6. Therapy of isolated local recurrence – Soft Tissue Sarcoma
6.1 Frequency and prognosis
Local recurrences of soft tissue sarcomas are associated with a higher risk of further local recurrence and distant metastasis compared with primary tumors.
- Consensus
- Strong consensus
There are no prospective randomized studies on local therapy of local recurrences of soft tissue sarcomas.
- Consensus
- Strong consensus
Background
The incidence of local recurrence is best documented for sarcomas of the extremities. In specialized centers, this is usually below 15 % in series treated after 1995 [155]. Higher local recurrence rates are reported for localization to the trunk or retroperitoneum [321]. Local recurrences are most frequently observed in the first 2 years after completion of primary therapy. According to Eilber et al [432] 65 % of all local recurrences occur during this period and within 4 years approximately 90 %. Consistently, the highest risk of local recurrence is after marginal and intralesional resections according to the results of multivariate analyses from several databases [134], [155], [316], [433]. In contrast, tumor size, grading, and tumor location (for extremity sarcomas) were significant risk factors in these databases only in univariate analysis.
In the MSKCC database, age older than 50 years, history of local recurrence, and histologic subtype of MPNST were also associated with an increased risk of local recurrence on multivariate analysis [134]. The prognosis of patients with local recurrence is not significantly worse than after therapy for the primary tumor in all databases. In the multivariate analyses, the rates of distant metastasis after local recurrence were shown to be only slightly increased. Data from the Scandinavian Sarcoma Group demonstrate that although there is a statistical correlation, a causal relationship cannot be established because other prognostic factors for metastasis such as initial tumor size and, most importantly, grading play a decisive role [161]. Short intervals (<2 years) until local recurrence are associated with a less favorable prognosis [434]. Therefore, consistent local therapy is as important in isolated local recurrence as in primary therapy.
6.2 Local recurrences pretreated by surgery alone
6.2.1 Surgical therapy
If no preoperative or postoperative radiotherapy or medical tumor therapy has been given during primary treatment, local recurrences of soft tissue sarcomas shall be treated diagnostically and surgically according to the same recommendations as for primary therapy.
- Consensus
- Strong consensus
Background
The criteria for surgical treatment of local recurrence do not differ from those in primary treatment. In some cases, however, a more complex local situation is present after previous plastic-reconstructive surgery. Accordingly, the rate of recurrence of local recurrence even after achieving R0 resection is somewhat higher than in primary therapy [134], [433].
As with initial surgery, the prognosis of patients with local recurrence is much better if R0 resection is achieved [434], [435]. Therefore, the goal of surgery for isolated local recurrence is to achieve R0 resection, just as in the primary setting. If a complete resection is not achievable despite neoadjuvant therapies (see next paragraph), amputation may also be useful in the case of unfavorably located recurrences in the extremities.
6.2.2 Preoperative / neoadjuvant therapies (without previous therapy)
In local recurrences of soft tissue sarcomas not pretreated with neoadjuvant or adjuvant therapy, a multimodal therapy concept shall be defined in an interdisciplinary sarcoma board.
- Consensus
- Strong consensus
Background
For marginally resectable primary tumors and highly malignant local recurrences, the value of neoadjuvant therapies has not been systematically studied (radiotherapy, chemotherapy +/- hyperthermia, isolated limb perfusion). Some of the studies addressing these questions have included small numbers of cases not previously treated with neoadjuvant or adjuvant therapy with local recurrences after surgery alone [271], [O'Sullivan, B. et al. 2002], [375]. The benefit of neoadjuvant chemotherapy in combination with hyperthermia compared with neoadjuvant chemotherapy alone was as great in the local recurrence subgroup in terms of DFS and overall survival as with primary therapy [271], [375]. In Gronchi et al. [375] (neoadjuvant chemotherapy) and O’Sullivan et al. [O'Sullivan, B. et al. 2002] (preoperative radiotherapy), local recurrence outcomes were not reported separately. Since local recurrences are associated with an increased risk of further local and distant recurrence and are less frequently R0-resectable than primary cases, it seems plausible to assume that the benefit of neoadjuvant therapeutic procedures for local recurrence is, if anything, even higher than in the primary situation. The possibility of multimodal therapy should therefore be reviewed in the interdisciplinary sarcoma board.
