成人软组织肉瘤化疗方案

1、成人软组织肉瘤化疗Contents OverviewDrugsTreatmentneoadjuvant chemotherapyadjuvant chemotherapyAdvanced or metastatic diseases chmeotherapytargeted therapyContents OverviewDrugsTreatmentneoadjuvant chemotherapyadjuvant chemotherapytargeted therapySarcomas constitute a heterogeneous group of rare solid tumors

2、ofmesenchymal cell origin with distinct clinical and pathological features成人软组织肉瘤（Soft tissue sarcomas ，STSs），包括一组发病相对较少，组织学多样的恶性肿瘤。起源中胚层和外胚层。占成人恶性肿瘤的1%和儿童恶性肿瘤的5%。尚无特别有效的治疗方法，需多学科联合。 Categories Sarcomas of soft tissues (including fat, muscle, nerve and nerve sheath, blood vessels, and other connecti

3、ve tissues) Sarcomas of bone.The anatomic site of the primary diseaseExtremities (60%) the trunk (19%) retroperitoneum (15%) head and neck (9%)Risk factorsAge. Soft tissue sarcomas can occur at any age, but overall are more common in older adults. The average age at diagnosis is 57 years. Certain ty

4、pes of sarcomas are more common in children, however. Chemical exposure. Being exposed to certain chemicals, such as vinyl chloride and dioxin, can increase the risk of soft tissue sarcomas. Radiation exposure. Previous radiation treatment for other cancers can increase the risk of soft tissue sarco

5、mas.Signs and symptomsa new lump or a lump that is growing anywhere in the body may or may not cause pain may include abdominal swelling or a lump in the abdomennausea vomiting heartburn abdominal pain blood in vomit or stoolAdult soft tissue sarcoma diagnosedIncisional biopsy: The removal of part o

6、f a lump or a sample of tissue. Core biopsy: The removal of tissue using a wide needle. Excisional biopsy: The removal of an entire lump or area of tissue that doesnt look normal.core needle biopsyPathology and stagingthe type of soft tissue sarcoma the stage of the cancer (how far the cancer has pr

7、ogressed) the grade of the tumour (how abnormal the cancer cells look and behave) Pleomorphic sarcoma also known as malignant fibrous histiocytoma (MFH) GISTsLiposarcoma leiomyosarcoma synovial sarcoma malignant peripheral nerve sheath tumorsIncidence of Soft Tissue Sarcoma Subtypes (1978-2001)Histo

8、logic Subtype%平滑肌肉瘤23.9恶性纤维组织细胞瘤17.1脂肪肉瘤11.5皮肤纤维肉瘤10.5横纹肌肉瘤4.6血管肉瘤4.1Sites of MetastasisGadd M, et al, Ann Surg, 1993Contents OverviewDrugsTreatmentneoadjuvant chemotherapyadjuvant chemotherapytargeted therapyChemotherapy Single Agents DoxorubicinIfosfamideDacarbazineGemcitabinePaclitaxelDocetaxelCh

9、emotherapyPemetrexedTemozlomideIrinotecanTopotecanPelyated liposmal doxorubicinTrabectedinDoxorubicinThe single agent response rates (RR) are in the range of 20 to 30% survival in the range of 7.7 -12 months The best response rates are seen with dosages in the range of 75 mg/m 2 to 90 mg/m 2 Doxorub

10、icinEpirubicin is a less cardiotoxic analog of doxorubicin, which failed to demonstrate any benefit as compared to doxorubicinliposomal doxorubicin can be used in patients where doxorubicin is contraindicated, but the response rates of this drug as a single agent are lower than the conventional doxo

11、rubicin. Ifosfamidea dose- response relationship and higher doses can be used as it lacks cardiotoxicity monotherapy with an identical dose (9 g/m 2 ), given over three days, by either continuous infusion or three-hour infusions daily Dacarbazinein combination with doxorubicin and ifosfamide (MAID)

12、given as a short infusion of 1.2 g/m 2 over 20 minutes with the availability of effective antiemetics.TemozolamideTemozolamide, the oral equivalent of dacarbazine, appears to have the same activity against leiomyosarcoma as well.Trabectedin (Ecteinascidin-743, ET743, Yondelis) This tetrahydroisoquin

