Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Regional chemotherapy by isolated limb perfusion prior to surgery compared with surgery and post-operative radiotherapy for primary, locally advanced extremity sarcoma: a comparison of matched cohorts

Regional chemotherapy by isolated limb perfusion prior to surgery compared with surgery and... Background: Induction chemotherapy by isolated limb perfusion (ILP) with melphalan and tumour necrosis factor‑ α is an effective strategy to facilitate limb ‑ conserving surgery in locally advanced extremity sarcoma. In a comparison of cohorts matched for grade, size and surgical resectability, we compared the outcome of patients undergoing induc‑ tion ILP prior to limb‑ conserving surgery and selective post‑ operative radiotherapy with patients undergoing limb‑ conserving surgery and routine post‑ operative radiotherapy. Methods: Patients with primary, grade 2/3 sarcomas of the lower limbs over 10 cm in size were identified from prospectively maintained databases at 3 centres. Patients treated at a UK centre underwent limb‑ conserving surgery and post‑ operative radiotherapy (Standard cohort). Patients at two German centres underwent induction ILP, limb‑ conserving surgery and selective post‑ operative radiotherapy (ILP cohort). Results: The Standard cohort comprised 80 patients and the ILP cohort 44 patients. Both cohorts were closely matched in terms of tumour size, grade, histological subtype and surgical resectability. The median age was greater in the Standard vs the ILP cohort (60.5 years vs 56 years, p = 0.033). The median size was 13 cm in both cohorts. 5‑ year local‑ recurrence (ILP 12.2%, Standard 20.1%, p = 0.375) and distant metastases‑ free survival rates (ILP 49.6%, Standard 46.0% p = 0.821) did not differ significantly between cohorts. Fewer patients received post ‑ operative radiotherapy in the ILP cohort compared with the Standard cohort (27% vs 82%, p < 0.001). Conclusion: In comparative cohorts, the outcomes of patients undergoing induction ILP prior to surgery did not differ from those undergoing standard management, although induction ILP was associated with a reduced need for adjuvant radiation. Keywords: Soft tissue sarcoma, Isolated limb perfusion, Adjuvant radiotherapy, Postoperative complications *Correspondence: andrew.hayes@rmh.nhs.uk Jens Jakob and Henry George Smith contributed equally to this work Sarcoma Unit, Department of Academic Surgery, Royal Marsden Hospital NHS Foundation Trust, Fulham Road, London SW3 6JJ, UK Full list of author information is available at the end of the article © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Jakob et al. Clin Sarcoma Res (2018) 8:12 Page 2 of 9 oncological outcomes differed between these alternative Background multi-modality approaches to large high-grade sarcoma Extremity soft tissue sarcomas (ESTS) are rare tumours of the lower limb. comprising over 50 different histological subtypes [1, 2]. Optimal management of locally advanced ESTS requires Patients and methods multimodal therapy and the precise role of isolated limb Patient selection perfusion (ILP) in the overall treatment strategy remains Patients were identified from 1996 to 2010 using pro - to be fully defined. For small or superficial ESTS, treat - spectively maintained databases at the Royal Marsden ment usually involves surgery alone, gaining wide sur- Hospital London, UK (defined as the Standard cohort) gical margins while preserving function. Adjuvant and the Sarcoma Center Berlin-Brandenburg and the radiotherapy is reserved for high-grade tumours greater University Medical Center Mannheim, Germany (defined than 5 cm or small tumours that focally involve margins as the ILP cohort). In the ILP cohort, all patients with a adjacent to a critical structure [3]. When sarcomas attain primary, unifocal, intermediate or high-grade (G2 and even greater dimensions, such as over 10 cm, it becomes G3) ESTS of the lower limb with a maximum dimension increasingly difficult to achieve negative margins with - of over 10  cm who underwent an induction ILP prior out recourse to amputation or function-limiting surgery. to a surgical resection were included. In the Standard While amputation for ESTS does not improve survival cohort, all patients with the same characteristics but who for sarcoma over limb-conserving surgery, it may still had undergone limb-conserving surgery were included. be considered for large sarcomas when the risk for local Patients with disseminated disease at diagnosis or who recurrence is viewed as significant [4–6]. had received pre-operative systemic chemotherapy were Induction chemotherapy by ILP using melphalan excluded. with recombinant human tumour necrosis factor alpha Grading was according to the FNCLCC system [12]. (TNFα) prior