软组织肿瘤课件.ppt

1、软组织肿瘤软组织肿瘤l成人软组织肉瘤（成人软组织肉瘤（Soft tissue sarcomas，STSs），包），包括一组发病相对较少，组织学多样的恶性肿瘤。括一组发病相对较少，组织学多样的恶性肿瘤。l起源中胚层和外胚层。起源中胚层和外胚层。l占成人恶性肿瘤的占成人恶性肿瘤的1%和儿童恶性肿瘤的和儿童恶性肿瘤的5%。l尚无特别有效的治疗方法，需多学科联合。尚无特别有效的治疗方法，需多学科联合。Categories lSarcomas of soft tissues(including fat,muscle,nerve and nerve sheath,blood vessels,and oth

2、er connective tissues)l Sarcomas of bone.The anatomic site of the primary diseaselExtremities(60%)l the trunk(19%)l retroperitoneum(15%)lhead and neck(9%)Risk factorslAge.Soft tissue sarcomas can occur at any age,but overall are more common in older adults.The average age at diagnosis is 57 years.Ce

3、rtain types of sarcomas are more common in children,however.lChemical exposure.Being exposed to certain chemicals,such as vinyl chloride and dioxin,can increase the risk of soft tissue sarcomas.lRadiation exposure.Previous radiation treatment for other cancers can increase the risk of soft tissue sa

4、rcomas.Signs and symptomsla 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 abdomenlnausea lvomiting lheartburn labdominal pain lblood in vomit or stoolAdult soft tissue sarcoma diagnosedlIncisional biopsy:The removal

5、of part of a lump or a sample of tissue.lCore biopsy:The removal of tissue using a wide needle.lExcisional biopsy:The removal of an entire lump or area of tissue that doesnt look normal.core needle biopsyPathology and staginglthe type of soft tissue sarcoma lthe stage of the cancer(how far the cance

6、r has progressed)lthe grade of the tumour(how abnormal the cancer cells look and behave)lPleomorphic sarcoma also known as malignant fibrous histiocytoma(MFH)l GISTslLiposarcomal leiomyosarcomal synovial sarcomal malignant peripheral nerve sheath tumorsIncidence of Soft Tissue Sarcoma Subtypes(1978-

7、2001)Sites of MetastasisGadd M,et al,Ann Surg,1993Contents lOverviewlDrugslTreatmentneoadjuvant chemotherapyadjuvant chemotherapytargeted therapyChemotherapy lSingle Agents DoxorubicinIfosfamideDacarbazineGemcitabinePaclitaxelDocetaxelChemotherapyPemetrexedTemozlomideIrinotecanTopotecanPelyated lipo

8、smal doxorubicinTrabectedinDoxorubicinlThe single agent response rates(RR)are in the range of 20 to 30%lsurvival in the range of 7.7-12 months lThe best response rates are seen with dosages in the range of 75 mg/m 2 to 90 mg/m 2 DoxorubicinlEpirubicin is a less cardiotoxic analog of doxorubicin,whic

9、h failed to demonstrate any benefit as compared to doxorubicinlliposomal 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.Ifosfamidela dose-response relationship and higher doses

10、 can be used as it lacks cardiotoxicity lmonotherapy with an identical dose(9 g/m 2),given over three days,by either continuous infusion or three-hour infusions daily Dacarbazinelin combination with doxorubicin and ifosfamide(MAID)lgiven as a short infusion of 1.2 g/m 2 over 20 minutes with the avai

11、lability of effective antiemetics.TemozolamidelTemozolamide,the oral equivalent of dacarbazine,appears to have the same activity against leiomyosarcoma as well.Trabectedin(Ecteinascidin-743,ET743,Yondelis)lThis tetrahydroisoquinsoline molecule was derived originally from a tunicate,or sea squirt,Ect

12、einascidia turbinate(found in the Carribbean and Mediterranean waters)lA pooled analysis of 183 patients from the three single arm phase II studiesl1.5 mg/m 2 administered as a 24-hour infusion once every three weekslIn this analysis though the ORR was only 7.7%,the rate of tumor control(i.e.,ORR pl

