2010 欧洲肿瘤医学会：软组织肉瘤

Annals of Oncology 21 (Supplement 5): v198–v203, 2010 doi:10.1093/annonc/mdq209clinical practice guidelines Soft tissue sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up P. G. Casali1 & J.-Y. Blay2 On behalf of the ESMO/CONTICANET/EUROBONET Consensus Panel of experts* 1Department of Cancer Medicine, Istituto Nazionale dei Tumori, Milan, Italy; 2INSERM U590, Claude Bernard University and Department of Oncology, Edouard Herriot Hospital, Lyon, France The following recommendations apply to adult-type soft tissue sarcomas arising from limbs and superficial trunk. Recommendations on retroperitoneal sarcomas, desmoid- type fibromatosis, uterine sarcomas head and neck sarcomas and breast sarcomas are provided separately at the end of the chapter with regard to those main aspects by which they differ from more frequent soft tissue sarcomas. In general, the main principles of diagnosis and treatment may well apply to all soft tissue sarcomas, including the rarest presentations [e.g. visceral sarcomas other than gastrointestinal stromal tumours (GISTs)], which therefore are not specifically covered. Specific histological types, however, may deserve specific approaches, not necessarily covered hereafter, given the scope of these Recommendations. Extraskeletal Ewing sarcoma as well as embryonal and alveolar rhabdomyosarcoma are covered by other ESMO Clinical Practice Guidelines, inasmuch as they need completely different approaches. The same applies to GIST. Kaposi’s sarcoma is excluded from this chapter. incidence Adult soft tissue sarcomas are rare tumours, with an estimated incidence averaging 5/100 000/year in Europe. diagnosis Soft tissue sarcomas are ubiquitous in their site of origin, and are often treated with multimodality treatment. A multidisciplinary approach is therefore mandatory in all cases (involving pathologists, radiologists, surgeons, radiation therapists, medical oncologists and paediatric oncologists if applicable). This should be carried out in reference centres for sarcomas and/or within reference networks sharing multidisciplinary expertise and treating a high number of patients annually. These centres are involved in ongoing clinical trials, in which sarcoma patients’ enrolment is highly encouraged. This centralized referral should be pursued from the time of the clinical diagnosis of a suspect sarcoma. In practice, referral of all patients with a lesion likely to be a sarcoma would be recommended. This would mean referring all patients with an unexplained deep mass of soft tissues, or with a superficial lesion of soft tissues having a diameter of >5 cm, or arising in paediatric age. In soft tissue tumours, MR is the main imaging modality, although radiographs should be the first step to rule out a bone tumour, to detect a bone erosion with a risk of fracture and to show calcifications. CT has a role in calcified lesions to rule *Correspondence to: ESMO Guidelines Working Group, ESMO Head Office, Via L. Taddei 4, CH-6962 Viganello-Lugano, Switzerland; E-mail: clinicalrecommendations@esmo.org Approved by the ESMO Guidelines Working Group: August 2003, last update March 2010. This publication supercedes the previously published version—Ann Oncol 2009; 20 (Suppl 4): iv132–iv136. Conflict of interest: Dr Casali has reported that he is currently conducting research sponsored by Amgen Dompe´, Merck SD, Glaxo SK, Lilly, Novartis, Pfizer, PharmaMar, Sanofi-Aventis and Schering Plough. He had a consultancy role with and/or received honoraria for lectures from Merck SD, Novartis, Pfizer, PharmaMar, Sanofi-Aventis. He has received travel coverage for medical meetings from Novartis and PharmaMar; Prof. Blay has reported that he is a consultant for Pfizer, Novartis, GSK, Roche and Pharmamar. Consensus panel’s conflict of interest: Prof. Aglietta has reported that he has received research grants from Bayer, Amgen, Roche and Novartis; Prof. Alvega˚rd has reported no conflicts of interest; Dr Athanasou has reported no conflicts of interest; Dr Bihn has not reported any conflicts of interest; Dr Bonvalot has reported that she has received honoraria from Novartis and grants from Pharmamar; Dr Boukovinas has reported that he is a member of the speakers’ bureau for Novartis; Prof. De Alava has reported no conflicts of interest; Dr Dei Tos has reported no conflicts of interest; Dr Dileo has reported no conflicts of interest; Dr Eriksson has reported that he has received honoraria from Novartis, MSD, Pfizer, Swedish Orphan and GSK; Dr A. Ferrari has reported no conflicts of interest; Dr S. Ferrari has reported that he has participated in researches sponsored by Pharmamar and Ariad; Dr Garcia Del Muro has reported no conflicts of interest; Dr Gronchi has reported no conflicts of interest; Dr Hall has reported no conflicts of interest; Prof. Hassan has reported that at present he has no conflicts of interest, but he is planning