本帖最后由 做凡人 于 2013-7-27 10:32 编辑
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~雷利度胺~~~~~~~~~~~~~~~~~~~~~~
40个病人入组，1个CR，3个PR，21个SD。25个病人6个月内出现进展，6个人6-12个月进展，9个人12个月以上进展。副作用可耐受。
http://www.ncbi.nlm.nih.gov/pubmed/18525302
Abstract
PURPOSE:
Treatments for refractory metastatic renal cell cancer (RCC) are limited. Oral lenalidomide, a thalidomide-based drug having enhanced immunomodulatory and antiangiogenic properties and reduced toxicity, was evaluated for safety and efficacy in this setting.
METHODS:
In an open-label, single-center phase II trial, adults (> or =18 years old) with newly diagnosed RCC seen at our institution between December 2003 and April 2004 were recruited to receive at least three 28-day cycles (21 days on drug and 7 days off) of oral lenalidomide (25 mg/d). The dose was reduced as needed in cases of toxicity. The primary endpoint was tumor response rate. Secondary endpoints were time to tumor progression, response duration, 6-month and 12-month progression-free survival, overall survival, and safety.
RESULTS:
Thirty-nine of 40 patients (97%) were evaluable for response. Many in the evaluable population [63 (38-73) years; male, 73% (29/39)]; Zubrod performance status < or =1, 97% (38/39) had the clear cell histotype [85% (33/39)], had undergone previous immunotherapy or chemotherapy [59% (23/39)]; and had > or =2 metastatic sites [69% (27/39)]. Most [92% (36/39)] completed at least 3 treatment cycles (12 weeks). A complete response was observed in 1 patient (3%), partial response in 3 (8%), stable disease in 21 (53%), and progressive or unknown-status disease in 15 (38%). Time to tumor progression was < or =6 months in 24 patients (62%), 6 to 12 months in 6 (15%), and >12 months in 9 (23%). Median response duration was 6 (2-22) months and median overall survival was 17 months (0.80-39.6). The most common treatment-related adverse event was grade < or =2 fatigue [60% (24/40)]. The most common laboratory abnormalities were grade > or =3 neutropenia [50% (20/40)] and thrombocytopenia [28% (11/40)].
CONCLUSION:
Lenalidomide is a safe and effective therapy for refractory metastatic RCC. Further studies of lenalidomide in this setting are warranted.
~~~~~~~~~~~~~~~~~~~~~~~~Gemcitabine + Capecitabine 吉西他滨+卡培他滨~~~~~~~~~~~~~~~~~~~~~~
这个帖子总结了几个临床试验，介绍了两个CR的病人，都是免疫治疗活着靶向治疗失败，病情进展，几个临床试验我还没查，等有空更新上来，不过这个帖子提到 Response rates have ranged from 8.4% to 16%, stable disease rates from 48% to 67%, and median progression-free survival from 4.6 to 7.6 months.
反应率从8.4%到16%不等（我觉得挺高的了），SD从48%到67%不等。（我觉得也挺高的了哈）。然后中位无进展生存期4.6到7.6个月不等（作为靶向疗法外的疗法我觉得也挺高的了哈），而且似乎耐受不错的。
http://jco.ascopubs.org/content/29/8/e203.full
Targeted therapy is the current standard of care for the systemic treatment of metastatic RCC. The multitargeted tyrosine kinase inhibitors sunitinib and pazopanib as well as the combination of bevacizumab plus interferon alfa are the accepted first-line therapies for patients with metastatic clear cell RCC at good to intermediate risk.1–4 The mammalian target of rapamycin (mTOR) inhibitor temsirolimus is the accepted first-line therapy for patients with advanced poor-risk RCC.5 Sorafenib, sunitinib, and pazopanib are accepted second-line therapies after cytokine failure; the mTOR inhibitor everolimus is the approved treatment after sorafenib and/or sunitinib failure.6,7 Approximately 20% of patients with metastatic RCC have primary resistance to anti–vascular endothelial growth factor (VEGF) therapies. Furthermore, there is no established third-line therapy for patients who develop progressive disease after VEGF- and mTOR-targeted therapies or for patients who are intolerant of these targeted agents. Metastatic RCC has traditionally been considered unresponsive to cytotoxic chemotherapy.8 The combination of gemcitabine and capecitabine has been studied in several case series and four single-arm phase II trials in patients with metastatic RCC refractory to immunotherapy and, to a lesser extent, refractory to targeted therapy. Response rates have ranged from 8.4% to 16%, stable disease rates from 48% to 67%, and median progression-free survival from 4.6 to 7.6 months.9–12
We report two patients with metastatic RCC who achieved durable remissions after treatment with the chemotherapy regimen of gemcitabine and capecitabine after failure of targeted therapies. One patient has been in remission more than 6 years since rapid disease progression while receiving high-dose IL-2 and sorafenib. The second patient demonstrated a second tumor response on rechallenge with this chemotherapy regimen after rapid disease progression while receiving two prior anti-VEGF therapies (bevacizumab and sunitinib). The mechanisms of resistance of RCC to anti-VEGF agents and mTOR inhibitors are poorly understood. Clinicopathologic studies have demonstrated that higher tissue levels of phosphorylated Akt in nephrectomy specimens from patients with metastatic RCC subsequently treated with sorafenib are associated with shorter progression-free survival.13 A study evaluating nephrectomy specimens from patients with metastatic RCC who received bevacizumab-based therapy before nephrectomy demonstrated that critical components of the PI3-kinase pathway are upregulated in individuals with shorter progression-free survival.14 Although these data do not prove a direct mechanistic association between PI3-kinase pathway upregulation and poor clinical outcome in patients treated with antiangiogenic agents, they provide hypothesis-generating studies for testing.
Gemcitabine (2′,2′-difluorodeoxycytidine, LY188011, dFdCyd) is a pyrimidine antimetabolite. Cell-cycle kinetic studies with gemcitabine have shown specificity for proliferation in the S phase of the cell cycle, with no effect on progress through the early G1, G2, or M phase.15 We postulate that c-Myc activation may provide a specific vulnerability to this class of agents by driving cells to accumulate higher levels of abnormal DNA in the presence of gemcitabine, generating in effect a synthetic lethal phenotype. Evan et al16 reviewed mechanisms by which increased DNA damage in conjunction with c-Myc activation could lead to susceptibilities to DNA-damaging processes. In patients with rapidly progressing disease with high cell-cycle activity, RCC tumors may be more susceptible to cytotoxic chemotherapy. A DNA analog like gemcitabine, in the background of the pre-existing gross chromosomal abnormalities seen in RCC, may be sufficient to drive a c-Myc–dominant tumor—the DNA repair mechanisms of which are down-regulated—into apoptosis.17,18 The combination of gemcitabine and capecitabine is an effective and well-tolerated regimen, with the potential for achieving durable remissions in metastatic RCC. We believe this regimen should be evaluated in the treatment paradigm of metastatic RCC refractory to targeted therapies. |
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