13、us minor responses plus disease stabilization)was 51%.Contents lOverviewlDrugslTreatmentneoadjuvant chemotherapyadjuvant chemotherapyAdvanced or metastatic diseases chmeotherapytargeted therapyTreatmentlsurgery Surgery is the most common treatment for many soft tissue sarcomas.Depending on the size

14、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 tissue sarcoma that occurs in an arm or leg and amputation can be avoided.However,in

15、 some cases,soft tissue sarcoma in a limb may require the limb to be amputated.lradiation therapy Radiation therapy may be used before or after surgery or,less commonly,instead of surgery.lchemotherapy If the soft tissue sarcoma has spread to other parts of the body,chemotherapy may be used to contr

16、ol 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.软组织肉瘤软组织肉瘤:传统治疗传统治疗l局限期肉瘤:扩大范围的手术为标准治疗l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;353:7

17、01-711.2.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 ManagementlMainstay of treatment for all STS of the extremity is wide local excision(+/-)XRT Adjuvant/neoadjuvantRole of neoadjuvant chemotherapylWiden bloc resection 1-2 cm margins in all directions Limiting facto

18、rs:neurovascular juxtaposition Bony juxtapositionRadical Surgical MarginAmputation新辅助化疗新辅助化疗l134例患者，单纯手术组与新辅助化疗例患者，单纯手术组与新辅助化疗+手术，每组手术，每组67例。例。l成人高危成人高危STSs（肿瘤（肿瘤 or=8 cm，不论分级如何；或分级为，不论分级如何；或分级为 II/III，但肿瘤但肿瘤 5 cm，以及深部肿瘤，以及深部肿瘤 Role of Adjuvant ChemotherapylSarcoma meta-analysis collaboration,lancet

19、,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)lData does not support routine use of adjuvant chemotherapy outside a clinical trialAdjuvant Chemotherapy T

20、rialsMeta-Analysis#2Metastatic diseases chemotherapyAn EORTC STBSG studylA total of 2,185 patients with advanced soft tissue sarcomas who had been treated in seven clinical trialsResultsResultsMetastaic Soft-Tissue Sarcomas chemotherapyMetastaic Soft-Tissue Sarcomas chemotherapyDose-intensive chemot

21、herapy 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 lDose-intensive chemotherapy with growth factor support is not recommended in the first-line treatment of pati

22、ents with inoperable locally advanced or metastatic soft tissue sarcoma.lThe 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.lEligible patients should be encouraged to enter

23、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 triallForty-two women enrolled,with 39 evaluable fo

24、r responsel900 mg/m2 over 90 minutes,d1 and d8;docetaxel 100 mg/m2 on day 8,lWith granulocyte growth factor support day nine of a 21-day cycle.Response lORR 15 of 42 patients(35.8%overall;CR 4.8%,PR 31%,90%CI 23.5 to 49.6%),l11(26.2%)SDlmedian progression-free survival(PFS)4.4 months(range 0.4 to 37

25、.2+months)lMedian 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 studylForty-one women enrolled,with 48 evaluable for response unresectable uterine leiomyosar

26、coma progressing after prior cytotoxic therapylgemcitabine 900 mg/m2,d1and d8 90 minutes,ldocetaxel 100 mg/m2 d8,21-day cycle lwith granulocyte growth factor CR 6.3%(3/48),PR 20.8%(10/48)ORR 27%(95%confidence interval 15.3%41.8%).An additional 50%(24/48)SD,clinical benefit rate of 77%.Median PFS for

27、 all 48 patients was 6.7+months(range 0.7 27+months)Adverse eventslThe predominant toxicity was myelosuppressionl leukopenia grade 3(14.5%),grade 4(8.3%)l thrombocytopenia grade 3(29%),grade 4(10.4%)l neutropenia grade 3(12.5%),grade 4(8.3%)lanemia grade 3(20.8%),grade 4(4.2%).Randomized Phase II St

