软组织肿瘤.ppt

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1、成人软组织肉瘤化疗,Contents,OverviewDrugsTreatmentneoadjuvant chemotherapyadjuvant chemotherapyAdvanced or metastatic diseases chmeotherapytargeted therapy,Contents,OverviewDrugsTreatmentneoadjuvant chemotherapyadjuvant chemotherapytargeted therapy,Sarcomas constitute a heterogeneous group of rare solid tumo

2、rs 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 connective

3、 tissues)Sarcomas of bone.,The anatomic site of the primary disease,Extremities(60%)the trunk(19%)retroperitoneum(15%)head and neck(9%),Risk factors,Age.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 types of sar

4、comas 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 sarcomas.,Signs and sy

5、mptoms,a 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 stool,Adult soft tissue sarcoma diagnosed,Incisional biopsy:The removal of part of a lump or a

6、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 biopsy,Pathology and staging,the type of soft tissue sarcoma the stage of the cancer(how far the cancer has progressed)the gra

7、de 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 tumors,Incidence of Soft Tissue Sarcoma Subtypes(1978-2001),Sites of Metastasis,Gadd

8、 M,et al,Ann Surg,1993,Contents,OverviewDrugsTreatmentneoadjuvant chemotherapyadjuvant chemotherapytargeted therapy,Chemotherapy,Single Agents DoxorubicinIfosfamideDacarbazineGemcitabinePaclitaxelDocetaxel,Chemotherapy,PemetrexedTemozlomideIrinotecanTopotecanPelyated liposmal doxorubicinTrabectedin,

9、Doxorubicin,The 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,Doxorubicin,Epirubicin is a less cardiotoxic analog of doxorubicin,which failed to demonstrate any b

10、enefit 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 doxorubicin.,Ifosfamide,a dose-response relationship and higher doses can be used as it lacks card

11、iotoxicity monotherapy with an identical dose(9 g/m 2),given over three days,by either continuous infusion or three-hour infusions daily,Dacarbazine,in combination with doxorubicin and ifosfamide(MAID)given as a short infusion of 1.2 g/m 2 over 20 minutes with the availability of effective antiemeti

12、cs.,Temozolamide,Temozolamide,the oral equivalent of dacarbazine,appears to have the same activity against leiomyosarcoma as well.,Trabectedin(Ecteinascidin-743,ET743,Yondelis),This tetrahydroisoquinsoline molecule was derived originally from a tunicate,or sea squirt,Ecteinascidia turbinate(found in

13、 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 analysis though the ORR was only 7.7%,the rate of tumor control(i.e.,ORR plus minor responses plus disease

14、stabilization)was 51%.,Contents,OverviewDrugsTreatmentneoadjuvant chemotherapyadjuvant chemotherapyAdvanced or metastatic diseases chmeotherapytargeted therapy,Treatment,surgery Surgery is the most common treatment for many soft tissue sarcomas.Depending on the size and location of the sarcoma,all o

15、r 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 tissue sarcoma that occurs in an arm or leg and amputation can be avoided.However,in some cases,soft tissue sarcoma i

16、n 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 tissue sarcoma has spread to other parts of the body,chemotherapy may be used to control the cancer and relieve symptoms.

17、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

18、:513-524.,但是仍有50%的软组织肉瘤患者会出现远处转移2,Surgical Management,Mainstay of treatment for all STS of the extremity is wide local excision(+/-)XRTAdjuvant/neoadjuvantRole of neoadjuvant chemotherapyWiden bloc resection 1-2 cm margins in all directions Limiting factors:neurovascular juxtapositionBony juxtaposit

19、ion,Radical Surgical Margin,Amputation,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 8 cm；或分级 II/III局部复发的肿瘤；或分级 II/III肿瘤在6周内所手术未完全切除需要再次手术）。doxorubicin 50 mg/m(2)intravenous(i.v.)bolus and ifosfamide 5 g/m(2)(24 h infusion),Q3W3。化疗没有影响预定的手术以及伤口愈合。中位随访7.3年，5年DFS新辅助化疗组56