For hyperthermic isolated extremityperfusion (TN-ILP) with rhTNF-alpha and melphalan, available in accredited centers, response rates of up to 85 % (defined as more than 90 % tumor necrosis in the resected tumor) could be achieved in case series of up to 208 patients [373], [436]. In patients with recurrences completely resectable only by amputation in most cases, the amputation rate after 5 years was about 20 %, which was higher than in patients with the same treatment for the primary tumor [356]. Clearly, the results of TNF-ILP are less favorable in patients with recurrent tumor [436]. It is particularly important to consider that efficacy and toxicity are negatively influenced by previous radiotherapy [437], [438]. Relevant acute toxicities have been reported in approximately 10 % of patients after TNF-ILP. Late toxicities depend on the extent of surgery. In particular, the fracture risk associated with periosteal stripping during resection surgery is relevant [169]. The rate and extent of lymphedema is also influenced by the additive toxicity of TNF-ILP (lymphodynamic insufficiency) and postoperative adjuvant radiotherapy.
6.2.3 Radiotherapy (without previous radiotherapy)
Preoperative or postoperative radiotherapy shall be given for local recurrences of poorly differentiated (G2-3) or >5 cm soft tissue sarcomas in tissues of the extremities or trunk that have not been preirradiated.
- Consensus
- Strong consensus
Preoperative radiation therapy may be given for local recurrences of retroperitoneally located liposarcomas.
- Consensus
- Strong consensus
Background
The effects of preoperative or postoperative radiotherapy have not been explicitly tested in randomized trials for local recurrences compared with surgery alone. However, randomized trials of the effect of preoperative or postoperative percutaneous radiotherapy [189], [O'Sullivan, B. et al. 2002], [330] and postoperative brachytherapy [316] in primary therapy also included smaller numbers of patients with local recurrence after surgery alone as primary treatment. The results for patients treated for local recurrence have not been published separately, even as a subgroup analysis. There is no reason to assume that in the absence of preirradiation, the beneficial effect of radiotherapy for local recurrence is different from that in primary treatment. If radiotherapy has not been given at primary treatment, it should be used for local recurrences in the extremities and trunk. Because of the demonstrated increased risk [134], [433] of local recurrence compared with primary treatment, the indication for postoperative radiotherapy of even well-differentiated (G1) soft tissue sarcomas <5 cm should be more generous than in the primary situation.
For local recurrences of non-preirradiated retroperitoneal soft tissue sarcomas, the data are extremely limited. However, well-differentiated liposarcomas may benefit from preoperative radiotherapy (50.4 Gy in 28 fractions as IMRT) given the results of the STRASS trial) [264]. However, it must be taken into account that due to the possibility that scarred small bowel loops may be fixed in the former surgical area, the side effects rate of preoperative radiotherapy may be higher. For the surgical procedure, this means a higher risk of complications after possible bowel resection in the irradiated area, since the irradiation dose is less distributed to mobile bowel loops.
6.2.4 Adjuvant chemotherapy (without prior chemotherapy)
In the trials of adjuvant chemotherapy, series also included patients with local recurrences that had been pretreated only surgically [272]. Subgroup analyses in this regard are not available from most trials. However, it seems plausible to assume at least the same (small) benefit in terms of overall survival for adjuvant chemotherapy in the relapse setting. Therefore, it is advisable to inform patients with large, highly malignant recurrences in the extremities about the potential benefit of adjuvant chemotherapy.
6.3 Therapy after preoperative/neoadjuvant or adjuvant therapy.
The following factors argue for repeat external beam radiation therapy of previously irradiated tissues:
- Interval until recurrence >2 years
- Minor late sequelae of previous radiotherapy (fibrosis, atrophy, limitation of movement).
- Highly malignant sarcoma (grading 2-3)
- Small resection margins or R1/R2 resection or expected small resection margins or R1/R2 resection.
- Consensus
- Strong consensus
Conformal irradiation techniques should be used for re-irradiation:
- Brachytherapy (intraoperative insertion of catheters).