13、soline molecule was derived originally from a tunicate, or sea squirt, Ecteinascidia turbinate (found in the Carribbean and Mediterranean waters)A pooled analysis of 183 patients from the three single arm phase II studies1.5 mg/m 2 administered as a 24-hour infusion once every three weeksIn this ana

14、lysis though the ORR was only 7.7%, the rate of tumor control (i.e., ORR plus minor responses plus disease stabilization) was 51%. Contents OverviewDrugsTreatmentneoadjuvant chemotherapyadjuvant chemotherapyAdvanced or metastatic diseases chmeotherapytargeted therapyTreatmentsurgery Surgery is the m

15、ost common treatment for many soft tissue sarcomas. Depending on the size and location of the sarcoma, all or part of the tumour may be removed. If the whole tumour is removed, a wide margin of healthy tissue around it is also removed. In many cases, limb-sparing surgery can be done for a soft tissu

16、e sarcoma that occurs in an arm or leg and amputation can be avoided. However, in some cases, soft tissue sarcoma in a limb may require the limb to be amputated.radiation therapy Radiation therapy may be used before or after surgery or, less commonly, instead of surgery.chemotherapy If the soft tiss

17、ue sarcoma has spread to other parts of the body, chemotherapy may be used to control the cancer and relieve symptoms. Chemotherapy is sometimes used before surgery to shrink a tumour or after surgery to help reduce the chance of the cancer recurring.软组织肉瘤: 传统治疗局限期肉瘤: 扩大范围的手术为标准治疗对于高度或中度复发风险或者切缘阳性的软

18、组织肉瘤而言，通常需行术后放疗1三维适形放疗, 近距离放疗, 或调强放疗1. Clark MA, et al. N Engl J Med. 2005;353:701-711.2. Wunder JS, et al. Lancet Oncol. 2007;8:513-524.但是仍有50%的软组织肉瘤患者会出现远处转移2 Surgical ManagementMainstay of treatment for all STS of the extremity is wide local excision (+/-) XRTAdjuvant/neoadjuvantRole of neoadjuva

19、nt chemotherapyWiden bloc resection 1-2 cm margins in all directions Limiting factors:neurovascular juxtapositionBony juxtapositionRadical Surgical MarginAmputation新辅助化疗134例患者，单纯手术组与新辅助化疗+手术，每组67例。成人高危STSs（肿瘤 or =8 cm ，不论分级如何；或分级为 II/III，但肿瘤 5 cm，以及深部肿瘤 Role of Adjuvant ChemotherapySarcoma meta-anal

20、ysis collaboration, lancet, 1997 1568 patients from 14 studies Median follow-up 9.4 years 10-yr. DFS improved from 45 to 55% (p = 0.0001) Local 10-yr. DFS improved from 75 to 81% (p = 0.016) OS only improved from 50 to 54% (p = 0.12)Data does not support routine use of adjuvant chemotherapy outside

21、a clinical trialAdjuvant Chemotherapy TrialsMeta-Analysis #2Metastatic diseases chemotherapyAn EORTC STBSG studyA total of 2,185 patients with advanced soft tissue sarcomas who had been treated in seven clinical trialsResultsResultsMetastaic Soft-Tissue Sarcomas chemotherapyMetastaic Soft-Tissue Sar

22、comas chemotherapyDose-intensive chemotherapy with growth factor or autologous bone marrow or stem-cell transplant support in first-line treatment of advanced or metastatic adult soft tissue sarcoma: a clinical practice guideline Dose-intensive chemotherapy with growth factor support is not recommen

23、ded in the first-line treatment of patients with inoperable locally advanced or metastatic soft tissue sarcoma. The data are insufficient to support the use of high-dose chemotherapy with autologous bone marrow or stem-cell transplantation as first-line treatment in this group of patients. Eligible

24、patients should be encouraged to enter clinical trials assessing novel approaches or compounds. Combination Regimens beyond Ifosfamide and Adriamycin Fixed-dose rate gemcitabine plus docetaxel as first-line therapyfor metastatic uterine leiomyosarcoma: a Gynecologic OncologyGroup phase II trialForty

