晚期肠癌标准治疗失败后可能的选择 --最后更新2012.07.26

这个贴子用来讨论晚期肠癌标准治疗失败后可以做的一些选择，欢迎战友们踊跃跟帖

1. A phase II trial of salvage treatment with gemcitabine and S-1 combination in heavily pretreated patients with metastatic colorectal cancer.

Background: We conducted a phase II trial of gemcitabine with S-1 to evaluate the activity and toxicity of such a combination in heavily pre-treated patients (pts) with metastatic colorectal cancer (mCRC) who have progressed after treatment with 5-fluorouracil, oxaliplatin and irinotecan. Methods: Between Dec 2009 and Nov 2011, 23 pts were enrolled, with the following characteristics: 12 males and 11 females, median age 57 years (28-72). S-1 was given orally (30 mg/m2) b.i.d for 14 consecutive days and gemcitabine (1000 mg/m2) was given on days 1 and 8, every 21 days, until disease progression and for a maximum of 9 cycles. The primary endpoint was objective response rate (ORR). Results: The median number of cycles was four (range 1-9). OR was 8.7% (95% confidence interval [CI] 0-20.2) and disease control rate was 56.5% (95% CI 36.4-76.9) with two partial responses and eleven stable diseases. Median duration of disease control was 8.5 months (95% CI 3.8-13.2). Median progression-free survival was 3.2 months (95% CI 1.9-4.5) and median overall survival was 11.8 months (95% CI 4.0-19.5). Grade 3-4 toxicities were neutropenia (8%) and thrombocytopenia (4%). Conclusions: Combination chemotherapy with gemcitabine and S-1 was well tolerated and efficacious for refractory mCRC pts.

吉西他滨原先的适应症主要在肺癌方面，近年来逐步扩大了适应证的范围。上文中的临床就是吉西他滨联合S-1（替吉奥）在晚期肠癌标准方案治疗失败后的尝试。从数据上来看还是不错的，疾控率达到56.5%，3-4级毒性也控制在很低的范围内，不失为所有标准方案失败后的一种选择。目前尚未有联合靶向的实验，因此联合靶向是否可以进一步提高疾控率延长PFS值得期待。

2. CORRECT Trial Results: Regorafenib Potential New Standard of Care for Refractory mCRC
Findings from the CORRECT trial indicate that regorafenib, an investigational, oral multi-kinase inhibitor, is the first and only agent in phase III analysis to significantly improve overall survival in patients with metastatic colorectal cancer (mCRC) who have failed all approved standard therapies (Abstract LBA385). Consequently, regorafenib could help address the high unmet clinical need faced by this patient population once the drug receives regulatory approval, according to principal investigator Axel Grothey, MD, of the Mayo Clinic in Minnesota.

Interim analysis of data from the global, randomized, double-blind, placebo-controlled trial showed that the addition of regorafenib to best supportive care significantly prolonged median overall survival—the primary endpoint—from 5.0 to 6.4 months in 760 patients with documented mCRC and disease progression during or within 3 months after their last standard therapy (p = 0.0052, 1-sided). This translated into a 23% reduction in the risk of death with regorafenib.

Regorafenib also significantly prolonged median progression-free survival (PFS) from 1.7 months to 1.9 months when added to best supportive care (p < 0.000001, 1-sided). The 0.2-month difference in PFS belies the 51% reduction in the risk of disease progression with regorafenib. “The PFS curves shown here clearly [identify] that the median difference in PFS does not fully reflect the efficacy of this drug in this patient population,” Dr. Grothey commented.

Regorafenib appeared to be well tolerated, with side effects considered manageable with dose reduction or supportive care. The most common adverse events of grade 3 or higher included hand-foot skin reaction (16.6%), fatigue (9.6%), diarrhea (7.2%), hypertension (7.2%), and rash/desquamation (5.8%). Approximately 8% of patients assigned to regorafenib permanently discontinued treatment due to adverse events, compared with 1% in the placebo arm.