- Intraoperative radiation therapy with electrons (IOERT)
- External beam: IMRT or VMAT with IGRT
- Consensus
- Strong consensus
Local recurrences in oligometastatic patients should be treated according to the same recommendations as nonmetastatic patients, provided that all distant metastases can be treated surgically or with local ablative procedures.
- Consensus
- Strong consensus
Background
After neoadjuvant treatment (limb perfusion, radiation, chemotherapy with hyperthermia) or adjuvant treatment (radio- or chemotherapy) the initial conditions for resection of local recurrences are often much less favorable than for primary therapy. Higher local complication rates after repeat surgery are typical in these cases [435]. Only the results of smaller, heterogeneously treated case collections are available [256], [434], [435], [437], [438], [439], [440], [441], [442], [443], [444], [445], [446], [447], [448], [449], [450], [451].
There is consensus among the authors that surgical treatment with the goal of R0 resection should be pursued even for recurrences not treated by surgery alone. The rate of R0 resection is significantly lower than in primary treatment, and the incidence of recurrence of local recurrence despite R0 resection is also significantly higher. Reported recurrence rates of local recurrence range from 15% to over 50% even after R0 resection, although the majority of patients also received additional neoadjuvant or adjuvant therapies (radiotherapy, chemotherapy +/- hyperthermia) and/or intraoperative radiotherapy or brachytherapy. Contributing to this is the fact that local recurrence predominantly occurs in G2/G3 sarcomas, which in any case have a less favorable tumor biology. Studies on the aforementioned therapeutic procedures in combination with surgery or on resection alone are either completely lacking or not usable due to bias that cannot be assessed.
Repeat pre- or postoperative percutaneous radiotherapy for local recurrence is not associated with an increased risk of acute radiation side effects, but the risks of wound healing complications after preoperative radiotherapy and grade III-IV late toxicities, such as fibrosis and necrosis, are increased with reported rates of 20 - 50 % [434] , [442], [443]. However, experimental and clinical data are available that tolerance of irradiated tissues to re-irradiation 1-2 years after 1st radiotherapy returns to 50 - 90% of tolerance of unirradiated tissues [452]. In particular, if the first radiotherapy has not left any serious late sequelae and was performed more than 1 year ago, and the pre-irradiated area has been resected, a new radiotherapy can therefore be performed with only a slightly increased risk of complications. Since it is known from therapy in the primary situation that preoperative radiotherapy with 50 Gy in 25 fractions is equivalent to postoperative 66 Gy in 33 fractions, it makes sense in the case of planned re-irradiation to perform it preoperatively, especially since with preoperative irradiation the irradiated volume can also be kept smaller [O'Sullivan, B. et al. 2002], [329]. Especially at the lower extremity, however, wound healing disorders occur more frequently after preoperative radiotherapy.
In smaller case series, intraoperative radiotherapy has been used additionally or alone, especially for regions where only marginal (R1) surgical resection was expected prior to the surgical proicedure or documented intraoperatively. Because of the small volume of irradiation, toxicity is relatively low. However, increased rates of wound infection, seroma, and, with direct irradiation of larger nerves, nerve damage have also been reported [439], [447].
More reports are available on adjuvant brachytherapy using intraoperative inser-tion of afterloading catheters. In experienced hands, highly conformal dose distributions can be achieved. Toxicity is also increased compared with that of primary treatment, with reports of increased rates of wound healing problems and infections [439], [440], [445], [446].
In patients with local recurrence who have received radiotherapy as a sole treatment besides surgery, neoadjuvant chemotherapy can also be given in combination with hyperthermia without significantly increased acute toxicity compared with primary treatment. The few very small case series indicate an increased complication rate of subsequent surgery [453], [454].
The combination of neoadjuvant chemotherapy with hyperthermia and re-irradiation is also applicable according to the results in a few small patient series with an increased but acceptable toxicity compared to primary treatment [336], [337], [338], [455].
Which of the described procedures should be applied depends on the individual situation, availability and experience at the centers and should be discussed in the multidisciplinary sarcoma board.
Synchronous or previous distant metastasis is found in up to 30% of patients with local recurrences [451]. In the presence of oligometastasis, a curative chance still exists for a smaller proportion of patients [456]. Therefore, it seems reasonable to treat local recurrences in patients according to the same principles as in non-metastatic patients.
