thus, we took PFS as the primary end point like in most studies with BV. In ECOG 4599 study, BV single-agent maintenance treatment after chemotherapy was associated with better PFS, [20] so it may also be worthy of trying BV maintenance therapy in prospective trials for TETs.
There are some limitations in our study. First, it is a single-center retrospective study of small sample due to the rarity of TETs. Second, most of the target lesions in thymoa patients are pleural dissemination, while it is only one manifestation of late-staged thymoma. Third, there is inconsistence in chemotherapy regimen, such as cisplatin and carboplatin are both administrated, although our limited cases showed there was no difference in the efficacy.
In conclusion, paclitaxel and platinum plus BV showed promising effect in refractory or relapsed advanced TETs without severe toxicity. Even applied as salvage therapy, this regimen resulted in better ORR than the front-line chemotherapy. Further prospective investigation in first-line setting for unresctable TETs is warranted.