to a limb-conserving surgical resection Each tumour was staged as T2b N0 MO G2 or G3, corre- was introduced as a strategy for locally advanced sar- sponding to stage IIb or III in the AJCC system [13]. Size comas considered irresectable other than by an ampu- was defined by pre-operative cross sectional imaging (CT tation [7]. TNFα is a multifunctional cytokine, which or MRI) and confirmed after pathological analysis. The causes increased vascular permeability, associated with administration of adjuvant radiotherapy in either cohort increased extravasation of cytotoxic agents and selective was not an inclusion criterion and all decisions relating destruction of tumour-associated vessels by endothelial to radiotherapy were made on an individual patient basis. apoptosis and inflammation [8–10]. A multi-institutional case series of patients with locally advanced sarcomas, Treatment considered to be irresectable with limb-conserving sur- The ILP cohort underwent induction ILP with TNFα gery and adjuvant radiotherapy, which were treated using (Beromun , Boehringer Ingelheim, Germany) and mel- ILP with TNFα reported a limb salvage rate of 84% [7]. phalan followed by a wide or compartmental resection In light of these results, TNFα has been licensed for this of the tumour 6–10  weeks later. Adjuvant radiation was indication since 2006. not given routinely but considered in case of R1 resec- ILP is now used more widely in large, high-grade tions or where the rate of necrosis post-ILP was consid- tumours that are compatible with limb-conserving sur- ered suboptimal. The Standard cohort underwent a wide gery but risk positive resection margins. Such patients or compartmental resection, with radiotherapy offered at would undergo an induction ILP prior to a wide resection 6–12 weeks post-operatively [14]. of the primary tumour, with the aim of gaining as wide a margin as is compatible with preserving limb function. Isolated limb perfusion Post-operative radiotherapy is then typically only offered ILP has been described in detail before [7]. The proce - if the pathology specimen demonstrates viable tumour dure was performed under general anaesthesia. The per - at a compromised margin. The alternative, which might fusions were hyperthermic, with a target temperature of be considered the standard management, would be a 38–39.5  °C. TNFα was administered after a stable limb function-preserving wide resection with adjuvant radio- circuit without leakage had been established, at a dose of therapy to compromised margins. It is known that with 2–4 mg. Melphalan was applied 15 min later, at a dose of adjuvant radiotherapy, planned microscopic positive 10  mg/L of perfused limb volume. Total perfusion time margins over a critical structure are fully compatible with was 90 min. The extremity was then rinsed with hydroxyl long-term local control [11]. ethyl starch. In a retrospective cohort analysis, we sought to determine whether the peri-operative morbidity and Jakob et al. Clin Sarcoma Res (2018) 8:12 Page 3 of 9 Surgical resection the images based on resectability from 1 to 10, with 1 The surgical approach in both cohorts was to achieve being easily resectable by limb-conserving surgery and negative surgical histopathological margins where pos- 10 indicating that limb conservation was impossible and sible in the context of a limb-conserving operation. En- amputation was required (Fig. 1). bloc resections with wide margins (1–2 cm of uninvolved tissue or an intact adjacent fascial layer) were performed Statistical analysis whenever possible. When the tumour abutted major ves- To identify risk factors for local recurrence, metastasis sels or motor nerves, the adventitia or epineurium was and death from disease, stepwise Cox proportional-haz- taken as the margin of resection. When vessels were ards regression analyses were performed using SPSS ver- encased, they were resected and reconstructed. When sion 20. The influence of age (< 65 vs. ≥ 65 years), tumour the tumour abutted the bone, the periosteum was taken size, tumour grade (2 vs. 3), resection margin (R0 vs. R1), en-bloc with the tumour. Soft tissue reconstruction post-operative irradiation (yes vs. no), and local recur- with pedicled or free-flaps was performed whenever rence were assessed. Overall survival, systemic and local necessary. recurrences were calculated using Kaplan–Meier method and compared using the logrank test (Graphpad Prism, Adjuvant radiotherapy Version 6.0). Post-operative radiotherapy was administered 6–10  weeks post-surgery. In the Standard cohort, post- Results operative radiotherapy was considered for all cases. How- Patient characteristics ever, the final decision was made by a multi-disciplinary Details of patient demographics are shown in Table  1. team in light of post-operative histology, the surgical 80 patients were identified in the Standard cohort and margins and the patient’s age and co-morbidities. In the compared to 44 patients in the ILP cohort (Fig.  2). The ILP cohort, radiotherapy was administered in selected median age of patients in the Standard cohort was cases when there was a suboptimal histopathological 60.5  years (range 18–92), which was significantly older response (less than 90% necrosis or viable tumour pre- than the ILP cohort with a median age of 56 years (range sent at a surgical margin). 