In some patients, the local recurrences are so unfavorable or so extensive that, regardless of the previous therapy, a complete resection with acceptable morbidity or surgical risk is not possible. Smaller case series have shown that a good palliative effect can be achieved even without resection or in rare cases even after incomplete resection with conservative therapies (radiotherapy, system therapies, chemotherapy or radiotherapy +/- hyperthermia). In the subgroup of smaller recurrences (<5-10 cm in diameter), this approach can also achieve long-term local tumor control [336], [337], [338]. In patients with multiple distant metastases, local treatment of an additional (symptomatic) local recurrence may help, especially if local complications are imminent. The aforementioned therapeutic options can usefully complement palliative medical care and be discussed in an interdisciplinary manner.
6.3.1 Preoperative chemotherapy
In resectable, isolated local recurrence of high-risk (G2/3) sarcoma not pretreated with chemotherapy according to guidelines and with a chemosensitive subtype, preoperative chemotherapy may be given.
- Consensus
- Strong consensus
In resectable, isolated local recurrence of sarcoma pretreated with chemotherapy according to guidelines, no additional preoperative chemotherapy should be given.
- Consensus
- Strong consensus
In isolated and non-resectable local recurrence, a multidisciplinary therapeutic decision shall be made.
- Consensus
- Strong consensus
If systemic therapy is used for isolated and non-resectable local recurrence, anthracycline-based combination therapy should be used if the subtype is chemosensitive and resectability is expected in the case of tumor shrinkage or to relieve local symptoms. Otherwise, the choice of chemotherapeutic agents is analogous to the metastatic situation.
- Consensus
- Strong consensus
Background
When isolated local recurrence occurs, the approach differs between local recurrence judged to be R0 resectable and non-R0 resectable. In resectable local recurrence, there is no proven benefit to the use of systemic therapy in addition to tumor resection. This is true in both the preoperative and postoperative settings. Studies on the value of systemic therapy in localized soft tissue sarcoma are only available for primary tumors (see Chapter 5.6). Accordingly, the use of preoperative chemotherapy can be considered as a case-by-case decision in the case of local recurrence not previously treated with chemotherapy and meeting the high-risk criteria (T2, G2/3). In all other cases, only resection of the local recurrence is recommended [86] with or without the use of radiotherapy as discussed in Chapter 5.4. A retrospective study by Gustafson et al. in 1993 describes metastasis-free long-term survival after resection and radiotherapy alone for an isolated local recurrence, but refers mainly to patients with smaller low-grade tumors [457].
Patients with local recurrence are at increased risk of distant metastases and therefore require close follow-up [458]. In the case of non-resectable local recurrence, the therapeutic principles are based on the procedure for metastatic soft tissue sarcoma (see Chapter 7.1).
6.3.2 Additive chemotherapy
Additive chemotherapy may be given after complete resection of an isolated high-risk local recurrence that has not been pretreated with chemotherapy according to guidelines.
- Consensus
- Strong consensus
After incomplete resection of an isolated local recurrence, whether pretreated with chemotherapy according to guidelines or not, a multidisciplinary therapeutic decision shall be made.