trials with Takeda and Pharmamar; Prof. Hogendoorn has reported no conflicts of interest; Dr Hohenberger has not reported any conflicts of interest; Dr Gelderblom has reported no conflicts of interest; Dr Grimer has reported no conflicts of interest; Prof. Issels has reported no conflicts of interest; Dr Joensuu has reported no conflicts of interest; Dr Jost has reported no conflicts of interest; Prof. Judson has reported that he has received honoraria for participation in advisory boards meetings from Novartis, Pfizer, PharmaMar and Ariad; Dr Juergens has reported no conflicts of interest; Dr Le Cesne has reported that he has received honoraria from Novartis, Pfizer and PharmaMar; Dr Leyvraz has not reported any conflicts of interest; Dr Martin-Broto has reported no conflicts of interest; Dr Montemurro has reported no conflicts of interest; Prof. Nishida has reported that he is currently conducting research partly funded by Novartis Pharma; Dr Shreyaskumar has reported no conflicts of interest; Dr Reichardt has reported that he is a member of the speakers’ bureau and Advisory Board for PharmaMar; Dr Robinson has reported no conflicts of interest; Dr Rutkowski has reported that he has received honoraria from and that he is a member of the speakers’ bureau of Novartis; Prof. Scho¨ffski has reported that he is conducting research sponsored by Novartis, Pfizer, PharmaMar, Eisai, GlaxoSmithKline, Infinity and Genentech and that he is a member of the speakers’ bureau for Novartis, Pfizer, PharmaMar, Eisai, GlaxoSmithKline; Dr Schlemmer has reported that he is currently conducting research funded by Novartis; Dr Sleijfer has reported no conflicts of interest; Dr Van der Graaf has reported no conflicts of interest; Dr Vanel has reported no conflicts of interest; Prof. Verweij has reported no conflicts of interest; Dr Wardelmann has not reported any conflicts of interest; Dr Whelan has reported no conflicts of interest. ª The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org at St Jude Childrens Research Hospital on Septem ber 4, 2010 a n n o n c.o xfordjournals.org D ow nloaded from out a myositis ossificans, and in retroperitoneal tumours, where the performance is identical to MR. Following proper imaging assessment, the standard approach to diagnosis consists of multiple core needle biopsies (by using needles >16G). However, an excisional biopsy may be the most practical option for superficial lesions of <5 cm. An open biopsy may be another option in selected cases. Immediate evaluation of tissue viability may be considered, to make sure the biopsy is adequate at the time it is done. However, a frozen-section technique for immediate diagnosis is not encouraged, because generally it does not allow a complete diagnosis, especially when a preoperative treatment is planned. Fine-needle aspiration is used only in some institutions, which have developed specific expertise on this procedure, and is not recommended outside these centres. A biopsy may underestimate the tumour malignancy grade, so that, when preoperative treatment is an option, radiological imaging may add to pathology in providing the clinician with information that helps to estimate the malignancy grade (e.g. necrosis). The biopsy should be performed by a surgeon or a radiologist, after interdisciplinary discussion, as needed. It should be planned in such a way that the biopsy pathway and the scar can be safely removed on definitive surgery. The biopsy entrance point is preferably tattooed. The tumour sample should be fixed in formalin in due time (Bouin fixation should be banned, since it prevents molecular analysis). Histological diagnosis should be made according to the latest World Health Organization (WHO) classification. A pathological expert second opinion is recommended in all cases where the original diagnosis was made outside reference centres. The malignancy grade should be provided in all cases in which this is feasible based on available systems. The Federation Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grading system is generally used, which distinguishes three malignancy grades based on differentiation, necrosis and mitotic rate. Whenever possible, the mitotic rate should be provided independently. An effort should be made to improve the reliability of mitotic count as actually recorded. Tumour site should be properly recorded. Tumour size and tumour depth (in relation to the muscular fascia) should be recorded, since they entail a prognostic value, along with malignancy grade. The pathology report after definitive surgery should mention whether the tumour was intact and should include an appropriate description of tumour margins (i.e. the status of inked margins and the distance between tumour edge and the closest inked margins). This allows assessment of marginal status (i.e. whether the minimum margin is intralesional, marginal, wide and distances