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又是个阴沉的早晨,因为科里来了位年轻患者,我们的肿瘤科,很少来年轻人,每次见到那朝气蓬勃的脸,看到他们充满希望和热情的眼睛,我总是心里一紧又有些无奈。这次也不例外,是一位右腿疼痛了半个多月的女孩,平时喜欢打羽毛球,以为是扭伤了,可是膝盖越来越肿,到医院一拍片,就发现了一个大肿瘤,很快穿刺结果出来,病理是骨肉瘤,也就是骨头上的肉瘤。

今天我们就借此讲讲肉瘤吧。肉瘤是起源于骨和骨外结缔组织(包括外周神经系统)的恶性肿瘤。肉瘤可起源于任何部位的间叶组织。软组织肉瘤(soft tissue sarcoma, STS)并不常见。在美国,每年诊断出13,000余例,在全部新诊断的恶性肿瘤中占比不到1%[1],中国报告的软组织肉瘤发病率约为2.38/10万,每年新发病例约4万人。一般而言,必须手术切除才可能治愈,但推荐存在肢体或浅表躯干(胸壁、侧腰、腹壁和脊柱旁肌肉组织)STS的患者要联合放疗,以最大程度降低局部复发风险,并尽可能保留功能和改善长期生存质量。经过所有这些治疗后,仍然有大量病人会复发,所以是预后不好的一个病种。

由于STS罕见且常需要多学科治疗,最好在具有肉瘤治疗专业技术的中心评估和治疗,该中心应该有病理科、肿瘤外科、骨外科、整形外科、成人或儿童肿瘤内科、肿瘤放射科及理疗科。STS的多学科治疗方法可优化治疗计划,减少重复诊断性检查,以及缩短接受根治性治疗方案的等待时间。

此外,亚专科医师提供的专业技术可改善临床结局。例如,一项研究根据患者转诊到瑞典南部医疗保健区(South Sweden Health Care Region)肿瘤中心的时间,评估了375例肢体和躯干STS患者的结局[2]。从未转诊的患者和仅在根治性手术后转诊的患者局部复发率分别是术前转诊患者的2.4倍和1.3倍。

今天这个病人是膝盖的骨肉瘤,属于肢体肉瘤。主要治疗目标是实现长期生存、避免局部复发、最大程度保留功能和尽可能减少并发症。由于各种不同解剖部位受累、组织学范围,以及肿瘤级别和大小的差异,存在多种多样的临床情况。因此,大多数患者必须个体化治疗。下列建议可作为一般治疗指南:

●对于身体和技术条件允许手术的大多数肢体STS患者,我们推荐采用手术+放疗。大多数情况下,与单独进行根治性或扩大切除手术或者放疗相比,联合治疗后肿瘤得到控制的可能性更高,且晚期功能和外观结果更好。我们必须考虑患者的功能状态、肿瘤行为的异质性和肿瘤部位,对肉瘤进行个体化多学科治疗。

术前和术后放疗的肿瘤学结局相似,但毒性反应有差异[3]。

●除了控制肿瘤,治疗肉瘤时还必须优先保留功能,尤其是肢体肉瘤。目前对比各种治疗的随机试验很少。对于中至高级别较大(>5cm)肿瘤患者,若无法参与试验,但健康状况适合且体能状态良好,我们认为可以用放化疗来替代单独放疗。尚未明确最佳的放化疗方法,治疗选择通常取决于机构的专业能力、经验和偏好。

另外,若患者存在局部晚期或复发性较大肢体STS,可给予全身性新辅助化疗,并联合区域性热疗或区域性(动脉内)操作,例如隔离肢体输注和隔离肢体灌注。这些治疗尚未广泛应用,但若有条件使用,则有可能为患者保肢。

●辅助化疗对常见成人肢体STS的益处仍有争议,其适应证或具体益处也缺少共识。应考虑患者的体能状态、共存疾病因素(包括年龄)、疾病部位、肿瘤大小和组织学亚型,个体化分析辅助化疗的适宜性。必须权衡潜在益处和预期的治疗相关毒性,包括较年轻患者的不孕不育、心肌病、肾脏损伤、第二癌症和对生存质量的总体影响。

我们的方法与以下组织发布的肢体和躯干软组织肿瘤多学科治疗共识指南一致:美国放射肿瘤学学会(American Society for Radiation Oncology, ASTRO)[4]、欧洲肿瘤内科学会(European Society for Medical Oncology, ESMO)[5]和美国国家综合癌症网络(National Comprehensive Cancer Network, NCCN)[6]。