- Consensus
- Strong consensus
References
[155] Jebsen, N. L., Trovik, C. S., Bauer, H. C., Rydholm, A., Monge, O. R., Hall, K. S., et.al. Radiotherapy to improve local control regardless of surgical margin and malignancy grade in extremity and trunk wall soft tissue sarcoma: a Scandinavian sarcoma group study, Int J Radiat Oncol Biol Phys, 2008. 71(4): p. 1196-203., https://www.ncbi.nlm.nih.gov/pubmed/18207661
[321] Delaney, T. F., Kepka, L., Goldberg, S. I., Hornicek, F. J., Gebhardt, M. C., Yoon, S. S., et.al. Radiation therapy for control of soft-tissue sarcomas resected with positive margins, Int J Radiat Oncol Biol Phys, 2007. 67(5): p. 1460-9., https://www.ncbi.nlm.nih.gov/pubmed/17394945
[432] Eilber, F. C., Brennan, M. F., Riedel, E., Alektiar, K. M., Antonescu, C. R., Singer, S., Prognostic factors for survival in patients with locally recurrent extremity soft tissue sarcomas, Ann Surg Oncol, 2005. 12(3): p. 228-36., https://www.ncbi.nlm.nih.gov/pubmed/15827815
[134] Pisters, P. W., Leung, D. H., Woodruff, J., Shi, W., Brennan, M. F., Analysis of prognostic factors in 1,041 patients with localized soft tissue sarcomas of the extremities, J Clin Oncol, 1996. 14(5): p. 1679-89., https://www.ncbi.nlm.nih.gov/pubmed/8622088
[316] Pisters, P. W., Harrison, L. B., Leung, D. H., Woodruff, J. M., Casper, E. S., Brennan, M. F., Long-term results of a prospective randomized trial of adjuvant brachytherapy in soft tissue sarcoma, J Clin Oncol, 1996. 14(3): p. 859-68., https://www.ncbi.nlm.nih.gov/pubmed/8622034
[433] Gronchi, A., Casali, P. G., Mariani, L., Miceli, R., Fiore, M., Lo Vullo, S., et.al. Status of surgical margins and prognosis in adult soft tissue sarcomas of the extremities: a series of patients treated at a single institution, J Clin Oncol, 2005. 23(1): p. 96-104., https://www.ncbi.nlm.nih.gov/pubmed/15625364
[161] Trovik, C. S., Bauer, H. C., Alvegard, T. A., Anderson, H., Blomqvist, C., Berlin, O., et.al. Surgical margins, local recurrence and metastasis in soft tissue sarcomas: 559 surgically-treated patients from the Scandinavian Sarcoma Group Register, Eur J Cancer, 2000. 36(6): p. 710-6., https://www.ncbi.nlm.nih.gov/pubmed/10762742
[434] Sugiura, H., Tsukushi, S., Yoshida, M., Nishida, Y., What Is the Success of Repeat Surgical Treatment of a Local Recurrence After Initial Wide Resection of Soft Tissue Sarcomas?, Clin Orthop Relat Res, 2018. 476(9): p. 1791-1800., https://www.ncbi.nlm.nih.gov/pubmed/30794216
[435] Torres, M. A., Ballo, M. T., Butler, C. E., Feig, B. W., Cormier, J. N., Lewis, V. O., et.al. Management of locally recurrent soft-tissue sarcoma after prior surgery and radiation therapy, Int J Radiat Oncol Biol Phys, 2007. 67(4): p. 1124-9., https://www.ncbi.nlm.nih.gov/pubmed/17208389
[271] Issels, R. D., Lindner, L. H., Verweij, J., Wessalowski, R., Reichardt, P., Wust, P., et.al. Effect of Neoadjuvant Chemotherapy Plus Regional Hyperthermia on Long-term Outcomes Among Patients With Localized High-Risk Soft Tissue Sarcoma: The EORTC 62961-ESHO 95 Randomized Clinical Trial, JAMA Oncol, 2018. 4(4): p. 483-492., https://www.ncbi.nlm.nih.gov/pubmed/29450452
[375] Gronchi, A., Ferrari, S., Quagliuolo, V., Broto, J. M., Pousa, A. L., Grignani, G., et.al. Histotype-tailored neoadjuvant chemotherapy versus standard chemotherapy in patients with high-risk soft-tissue sarcomas (ISG-STS 1001): an international, open-label, randomised, controlled, phase 3, multicentre trial, Lancet Oncol, 2017. 18(6): p. 812-822., https://www.ncbi.nlm.nih.gov/pubmed/28499583