from surrounding tissues). The pathological assessment of margins should be made in collaboration with the surgeon. If preoperative treatment was carried out, the pathology report should include a tumour response assessment. In contrast to osteosarcoma and Ewing sarcoma, however, no validated system is available at present in this regard, and no percentage of residual ‘viable cells’ is considered to have a specific prognostic significance. This depends on several factors, including the presence of non-treatment-related necrosis and haemorrhage and the heterogeneity of post- treatment changes. A multidisciplinary judgement is recommended, involving the pathologist and the radiologist. Pathological diagnosis relies on morphology and immunohistochemistry. It should be complemented by molecular pathology [fluorescent in situ hybridization (FISH), reverse transcription–polymerase chain reaction (RT–PCR)], especially when: (i) the clinical pathological presentation is unusual; (ii) the specific histological diagnosis is doubtful; (iii) it may have prognostic/predictive relevance. External quality assurance programmes are encouraged for laboratories performing molecular pathology assessments. Collection of fresh frozen tissue and tumour imprints (touch preps) is encouraged, because new molecular pathology assessments could be made at a later stage in the patient’s interest. Informed consent for tumour banking should be sought enabling later analyses and research, as long as this is allowed by local and international guidelines. stage classification and risk assessment The American Joint Committee on Cancer (AJCC)/ International Union against Cancer (UICC) stage classification system stresses the importance of the malignancy grade in sarcoma. However, its use in routine practice is limited. In addition to grading, other prognostic factors are tumour size and tumour depth. Of course, tumour resectability is also important. staging procedures The surgical report, or patient chart, should provide details on: the preoperative and intraoperative diagnosis; the surgical conduct, including possible contamination (i.e. it should mention whether the tumour was opened, was ‘seen’ during the excision, etc.); surgical actual completeness vis-a`-vis planned quality of margins. A chest spiral CT scan is mandatory for staging purposes. Depending on the histological type and other clinical features, further staging assessments may be recommended (i.e. regional lymph node clinical assessment for synovial sarcoma, epithelioid sarcoma, alveolar soft part sarcoma, clear cell sarcoma; abdominal CT scan for myxoid liposarcoma, etc.). treatment limited disease Surgery is the standard treatment for all patients with adult- type, localized soft tissue sarcomas. It must be performed by a surgeon specifically trained in the treatment of this disease. The standard surgical procedure is a wide excision with negative margins (R0). This implies removing the tumour with a rim of normal tissue around. One centimetre has been selected as a cut-off in some studies, but it is important to realize that the margin can be minimal in the case of resistant anatomical barriers, such as muscular fasciae, periostium and perineurium. A marginal excision may be acceptable as an Annals of Oncology clinical practice guidelines Volume 21 | Supplement 5 |May 2010 doi:10.1093/annonc/mdq209 | v199 at St Jude Childrens Research Hospital on Septem ber 4, 2010 a n n o n c.o xfordjournals.org D ow nloaded from individualized option in highly selected cases, in particular for extracompartmental atypical lipomatous tumours. Wide excision followed by radiation therapy is standard treatment in high-grade, deep lesions, >5 cm. Radiation therapy is not given in the case of a truly compartmental resection of a tumour entirely contained within the compartment. With exceptions to be discussed in a multidisciplinary setting, and in the face of a lack of consensus across reference centres, also high-grade, deep, <5 cm lesions are treated with surgery followed by radiation therapy. Radiation therapy is added in selected cases in the case of low-grade, superficial, >5 cm, and low-grade, deep, <5 cm soft tissue sarcoma. In the case of low-grade, deep, >5 cm soft tissue sarcoma, radiation therapy should be discussed in a multidisciplinary fashion, considering the anatomical site and the related expected sequelae versus the histological aggressiveness. Overall, radiation therapy has been shown to improve local control, but not overall survival. Radiation therapy should be administered postoperatively, with the best technique available, at a dose of 50–60 Gy, with fractions of 1.8–2 Gy, possibly with boosts up to 66 Gy, depending on presentation and quality of surgery. Alternatively, radiotherapy may be carried out preoperatively, normally using a dose of 50 Gy. Intraoperative radiation therapy (IORT) and brachytherapy are