17–82), (Mann–Whitney test p = 0.033). There was no difference in tumour size between the two cohorts with Histopathological analysis both having a median tumour size of 13  cm (Standard Histopathologic analysis included assessment of resec- range 10–29, ILP range 10–34), (p = 0.915 Mann–Whit- tion margins and pathological response. A macroscopi- ney test). The proportion of grade 2 and 3 tumours was cally positive margin was defined as R2 resection. If the also similar with the Standard cohort having 52 (65%) tumour extended into the resection margin (< 1 mm) on of patients with grade 3 tumours and the ILP cohort 31 microscopic examination, the margin was defined as R1 patients (70.5%) (p = 0.840 Fisher’s exact test). No sig- resection and margins without actual involvement of the nificant difference was found in the score of resectability resection margin (> 1 mm or an intact fascial plane) were between the two groups (Standard Cohort vs ILP median considered microscopically negative (R0). 4.45 vs 5.05 p = 0.314, mean 5.12 vs 4.23 p = 0.112) although the ILP cohort had slightly higher absolute Follow‑up scores (Additional file 1: Figure S1). Patients were followed up every 3–4 month intervals for the first 3 years, then twice a year for up to 5  years, and Treatment annually thereafter. Details of operative characteristics, complications, resec- tion margins, final tumour histology and follow-up are Cohort comparison for resectability shown in Table  2. Patients in the ILP cohort were sig- To ensure that the tumours in both cohorts were equiva- nificantly more likely to undergo vascular reconstruction. lent in terms of resectability, three independent sarcoma The use of flaps was also more common in this cohort. surgeons working at major European sarcoma centres No significant difference in significant complications, reviewed anonymised MRI’s from patients within each defined as wound infections or collections requiring sur - cohort and scored the compatibility of the tumours with gical or radiological intervention, was noted between the limb-conserving surgery and adjuvant radiotherapy two cohorts. Two patients (5%) in the ILP cohort required alone. Twenty patients were randomly selected from an amputation. One amputation was performed in the each cohort. The anonymised images, together with basic peri-operative period due to procedure-related complica- patient details (gender, age, histopathology and tumour tions. The other amputation was performed 18  months size), were then distributed to the assessors who ranked after surgery due to chronic ulceration following a Jakob et al. Clin Sarcoma Res (2018) 8:12 Page 4 of 9 Fig. 1 Examples of MRI imaging of patients used for comparison of tumour resectability in cohorts wound infection. No patients in the Standard cohort Standard cohort 20.1%, p = 0.375 log-rank test) and dis- required amputation. In the Standard cohort 66 (82%) of tant metastases-free survival (ILP cohort 49.6%, Standard patients received adjuvant radiotherapy compared to 12 cohort 46.0%, p = 0.821 log-rank test) did not signifi - (27%) patients in the ILP cohort (p < 0.001, Chi square). cantly differ between cohorts (Fig.  3). Furthermore, at the The reasons for omitting radiotherapy in the Standard time of writing, the local failure rate (i.e. patients devel- cohort were age and associated performance status (4 oping local recurrence or requiring amputation) for both patients, median age 87.3 years), a compartmental resec- treatment arms was identical at 16%. Treatment strategy tion achieving negative margins in all planes (6 patients, was not predictive of local or distant recurrence, with the median age 57.7 years) or the rapid development of pul- only factors found to increase the risk of local recurrence monary metastases in the early post-operative period (4 on multivariate analysis being age and a positive (R1) patients). In the ILP cohort, the local recurrence rate in resection margin (Table  3). The 5-year overall survival patients not receiving adjuvant radiotherapy was not sig- was worse in the Standard cohort compared to the ILP nificantly different to those who did (12.5% vs 8%, p = 1.0 cohort (46.8% vs 63.8%, p = 0.020 log-rank