Findings from the CORRECT trial will be used to support the applications for regulatory approval of regorafenib in the United States and abroad.

CORRECT实验在今年的ASCO上大出风头，虽然从数据上看并不起眼。但做为所有标准方案失效后的单药口服靶向小分子类药物仍有这种效力，这已是多年来肠癌治疗方面前所未有的突破。有鉴于此，Regorafenib很有可能成为新一代的肠癌治疗标准。在没有方案的时候不妨尝试下这个药物。

3. Final results of a multicenter phase II trial assessing sorafenib (S) in combination with irinotecan (i) as second- or later-line treatment in metastatic colorectal cancer (mCRC) patients (pts) with KRAS-mutated tumors (mt; NEXIRI).

Background: The raf kinase inhibitor S is the lead compound in a series of raf signalling pathway inhibitors that could inhibit cell growth and proliferation of pts in KRAS mt pts. The aim of this phase II trial was to evaluate the disease control rate (DCR) of i combined with S as second- or later line treatment (tt) in mCRC pts with KRAS mt. Methods: In the previous phase I, the recommended dose of I was 180 mg/m2 in a bi-weekly regimen with a fixed dose of S (400 mg twice daily) (1 cycle= 2 courses of I). In the phase II, pts received this combination until progression or toxicity. Eligibility criteria included: measurable and unresectable mCRC, age > 18 years, PS ≤ 2, progression after I-based chemotherapy, one or more previous lines and centralized confirmation of KRAS mt in codons 12 or 13 in the primary tumour (PT) or metastases. Primary endpoint was DCR according to RECIST criteria with independent review of CT-scan. Secondary were toxicity, PFS and OS. Tt regimen was considered promising if at least 14 out of 54 pts had DC in a two-stage Simon design. Pharmacokinetic, pharmacogenetic and pathologic studies were also undertaken. Results: Fifty-four pts were included between 06/09 and 12/09 from 10 centers. Median age was 60 yrs (range: 43-80), 59% were males, 46% PS 0, 63% PT in colon. Previous tts were 5FU 100%, I 100%, oxaliplatin 100%, bevacizumab 89%. The median number of cycles was 4 (1-8) and 13 pts (24%) completed at least 6 cycles. No toxic death was seen. Gr 3 toxicities were: hand-foot syndrome 15%, diarrhea 39%, neutropenia 19% and 16% showed Gr 4 neutropenia. In 46 pts (85%) S dose was reduced to 400 mg daily after two courses due to toxicity, then increased again to 800 mg in 55% of pts. The DCR was 64.9% [IC95%, 51-77] in intention to treat (52 evaluable pts). Median PFS and OS were 3.5 [IC95%, 2.0-3.7] and 7.7 months [IC95%, 4.8-9.7], respectively. Conclusions: NEXIRI regimen as second- or later-line tt for mCRC pts with KRAS mt shows promising activity in this heavily pre-treated KRAS mt population. These data justify conducting a randomized phase II/III trial to confirm the efficacy of this combination.

很多晚期肠癌患者因为Kras突变而少了一些治疗手段，多吉美因其广谱的靶点尤其是对raf通路的抑制使得治疗突变型患者变成可能。上述临床就是多吉美联合伊立替康在所有标准治疗失败后的尝试。从数据上看64.9%疾控率还是相当不错的，也给了晚期的患者更多的选择。不过需要注意的是多与伊立联合后的毒性。从上文看有不少是因毒性减量后又增量的。