切除 — 对于几乎所有肢体STS患者,必须对原发肿瘤进行广泛手术切除,即原发性肿瘤完全整块切除,不切入肿瘤组织,并有充分的正常组织边缘完全包绕肿瘤。对于大多数患者,可以切除肿瘤并获得充分的手术切缘,同时保留有功能的肢体;但对于小部分患者,可能最好选择一期截肢术。我们这个病人,因为是膝关节的大肿瘤,所以需要做整个膝关节切除,和人工关节置换。好在这个手术非常成熟了,术后正常走路是没有问题的。


手术技术 — 若有肿瘤假包膜,应围绕假包膜以外明显正常的未受累组织进行原发肿瘤的局部扩大切除(即,切除整块肿瘤)。

如果切到了肿瘤(即,病灶内手术)或切除不充分,可导致切除后有肉眼可见或显微镜下肿瘤残留,则即便联合放疗,局部失败率也较高。手术切缘状态是影响局部控制的最重要外科因素,但尚不清楚最有利于局部控制的确切阴性边缘宽度(厚度)。“充分”切缘的定义可能取决于组织类型。例如,筋膜切缘可以比肌肉或脂肪的切缘窄。大多数医生推荐,如果仅行手术,则切缘在各个方向的宽度至少应为1cm或包含筋膜屏障,但极少能在肿瘤四周均获得此类型切缘,尤其是神经血管束周围。如果采用手术+放疗,一般认为手术切缘宽度更薄不会影响局部控制。

由于肉瘤扩散到淋巴结并不常见,故在大多数病例中,仅当有临床或影像学证据表明存在区域淋巴节转移时才推荐行区域淋巴结清扫。


放疗 — 放疗+切除术可以减少截肢的必要,增加切除肉瘤的可能性,并能维持可接受的功能性结局和癌症结局。对于大多数STS患者,与单用保肢手术或放疗相比,两者联合治疗能实现更好的局部控制,尽管并不能改善生存。

除了改善肢体STS的局部控制,辅助放疗对保肢率也有重要影响。在20世纪70年代,多达一半的肢体STS患者进行截肢。随着放疗和先进重建技术的出现,截肢率已降到1%左右,而总生存率未明显下降[11-16]。

两项随机试验分析了保肢手术+放疗的益处,均显示与单独的保肢手术相比,保肢手术+放疗可使局部复发的绝对风险降低20%-25%,但未改善总生存情况[17,18]。

一项分析纳入报告至监测、流行病学和最终结果(Surveillance, Epidemiology and End Results, SEER)数据库的大量STS患者,联合保肢手术时,中等剂量(50-65Gy)放疗可有效根除超出肉眼病灶的显微镜下病灶延伸,其局部控制率与截肢或采取“根治性”切缘的手术切除相当[11]。大多数病例系列研究报道,联合治疗对肢体高级别STS的局部控制率为85%-90%,低级别STS为90%-100%,具体取决于肿瘤的大小[3,11,20-25]。

较高剂量的辅助放疗也可以改善切缘阳性患者的结局[26,27]。目前规模最大的回顾性研究纳入31年内154例切除了任何解剖学部位STS的患者,其中105例为肢体STS,9例为躯干STS,患者的切缘阳性,并接受了以治愈为目标的放疗[26]。对于所有患者,5年时的局部控制率、无病生存率和总生存率分别为76%、47%和65%。下列患者的结局最好:肢体原发性肿瘤(5年的局部控制率、无病生存率和总生存率分别为82%、48%和66%);放疗剂量>64Gy;有显微镜下(而不是肉眼可见)阳性切缘、肿瘤<5cm且位于浅表而不是深处。对于放疗剂量>64Gy的患者,85%在5年时获得局部控制。

然而,阳性切缘局部控制率仍比阴性切缘差,因此如果可以行额外的保守手术,优选再次切除以获得阴性切缘。


有不需要放疗的患者吗? — 有但是很少。随着更好的放疗技术应用于临床,我们有更多的病人接受了放疗,因为确实可以提高控制率,而副作用并不严重。

一般而言,我们仅将单独手术切除用于直径≤5cm的低级别浅表肿瘤的成人患者,以及某些存在单纯肌内小肿瘤(即使级别较高)的患者,但前提是可获得充分的手术切缘。

尽管现已明确高级别肿瘤的局部复发风险较高,但低级别肿瘤的局部复发风险并不都低。一项随机试验发现,放疗对局部控制的改善可能仅限于高级别组织病理学患者[17]。然而,另一项随机试验显示,放疗也能显著降低那些低级别肿瘤患者的局部复发风险(局部复发率:联合放疗组5% vs 单纯手术组30%)[18]。