[373] Jakob, J., Tunn, P. U., Hayes, A. J., Pilz, L. R., Nowak, K., Hohenberger, P., Oncological outcome of primary non-metastatic soft tissue sarcoma treated by neoadjuvant isolated limb perfusion and tumor resection, J Surg Oncol, 2014. 109(8): p. 786-90., https://www.ncbi.nlm.nih.gov/pubmed/24619722
[436] Deroose, J. P., Eggermont, A. M., van Geel, A. N., Burger, J. W., den Bakker, M. A., de Wilt, J. H., et.al. Long-term results of tumor necrosis factor alpha- and melphalan-based isolated limb perfusion in locally advanced extremity soft tissue sarcomas, J Clin Oncol, 2011. 29(30): p. 4036-44., https://www.ncbi.nlm.nih.gov/pubmed/21931039
[356] Jakob, J., Hohenberger, P., Role of isolated limb perfusion with recombinant human tumor necrosis factor alpha and melphalan in locally advanced extremity soft tissue sarcoma, Cancer, 2016. 122(17): p. 2624-32., https://www.ncbi.nlm.nih.gov/pubmed/27197621
[437] Bhangu, A., Broom, L., Nepogodiev, D., Gourevitch, D., Desai, A., Outcomes of isolated limb perfusion in the treatment of extremity soft tissue sarcoma: a systematic review, Eur J Surg Oncol, 2013. 39(4): p. 311-9., https://www.ncbi.nlm.nih.gov/pubmed/23351681
[438] Lans, T. E., Grunhagen, D. J., de Wilt, J. H., van Geel, A. N., Eggermont, A. M., Isolated limb perfusions with tumor necrosis factor and melphalan for locally recurrent soft tissue sarcoma in previously irradiated limbs, Ann Surg Oncol, 2005. 12(5): p. 406-11., https://www.ncbi.nlm.nih.gov/pubmed/15915375
[169] Seinen, J. M., Jutte, P. C., Been, L. B., Pras, E., Hoekstra, H. J., Fractures after multimodality treatment of soft tissue sarcomas with isolated limb perfusion and radiation; likely to occur and hard to heal, Eur J Surg Oncol, 2018. 44(9): p. 1398-1405., https://www.ncbi.nlm.nih.gov/pubmed/29789188
[189] Yang, J. C., Chang, A. E., Baker, A. R., Sindelar, W. F., Danforth, D. N., Topalian, S. L., et.al. Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity, J Clin Oncol, 1998. 16(1): p. 197-203., https://www.ncbi.nlm.nih.gov/pubmed/9440743
[330] Davis, A. M., O'Sullivan, B., Turcotte, R., Bell, R., Catton, C., Chabot, P., et.al. Late radiation morbidity following randomization to preoperative versus postoperative radiotherapy in extremity soft tissue sarcoma, Radiother Oncol, 2005. 75(1): p. 48-53., https://www.ncbi.nlm.nih.gov/pubmed/15948265
[264] Bonvalot, S., Gronchi, A., Le Pechoux, C., Swallow, C. J., Strauss, D., Meeus, P., et.al. Preoperative radiotherapy plus surgery versus surgery alone for patients with primary retroperitoneal sarcoma (EORTC-62092: STRASS): a multicentre, open-label, randomised, phase 3 trial, Lancet Oncol, 2020. 21(10): p. 1366-1377., https://www.ncbi.nlm.nih.gov/pubmed/32941794
[272] Pervaiz, N., Colterjohn, N., Farrokhyar, F., Tozer, R., Figueredo, A., Ghert, M., A systematic meta-analysis of randomized controlled trials of adjuvant chemotherapy for localized resectable soft-tissue sarcoma, Cancer, 2008. 113(3): p. 573-81., https://www.ncbi.nlm.nih.gov/pubmed/18521899
[256] Stojadinovic, A., Yeh, A., Brennan, M. F., Completely resected recurrent soft tissue sarcoma: primary anatomic site governs outcomes, J Am Coll Surg, 2002. 194(4): p. 436-47., https://www.ncbi.nlm.nih.gov/pubmed/11949749
[439] Cambeiro, M., Aristu, J. J., Moreno Jimenez, M., Arbea, L., Ramos, L., San Julian, M., et.al. Salvage wide resection with intraoperative electron beam therapy or HDR brachytherapy in the management of isolated local recurrences of soft tissue sarcomas of the extremities and the superficial trunk, Brachytherapy, 2015. 14(1): p. 62-70., https://www.ncbi.nlm.nih.gov/pubmed/25443530