28、udy 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 lFixed dose rate 10mg/m2/10min infusin gemcitabine at 1200mg/m2 d1 and d8 in gemcitabine armlGem-Doc arm,gemcitab

29、ne dose 900mg/m2 fixed dose rate infusion 90 min,d1 and d8;docetaxel 100mg/m2 d1 60minlRepeat every 21daysInvestigational New Drugs(targeted therapy)lMammalian target of rapamycin(mTOR)inhibitorsmTOR inhibitors in clinical development Three rapamycin analogs:CCI-779(temsirolimus),RAD001(everolimus),

30、and AP23573(deforolimus)lInsulin like growth factor 1 receptor(IGF-IR)inhibitorslOthersAngiogenesis and STSslAngiogenesis plays an important role in the growth and dissemination of STSs lthe VEGF/VEGFR pathway plays the most important role lHigh VEGF expression is an independent poor prognostic fact

31、or 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 intravenously every 23 weeks,Most patients received chemotherapy in

32、addition to bevacizumabOthers 苹果酸舒尼替尼苹果酸舒尼替尼 索坦索坦：药物结构：药物结构l小分子吲哚酮类化合物小分子吲哚酮类化合物l分子式：分子式：C22H27FN4O2C4H6O5l分子量：分子量：532.6 lATP位点竞争性抑制剂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

33、应抗肿瘤细胞增殖双重效应Sandrine F,et al.Nature,2007舒尼替尼治疗腺泡软组织肉瘤舒尼替尼治疗腺泡软组织肉瘤S.Stacchiotti,et al.Annal of Oncology,2011 Feb舒尼替尼治疗非舒尼替尼治疗非GIST软组织肉瘤软组织肉瘤晚期/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)持续治疗直持续治疗直至疾病进展至疾病进展舒尼替尼舒尼替尼37.5 mg,每天持续口服lII期临床：多中心、前瞻性舒尼替尼持续期临床：多中心、前瞻性舒尼替尼持续37.5mg口服口服 Arm A:血管结缔组织肿瘤血管结缔组织

34、肿瘤(n=18)平滑肌肉瘤平滑肌肉瘤,脊索瘤脊索瘤,血管肉瘤血管肉瘤,孤立的纤维瘤孤立的纤维瘤,硬纤维瘤硬纤维瘤,内膜肉内膜肉瘤瘤 Arm B:高分化多形性肉瘤高分化多形性肉瘤(n=21)恶性纤维组织细胞瘤恶性纤维组织细胞瘤,未分型肉瘤未分型肉瘤,未分化肉瘤未分化肉瘤,滑膜肉瘤滑膜肉瘤,脂肪肉脂肪肉瘤瘤,粗纤维增生性小圆细胞肿瘤粗纤维增生性小圆细胞肿瘤,脂肪肉瘤脂肪肉瘤,腺泡软组织肉瘤腺泡软组织肉瘤 Arm C:脊索瘤脊索瘤(n=9)J George,et al.JCO 2009,Vol 27II期临床：舒尼替尼治疗期临床：舒尼替尼治疗STS疗效疗效lII期临床提示舒尼替尼对STS具有抗肿瘤活

35、性l根据肿瘤代谢评价疗效PR 48%,SD 52%J George,et al.JCO 2009,Vol 27Conclusions l Sarcomas are a rare,heterogeneous group of diseases.l Existing challenges need to be overcome.l Progress is being made.ContlThe data for neoadjuvant chemotherapy is robust if regional hyperthermia is added to the combination of eto

36、poside,ifosfamide,and adriamycin lAdjuvant chemotherapy with single agent adriamycin should be considered if high-risk prognostic features are present lmetastatic STSs or developing metastatic disease after a treatment-free interval will require a multidisciplinary discussion and chemotherapy with a

37、 single agent adriamycin or combination therapy of ifosfamide and adriamycin lNovel 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