术前与术后放疗之间的选择 — 辅助放疗可以在术前(新辅助放疗)或术后(辅助放疗)给予。两种方法都有潜在优势。术前放疗能够向较小靶区给予较低剂量(50Gy)。术前放疗预计还可减少肿瘤负荷,理论上有助于实施较保守的手术治疗。术后放疗可方便对肿瘤标本行组织学检查,并且伤口并发症更少。

一般来说,对于大多数接受放疗的患者,我们建议术前而不是术后实施。这包括大多数中或高级别肿瘤患者,以及外科医生预计将获得窄切缘或阳性切缘的低级别较大肿瘤患者。对于符合这些情况的肢体和浅表躯干肉瘤患者,我们更倾向于选择术前放疗,因为急性伤口并发症通常可以处理,并且从长远来看最终可以愈合,但迟发治疗反应通常不可逆转。

然而,部分患者仍可选术后放疗,以作为原发性肢体或躯干肉瘤的局部控制治疗的组成部分。

针对已接受术前或术后放疗患者的回顾性观察性研究发现,术前放疗实现的局部控制和疾病特异性生存率至少与术后放疗相当[40-44],甚至可能更好[45,46]。

一项Ⅲ期临床试验(SR2研究)纳入了190例原发性(90%)或复发性(10%)肢体STS患者,并将其随机分配至接受术前或术后放疗,这些患者中83%为中或高级别STS[3]。术前放疗组共94例患者,术前接受50Gy的放疗,其中14例切缘阳性的患者术后追加了放疗(16-20Gy)。术后放疗者均接受初始放疗野的50Gy放疗,以及16-20Gy加量放疗。并发症定义为,肿瘤切除后120日内伤口二次手术、需住院进行伤口护理,或者需要深部填充或长时间使用伤口敷料。由于在计划的期中分析时发现非常显著的结果,该研究终止。中位随访3.3年发现,术前放疗组明显更常发生急性伤口并发症(35% vs 17%)[3]。与急性伤口并发症相关的其他因素为:切除组织的体积和肿瘤位于下肢。


一份后来的更新数据显示,中位随访6.9年时,术前放疗组和术后放疗组的局部控制率无差异(均>90%)[47]。区域和远处复发率及无进展和总体生存率也相近。然而,与术前放疗相比,术后放疗患者明显更常发生2-4级迟发毒性反应(86% vs 68%)。尤其是3级或4级皮下纤维化,术后放疗组的发生率显著更高(36% vs 23%);3级皮下纤维化是指,重度硬结和皮下组织丢失或照射野线性挛缩>10%,4级为坏死。

术后放疗组更常发生肢体水肿(23% vs 16%)和关节僵硬(23% vs 18%),但无统计学意义[48]。纤维化、水肿和关节僵硬都会对功能结局造成不良影响。

这项研究显示,术前和术后放疗的效果相似,术前放疗患者中通常可逆转的急性伤口愈合并发症发生率较高,但优势是通常不可逆转的迟发性并发症(包括3-4级纤维化)发生率较低。由于在两组患者中,上肢肿瘤均很少出现急性伤口愈合并发症(其他研究报道的结果[49,50]),故这些数据提示这类患者优选术前放疗。

术前调强放疗 —美国放射治疗肿瘤协作组(Radiation Therapy Oncology Group, RTOG)的一项研究对患者行靶区缩小的术前图像引导放疗(image-guided radiotherapy, IGRT),也报道了良好的迟发毒性反应情况[52]。

但对于下肢肉瘤患者,还需要采取额外策略来进一步降低急性伤口愈合问题的风险(针对术前放疗),或进一步降低迟发性治疗相关反应的风险(针对术后放疗)。例如,一项纳入234例STS患者的观察性研究显示,与病例匹配对照组相比,采用加速康复外科(enhanced recovery after surgery, ERAS)项目减少了并发症,包括伤口并发症更少和住院时长更短[53]。

根治性放疗 — 若患者身体方面不适合手术,或者无法在切除的同时保留功能且不接受截肢,则可以考虑单独放疗[57-59]。肉瘤细胞系对放疗的敏感性并不比上皮细胞系差[60]。黏液脂肪肉瘤是对放疗特别敏感的亚型[61]。

对于小的肉瘤,单独放疗可以取得较好的局部控制率。然而,对于体积估计在15-65mL(球体直径3-5cm)的肿瘤,需要大剂量放疗(>75Gy),才能使局部控制率>90%[13]。由于大多数治疗区相对较大,这类大剂量放疗几乎导致所有患者出现有临床意义的迟发性正常组织改变。


质子束放疗 — 还需要获得质子束放疗的进一步数据,才能决定是否将它纳入肉瘤患者的标准临床治疗。我们已知高度适形的质子束放疗已用于颅底和脊柱肉瘤,以及儿童横纹肌肉瘤。质子的优势

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