options in selected cases. Re-operation in reference centres must be considered in the case of R1 resections, if adequate margins can be achieved without major morbidity, taking into account tumour extent and tumour biology (e.g. it may be spared in extracompartmental atypical lipomatous tumours, etc.). In the case of R2 surgery, re-operation is mandatory, possibly with preoperative treatments if adequate margins cannot be achieved, or surgery is mutilating. In the latter case, the use of multimodal therapy with less radical surgery requires shared decision-making with the patient under conditions of uncertainty. Plastic repairs and vascular grafting should be used as needed, and the patient should be properly referred if necessary. Radiation therapy will obviously follow marginal or R1–R2 excisions, if these cannot be rescued through re-excision, even outside the usual indications (see above). In non-resectable tumours, or those amenable only to mutilating surgery (in this case, on an individualized basis after sharing the decision with the patient in conditions of uncertainty), chemotherapy and/or radiotherapy, or isolated hyperthermic limb perfusion with tumour necrosis factor-a (TNFa) + melphalan, if the tumour is confined to an extremity, or regional hyperthermia combined with chemotherapy, are options. Regional lymph node metastases should be distinguished from soft tissue metastases involving lymph nodes. They are rare, and constitute an adverse prognostic factor in adult-type soft tissue sarcomas. More aggressive treatment planning is therefore felt to be appropriate for these patients, although there is a lack of formal evidence to indicate that this improves clinical results. Surgery through wide excision (mutilating surgery is exceptionally done given the prognosis of these patients) may be coupled with adjuvant radiation therapy and adjuvant chemotherapy for sensitive histological types, as standard treatment for these presentations. Chemotherapy may be administered as preoperative treatment, at least in part. These treatment modalities adding to surgery should not be viewed as truly ‘adjuvant’, the context being in fact that of a likely systemic disease. In one large randomized phase III study (in patients with G2–3, deep, >5 cm soft tissue sarcomas), regional hyperthermia in addition to systemic chemotherapy was associated with a local and disease-free survival advantage. Isolated limb perfusion may be an option in this patient population, along with chemotherapy and radiation therapy. Data have been provided that adjuvant chemotherapy might improve, or at least delay, distant and local recurrence in high-risk patients. A meta-analysis found a statistically significant, limited benefit in terms of both survival and relapse-free survival. However, studies are conflicting, and a final demonstration of efficacy is lacking. It is also unknown whether adjuvant chemotherapy may be especially beneficial in specific subgroups. Therefore, adjuvant chemotherapy is not standard treatment in adult-type soft tissue sarcomas, and can be proposed as an option to the high-risk individual patient (having a >G1, deep, >5 cm tumour) for shared decision- making with the patient [II, C]. Adjuvant chemotherapy is not used in histologies known to be insensitive to chemotherapy. If the decision is made to use chemotherapy as upfront treatment, it may well be used preoperatively, at least in part. A local benefit may be gained, facilitating surgery. In one large randomized phase III study (in patients with G2–3, deep, >5 cm soft tissue sarcomas), regional hyperthermia in addition to systemic chemotherapy was associated with a local and disease-free survival advantage (no survival benefit demonstrated). If used, adjuvant chemotherapy should consist of the combination chemotherapy regimens proven to be most active in the advanced disease. The standard approach to local relapse parallels the approach to primary local disease, except for a wider resort to preoperative or postoperative radiation therapy, if not previously performed. extensive disease Metachronous resectable lung metastases without extrapulmonary disease are managed with complete excision of all lesions as standard treatment [IV, B]. Chemotherapy may be added as an option, taking into account the prognostic factors (a short previous free interval and a high number of lesions are adverse factors, encouraging the addition of chemotherapy), although there is a lack of formal evidence that this improves results. Chemotherapy is preferably given before surgery, in order to assess tumour response and thus modulate the length of treatment. In the case of lung metastases being synchronous, in the absence of extrapulmonary disease, standard treatment is chemotherapy [IV, B]. Especially when a patient benefit is achieved, surgery of completely resectable lung metastases may be offered as an option. E