[440] Classen, J., Hehr, T., Lamprecht, U., Zumbragel, A., Bamberg, M., Budach, W., Hyperfractionated 192Ir brachytherapy for recurrent retroperitoneal sarcoma: a technique for delivery of local tumor boost dose, Strahlenther Onkol, 2003. 179(2): p. 118-22., https://www.ncbi.nlm.nih.gov/pubmed/12590323
[441] Daigeler, A., Zmarsly, I., Hirsch, T., Goertz, O., Steinau, H. U., Lehnhardt, M., et.al. Long-term outcome after local recurrence of soft tissue sarcoma: a retrospective analysis of factors predictive of survival in 135 patients with locally recurrent soft tissue sarcoma, Br J Cancer, 2014. 110(6): p. 1456-64., https://www.ncbi.nlm.nih.gov/pubmed/24481401
[442] Calvo, F. A., Sole, C. V., Cambeiro, M., Montero, A., Polo, A., Gonzalez, C., et.al. Prognostic value of external beam radiation therapy in patients treated with surgical resection and intraoperative electron beam radiation therapy for locally recurrent soft tissue sarcoma: a multicentric long-term outcome analysis, Int J Radiat Oncol Biol Phys, 2014. 88(1): p. 143-50., https://www.ncbi.nlm.nih.gov/pubmed/24331661
[443] Essner, R., Selch, M., Eilber, F. R., Reirradiation for extremity soft tissue sarcomas. Local control and complications, Cancer, 1991. 67(11): p. 2813-7., https://www.ncbi.nlm.nih.gov/pubmed/2025846
[444] Indelicato, D. J., Meadows, K., Gibbs, C. P., Jr., Morris, C. G., Scarborough, M. T., Zlotecki, R. A., Effectiveness and morbidity associated with reirradiation in conservative salvage management of recurrent soft-tissue sarcoma, Int J Radiat Oncol Biol Phys, 2009. 73(1): p. 267-72., https://www.ncbi.nlm.nih.gov/pubmed/18707824
[445] Pearlstone, D. B., Janjan, N. A., Feig, B. W., Yasko, A. W., Hunt, K. K., Pollock, R. E., et.al. Re-resection with brachytherapy for locally recurrent soft tissue sarcoma arising in a previously radiated field, Cancer J Sci Am, 1999. 5(1): p. 26-33., https://www.ncbi.nlm.nih.gov/pubmed/10188058
[446] Janjan, N., Crane, C., Delclos, M., Ballo, M., Brachytherapy for locally recurrent soft-tissue sarcoma, Am J Clin Oncol, 2002. 25(1): p. 9-15., https://www.ncbi.nlm.nih.gov/pubmed/11823688
[447] Lehnert, T., Schwarzbach, M., Willeke, F., Treiber, M., Hinz, U., Wannenmacher, M. M., et.al. Intraoperative radiotherapy for primary and locally recurrent soft tissue sarcoma: morbidity and long-term prognosis, Eur J Surg Oncol, 2000. 26 Suppl A: p. S21-4., https://www.ncbi.nlm.nih.gov/pubmed/11130875
[448] Midis, G. P., Pollock, R. E., Chen, N. P., Feig, B. W., Murphy, A., Pollack, A., et.al. Locally recurrent soft tissue sarcoma of the extremities, Surgery, 1998. 123(6): p. 666-71., https://www.ncbi.nlm.nih.gov/pubmed/9626317
[449] Ikoma, N., Torres, K. E., Lin, H. Y., Ravi, V., Roland, C. L., Mann, G. N., et.al. Recurrence patterns of retroperitoneal leiomyosarcoma and impact of salvage surgery, J Surg Oncol, 2017. 116(3): p. 313-319., https://www.ncbi.nlm.nih.gov/pubmed/28557016
[450] Sugiura, H., Nishida, Y., Nakashima, H., Yamada, Y., Tsukushi, S., Yamada, K., Surgical procedures and prognostic factors for local recurrence of soft tissue sarcomas, J Orthop Sci, 2014. 19(1): p. 141-9., https://www.ncbi.nlm.nih.gov/pubmed/24081391
[451] Guerrero, W. M., Deneve, J. L., Local Recurrence of Extremity Soft Tissue Sarcoma, Surg Clin North Am, 2016. 96(5): p. 1157-74., https://www.ncbi.nlm.nih.gov/pubmed/27542648