20、%，没有新辅助化疗组52%；5年OS分别为 65 and 64(P=0.2204)。,新辅助热灌注化疗,EORTC，Phase II.59例初治或复发高危STSs.4疗程 etoposide,ifosfamide,and doxorubicin+或不+RHT.联合组ORR28.7%，单化组12.6%。中位PFS,热灌注化疗组45.3%，单化组 23.7%。,辅助化疗,Metal分析提示辅助化疗有一定的价值，但一些大的研究（EORTC adjuvant trial）结果阴性，因此，STSs辅助化疗价值仍有一些争论ESMO 建议高危患者给予辅助化疗高危因素包括：G2-G3,肿瘤 5 cm，以及深部

21、肿瘤,Role of Adjuvant Chemotherapy,Sarcoma meta-analysis 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 us

22、e of adjuvant chemotherapy outside a clinical trial,Adjuvant Chemotherapy Trials,Meta-Analysis#2,Metastatic diseases chemotherapy,An EORTC STBSG study,A total of 2,185 patients with advanced soft tissue sarcomas who had been treated in seven clinical trials,Results,Results,Metastaic Soft-Tissue Sarc

23、omas chemotherapy,Metastaic Soft-Tissue Sarcomas chemotherapy,Dose-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

24、 with growth factor support is not recommended 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 trea

25、tment in this group of patients.Eligible 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 Gynec

26、ologic OncologyGroup phase II trial,Forty-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

27、%),11(26.2%)SDmedian progression-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 study,Forty-one

28、women enrolled,with 48 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.

29、8%).An additional 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 events,The 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%),gr

30、ade 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 gemci

31、tabine 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 21days,Investigational New Drugs(targeted therapy),Mammalian target of rapamycin(mTOR)inhibitorsmTOR inhibitors in clinical developme

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

33、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/kgbody weight intr

34、avenously every 23 weeks,Most patients received chemotherapy in addition to bevacizumab,Others,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,Sutent Product Monograph,舒尼替尼主要作用靶点,*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.Nat

35、ure,2007,舒尼替尼治疗腺泡软组织肉瘤,S.Stacchiotti,et al.Annal of Oncology,2011 Feb,舒尼替尼治疗非GIST软组织肉瘤,晚期/转移性非GIST软组织肉瘤,既往可接受1-2个化疗方案失败，ECOG PS 0-2(N=53),持续治疗直至疾病进展,舒尼替尼37.5 mg,每天持续口服,II期临床：多中心、前瞻性舒尼替尼持续37.5mg口服Arm A:血管结缔组织肿瘤(n=18)平滑肌肉瘤,脊索瘤,血管肉瘤,孤立的纤维瘤,硬纤维瘤,内膜肉瘤Arm B:高分化多形性肉瘤(n=21)恶性纤维组织细胞瘤,未分型肉瘤,未分化肉瘤,滑膜肉瘤,脂肪肉瘤,粗纤

36、维增生性小圆细胞肿瘤,脂肪肉瘤,腺泡软组织肉瘤Arm C:脊索瘤(n=9),J George,et al.JCO 2009,Vol 27,II期临床：舒尼替尼治疗STS疗效,II期临床提示舒尼替尼对STS具有抗肿瘤活性根据肿瘤代谢评价疗效PR 48%,SD 52%,J George,et al.JCO 2009,Vol 27,Conclusions,Sarcomas are a rare,heterogeneous group of diseases.Existing challenges need to be overcome.Progress is being made.,Cont,The

37、 data for neoadjuvant chemotherapy is robust if regional hyperthermia is added to the combination of etoposide,ifosfamide,and adriamycin Adjuvant chemotherapy with single agent adriamycin should be considered if high-risk prognostic features are present,metastatic STSs or developing metastatic disea

38、se after a treatment-free interval will require a multidisciplinary discussion and chemotherapy with a single agent adriamycin or combination therapy of ifosfamide and adriamycin Novel therapeutic approaches are needed.Participation in clinical trials of newer targeted therapies like mTOR inhibitors,IGF-1R blockers,and VEGF inhibitors should be encouraged.The data for these newer drugs appear promising,Cont,