4. Phase II trial of bevacizumab (B) plus everolimus (E) for refractory metastatic colorectal cancer (mCRC).

Background: For patients (pts) with mCRC, treatment options are absent after progression on 5-FU, oxaliplatin, irinotecan, bevacizumab, and cetuximab/panitumumab. Preclinical data demonstrate combined VEGF and mTOR inhibition has greater antiangiogenic and antitumor activity than either monotherapy, and phase I data demonstrated that the combination of B + E is safe and generally well tolerated. This phase II trial evaluates efficacy and tolerability of B+E in mCRC patients who have progressed on standard therapies. Methods: 50 pts with refractory mCRC were treated with B 10 mg/kg q2 wks and E 10 mg PO QD until progression. Blood, skin, and tumor biopsies pre- and on-treatment were collected for markers of response and resistance. Results: 47 of 50 pts had prior B exposure; 42 pts had previously progressed on B. Median number of prior regimens was 4. Although no complete or partial responses were seen, 46% of pts achieved disease control for a median duration of 6.1 months (mos) (range 2.3-12.6): 8 pts had minor responses (median duration of response 4.1 mos, range 2.3-11.9+) and an additional 15 patients had SD (median duration of response 6.7 mos, range 3.2-12.6+). Three patients with prolonged stable disease have been on treatment > 1 year. There was one grade (Gr) 4 adverse event (AE) of hypokalemia. Noteworthy grade 3 AEs related to treatment were hypertension (n = 7), mucositis/proctitis (n = 3), fistula/abcess (n = 3), bowel perforation (n = 1), azotemia/proteinuria (n = 2), fatigue (n = 2), thrombocytopenia (n = 2), hyperglycemia (n = 6), hypokalemia (n = 6), hypophosphatemia (n = 2), hyperlipidemia (n = 3) and hyperbilirubinemia (n = 2). There was one Gr 3 event each of rhabdomyolysis, neuropathy, volume depletion, prolonged QT interval, GI hemorrhage and neutropenia. Other events of interest were: Gr 1-2 mucositis (68%, n = 34), Gr 1-2 hyperlipidemia (64%, n = 32). Biomarker data is pending. Conclusions: B + E has promising activity in refractory mCRC (even in pts who have progressed on a B-based regimen) with a disease control rate of 46%, suggesting B + E may overcome resistance to B.

依维莫斯做为mTON靶点的抑制剂，近年来受到越来越多的关注。上述临床就是阿瓦联合依维在所有标准治疗失败的尝试。46%的疾控率还是不错的，有甚者用这种治疗模式维持超过了一年。靶向联合用药应该是今后的大势所趋，这里的临床是一次有益的尝试，这只是开始。

看到新希望，辛苦了成长！

5. Clinical, pharmacokinetic and pharmacodynamic evaluations of metronomic UFT and cyclophosphamide plus celecoxib in patients with advanced refractory gastrointestinal cancers

Aims

To evaluate UFT and cyclophosphamide (CTX) based metronomic chemotherapy plus celecoxib (CXB) for the treatment of patients with heavily pre-treated advanced gastrointestinal malignancies.

Methods

Thirty-eight patients received 500&#160;mg/mq2 CTX i.v bolus on day 1 and, from day 2, 50&#160;mg/day CTX p.o. plus 100&#160;mg/twice a day UFT p.o. and 200&#160;mg/twice a day CXB p.o. Tegafur, 5-FU, 5-FUH2, GHB and uracil pharmacokinetics were assessed. Plasma vascular endothelial growth factor (VEGF), soluble VE-cadherin (sVE-C) and thrombospondin-1 (TSP-1) levels were detected by ELISA and real-time PCR of CD133 gene expression on peripheral blood mononuclear cell was also performed.

Results

Seventeen patients (45%) obtained stable disease (SD) with a median duration of 5.8&#160;ms (range, 4.2–7.4). Median progression free survival (PFS) and overall survival (OS) were 2.7&#160;ms (95% CI, 1.6–3.9&#160;ms) and 7.1&#160;ms (95% CI, 4.3–9.9&#160;ms), respectively. No toxicities of grade >1 were observed. Pharmacokinetics of 27 patients (13/14, SD/progressive disease, PD) after the first treatment of UFT revealed that 5-FU AUC and Cmax values greater than 1.313&#160;h&#160;×&#160;μg/ml and 0.501&#160;μg/ml, respectively, were statistically correlated with stabilization of disease and prolonged PFS/OS. VEGF and sVE-C plasma levels were greater in the PD group when compared to SD group. CD133 expression increased only in the PD patients.