25、-two women enrolled, with 39 evaluable for response900 mg/m2 over 90 minutes, d1 and d8 ; docetaxel 100 mg/m2 on day 8, With granulocyte growth factor support day nine of a 21-day cycle.Response ORR 15 of 42 patients (35.8% overall; CR 4.8%, PR 31%, 90% CI 23.5 to 49.6%), 11 (26.2%) SDmedian progres

26、sion-free survival (PFS) 4.4 months (range 0.4 to 37.2+ months)Median overall survival 16+ months (range: 0.4 41.3 months)Fixed-dose rate gemcitabine plus docetaxel as second-linetherapy for metastatic uterine leiomyosarcoma: a GynecologicOncology Group phase II studyForty-one women enrolled, with 4

27、8 evaluable for response unresectable uterine leiomyosarcoma progressing after prior cytotoxic therapygemcitabine 900 mg/m2,d1and d8 90 minutes,docetaxel 100 mg/m2 d8 , 21-day cycle with granulocyte growth factor CR 6.3% (3/48), PR 20.8% (10/48) ORR 27% (95% confidence interval 15.3%41.8%).An additi

28、onal 50% (24/48) SD, clinical benefit rate of 77%. Median PFS for all 48 patients was 6.7+ months(range 0.7 27+ months)Adverse eventsThe predominant toxicity was myelosuppression leukopenia grade 3 (14.5%), grade 4 (8.3%) thrombocytopenia grade 3 (29%), grade 4 (10.4%) neutropenia grade 3 (12.5%), g

29、rade 4 (8.3%) anemia grade 3 (20.8%), grade 4 (4.2%).Randomized Phase II Study of Gemcitabine and Docetaxel Compared With Gemcitabine Alone in Patients With Metastatic Soft Tissue Sarcomas: Results of Sarcoma Alliance for Research Through Collaboration Study 002 Fixed dose rate 10mg/m2/10min infusin

30、 gemcitabine at 1200mg/m2 d1 and d8 in gemcitabine armGem-Doc arm,gemcitabne dose 900mg/m2 fixed dose rate infusion 90 min,d1 and d8;docetaxel 100mg/m2 d1 60minRepeat every 21daysInvestigational New Drugs (targeted therapy)Mammalian target of rapamycin (mTOR) inhibitorsmTOR inhibitors in clinical de

31、velopmentThree rapamycin analogs: CCI-779 (temsirolimus), RAD001 (everolimus), and AP23573 (deforolimus) Insulin like growth factor 1 receptor (IGF-IR) inhibitorsOthersAngiogenesis and STSsAngiogenesis plays an important role in the growth and dissemination of STSs the VEGF / VEGFR pathway plays the

32、 most important role High VEGF expression is an independent poor prognostic factor for increased risk of metastases and decreased overall survival Compassionate use of bevacizumab (Avastin) in children and young adults with refractory or recurrent solid tumors Bevacizumab was administered at 510 mg/

33、kgbody weight intravenously every 23 weeks, Most patients received chemotherapy in addition to bevacizumabOthers 苹果酸舒尼替尼 索坦：药物结构小分子吲哚酮类化合物分子式：C22H27FN4O2C4H6O5分子量：532.6 ATP位点竞争性抑制剂抑制磷酸化和激活阻断信号传导NHONHF NHONOHCOOHHOOCHSutent Product Monograph舒尼替尼主要作用靶点信号传导通路肿瘤细胞效应肿瘤血管效应VEGFR-1,-2,-3PDGFR-*PDGFR-RETCSF1RFLT3（wild-type）KIT *对于GIST而言尤其重要；*对于GIST/乳腺癌和小细胞肺癌而言尤其重要舒尼替尼同时具有抗肿瘤血管生成与抗肿瘤细胞增殖双重效应Sandrine F, et al. Nature, 2007Table 1 Summary of the biological effects of sunitinib against target receptorsReceptorBiochemical K1 (M)Cellular IC50 (M)Receptor phosphorylationProliferationVEGFR1*0.002Not det