[452] Dorr, W., Gabrys, D., The Principles and Practice of Re-irradiation in Clinical Oncology: An Overview, Clin Oncol (R Coll Radiol), 2018. 30(2): p. 67-72., https://www.ncbi.nlm.nih.gov/pubmed/29233574
[329] Pawlik, T. M., Pisters, P. W., Mikula, L., Feig, B. W., Hunt, K. K., Cormier, J. N., et.al. Long-term results of two prospective trials of preoperative external beam radiotherapy for localized intermediate- or high-grade retroperitoneal soft tissue sarcoma, Ann Surg Oncol, 2006. 13(4): p. 508-17., https://www.ncbi.nlm.nih.gov/pubmed/16491338
[453] Wendtner, C., Abdel-Rahman, S., Baumert, J., Falk, M. H., Krych, M., Santl, M., et.al. Treatment of primary, recurrent or inadequately resected high-risk soft-tissue sarcomas (STS) of adults: results of a phase II pilot study (RHT-95) of neoadjuvant chemotherapy combined with regional hyperthermia, Eur J Cancer, 2001. 37(13): p. 1609-16., https://www.ncbi.nlm.nih.gov/pubmed/11527685
[454] Issels, R. D., Abdel-Rahman, S., Wendtner, C., Falk, M. H., Kurze, V., Sauer, H., et.al. Neoadjuvant chemotherapy combined with regional hyperthermia (RHT) for locally advanced primary or recurrent high-risk adult soft-tissue sarcomas (STS) of adults: long-term results of a phase II study, Eur J Cancer, 2001. 37(13): p. 1599-608., https://www.ncbi.nlm.nih.gov/pubmed/11527684
[336] Eckert, F., Braun, L. H., Traub, F., Kopp, H. G., Sipos, B., Lamprecht, U., et.al. Radiotherapy and hyperthermia with curative intent in recurrent high risk soft tissue sarcomas, Int J Hyperthermia, 2018. 34(7): p. 980-987., https://www.ncbi.nlm.nih.gov/pubmed/28826283
[337] Eckert, F., Matuschek, C., Mueller, A. C., Weinmann, M., Hartmann, J. T., Belka, C., et.al. Definitive radiotherapy and single-agent radiosensitizing ifosfamide in patients with localized, irresectable soft tissue sarcoma: a retrospective analysis, Radiat Oncol, 2010. 5: p. 55., https://www.ncbi.nlm.nih.gov/pubmed/20553599
[338] Aiba, H., Yamada, S., Mizutani, J., Yamamoto, N., Okamoto, H., Hayashi, K., et.al. Efficacy of radio-hyperthermo-chemotherapy as salvage therapy for recurrent or residual malignant soft tissue tumors, Int J Hyperthermia, 2018. 35(1): p. 658-666., https://www.ncbi.nlm.nih.gov/pubmed/30295115
[455] Linthorst, M., van Geel, A. N., Baartman, E. A., Oei, S. B., Ghidey, W., van Rhoon, G. C., et.al. Effect of a combined surgery, re-irradiation and hyperthermia therapy on local control rate in radio-induced angiosarcoma of the chest wall, Strahlenther Onkol, 2013. 189(5): p. 387-93., https://www.ncbi.nlm.nih.gov/pubmed/23549781
[456] Digesu, C. S., Wiesel, O., Vaporciyan, A. A., Colson, Y. L., Management of Sarcoma Metastases to the Lung, Surg Oncol Clin N Am, 2016. 25(4): p. 721-33., https://www.ncbi.nlm.nih.gov/pubmed/27591495
[86] Dangoor, A., Seddon, B., Gerrand, C., Grimer, R., Whelan, J., Judson, I., UK guidelines for the management of soft tissue sarcomas, Clin Sarcoma Res, 2016. 6: p. 20., https://www.ncbi.nlm.nih.gov/pubmed/27891213
[457] Gustafson, P., Dreinhofer, K. E., Rydholm, A., Metastasis-free survival after local recurrence of soft-tissue sarcoma, J Bone Joint Surg Br, 1993. 75(4): p. 658-60., https://www.ncbi.nlm.nih.gov/pubmed/8331127
[458] Sabolch, A., Feng, M., Griffith, K., Rzasa, C., Gadzala, L., Feng, F., et.al. Risk factors for local recurrence and metastasis in soft tissue sarcomas of the extremity, Am J Clin Oncol, 2012. 35(2): p. 151-7., https://www.ncbi.nlm.nih.gov/pubmed/21336091