Conclusion

Metronomic UFT and CTX with CXB in heavily pre-treated gastrointestinal patients were well tolerated and associated with interesting activity. Potential predictive pharmacokinetic parameters and pharmacodynamic biomarkers have been found.

有意义的尝试, 替加氟片 + 环磷酰胺 + 西乐葆(塞来西布) &#65377;中位的PFS在2.7个月, 中位的OS7.1个月&#65377;疾控率45%  从原文来看, 毒性是可控的&#65377;这是一个没有靶向药并且全口服的方案, 可做为贯序治疗的选择&#65377;

原文参见:
http://www.ncbi.nlm.nih.gov/pmc/ ... 912/?tool=pmcentrez

辛苦啦，成长，年过的如何丫，没看你上线啊

努力学习。、

TOMO   
TOMO是TOMOtherapy(螺旋断层放射治疗系统）的中文译名，此设备还有其它的简称为：拓拇刀、螺旋导航光子刀、TOMO等。

TOMO是集IMRT（调强适形放疗）、IGRT（影像引导调强适形放疗）、DGRT（剂量引导调强适形放疗）于一体，是当今世界上最先进的肿瘤放射治疗设备，其独创性的设计使直线加速器与螺旋CT完美结合，突破了传统加速器的诸多限制，在CT引导下360度聚焦断层照射肿瘤，对恶性肿瘤患者进行高效、精确的治疗。

简述   TOMO是以CT扫描的方式用扇形射野进行螺旋照射实现调强放疗的设备。螺旋TOMO的床和机架类似螺旋CT式连续运动的，滑环机架结构使TOMO可以轻易采集患者治疗摆位的CT图像，并用这一信息实现图像引导。

TOMO的发展史同样也是一个先进科技从学术研究到大学产业合作，最终商业化并大规模应用于临床的故事。  因为TOMO是在每次治疗前都进行MVCT图像扫描，依据GTV变化重新制定计划，所以可明显减少正常组织高剂量照射体积。并且有办法、有能力对付大范围、全身多发转移、中晚期、奇形怪状、极其复杂的肿瘤，甚至可以改变以前“姑息治疗”为“根治性治疗”。  全军肿瘤放疗中心主任夏廷毅教授曾介绍说，放疗主要分为四大部分，即现代放疗“四部曲”：定位、锁定、计算、实施。
  

特点
   
一、TOMO相比于传统疗法，最大的特点就是：肿瘤剂量适形度更高，肿瘤剂量强度调节更准，肿瘤周围正常组织剂量调节更细。
具体体现为：   1、360度旋转，51个弧度，全方位断层扫描照射。在线成像系统确定或精确调整肿瘤位置，数以千计的放射子野以螺旋方式围绕病人实施精确照射。从而可以使高度适形的处方剂量送达靶区，敏感器官的受量大大降低或避免。
2、卓越的图像引导功能。TOMO的成像和治疗采用同一放射源——兆伏级射线，在放疗的同时即可采集CT数据，使放射治疗和螺旋CT流畅结合。  
3、自适应放疗，动态跟踪定位。CT成像探测器会在放疗的同时收集穿透病人身体后的X线，从而推算出肿瘤实际吸收的射线能量，为以后的放疗剂量提供科学准确的参考数据。  
4、治疗范围广，治疗环节少，自动化程度高。TOMO集治疗计划、剂量计算、兆伏级CT 扫描、定位、验证和螺旋放射功能于一体，治疗摆位和验证自动化程度高，花费时间少。   

二、TOMO是至今最好的IMRT系统，且集IGRT与IMRT于一身，用螺旋CT旋转方式摄取图像和治疗肿瘤，并可达到自适应放疗（ART）或DGRT（剂量引导放疗）。