test). How- unpaired t-test). ever, in a Cox proportional hazard model, when the dif- ferences in age between the two cohorts were accounted Oncological Outcomes for, the overall survival on multivariate analysis between The median follow-up for the Standard and ILP cohorts the ILP and Standard cohorts was virtually identical (HR was 31 (4–194) months and 36 (8–163) months, respec- 1.02, 95% CI 1.00–1.04, p = 0.043). tively. The 5-year local recurrence-free (ILP cohort 12.2%, Jakob et al. Clin Sarcoma Res (2018) 8:12 Page 5 of 9 Table 1 Patient and tumour characteristics contrast, induction chemotherapy with ILP is widely rec- ognised to produce markedly better response rates than Standard cohort ILP cohort Overall systemic chemotherapy and has a well-established role Number of patients 80 44 124 in facilitating function-preserving resections in locally Age at operation (median), 60.5 56 57.5 advanced ESTS that would otherwise require amputation years [7, 19–24]. Gender With induction ILP increasingly used for ESTS that may Male 46 (57.5%) 24 (54.5%) 70 (56.5%) be amenable to standard surgical management, the ques- Female 34 (42.5%) 20 (45.5%) 54 (43.5%) tion as to which strategy, if either, is superior has arisen. Tumour site Previous case series have clearly shown that induction Thigh 74 (92.5%) 30 (68.2%) 104 (83.9%) ILP prior to surgery is an effective approach to deal with Popliteal fossa 1 (1.3%) 5 (11.4%) 6 (4.8%) compromised surgical margins, as wide surgical resec- Leg 5 (6.3%) 9 (20.5%) 14 (11.3%) tions were not possible. Similarly adjuvant radiotherapy Median tumour size (cm) 13 13 13 has been shown to be effective in preventing local relapse Tumour grade after positive surgical margins [25]. The ability to directly II 28 (35.0%) 13 (29.5%) 41 (33.1%) compare these treatment strategies is hampered by the III 52 (65.0%) 31 (70.5%) 83 (66.9%) rarity of locally advanced non-metastatic primary ESTS Histology and the scarcity of specialist centres performing ILP. As Pleomorphic 35 (43.8%) 20 (45.5%) 55 (44.4%) such, a randomized study comparing these strategies is not Liposarcoma 13 (16.3%) 10 (22.7%) 23 (18.5%) feasible [26]. Although subject to the limitations of any ret- Leiomyosarcoma 9 (11.3%) 5 (11.4%) 14 (11.3%) rospective study, this comparison of matched cohorts pro- Solitary fibrous tumour 3 (3.8%) 1 (2.3%) 4 (3.2%) vides valuable evidence to compare these two approaches. MPNST 2 (2.5%) 2 (4.5%) 4 (3.2%) The present study has found that the peri-operative and Other 18 (23.8%) 6 (13.6%) 24 (19.4%) oncological outcomes of patients undergoing induction MPNST malignant peripheral nerve sheath tumour ILP prior to surgical resection are very similar to those undergoing standard surgical management. No signifi - cant difference was found in the rate of peri-operative complications between cohorts. Although two patients in Discussion the ILP cohort required amputations, only one was due Standard treatment for locally advanced ESTS consists to procedure-related complications. Similarly, no signifi - of limb-conserving surgery with adjuvant radiotherapy cant difference was found in the rates of local recurrence that may be delivered pre or post-operatively [15]. The between these treatment arms, despite the use of adju- role of (neo)adjuvant chemotherapy outside of specific vant radiotherapy being significantly less frequent in the chemo-sensitive subtypes in ESTS is controversial. In the ILP cohort. There are no clear guidelines regarding the EORTC 62931 study, Woll et al. randomised patients with use of radiotherapy following ILP, although it is typically localised, grade II or III extremity sarcoma to receive considered following an inadequate response on histo- adjuvant cheomotherapy in the form of doxorubicin, ifos- logical assessment of the specimen. However, following a famide and lenogastrim in addition to surgery, radiother- microscopically complete resection with over 50% necro- apy and, if appropriate, ILP [16]. No benefit in terms of sis in the specimen, adjuvant radiotherapy is unlikely to relapse-free or overall survival with this adjuvant regime be of additional benefit [27]. compared to the control cohort were identified (5-year As a retrospective study, this series is subject to the OS 66.5% vs 67.8%). More recently, in the ISG-STS 1001 bias inherent with this methodology. However, analysis study, Gronchi et al. randomised patients with localised, of the tumour characteristics in terms of grade, size and high-grade extremity sarcoma of 5 specified subtypes histological subtype showed that the cohorts were well to receive neoadjuvant standard chemotherapy, in the matched and this is reflected in the identical rate of met - form of epirubicin and ifosfamide, or histotype-tailored astatic spread. Similarly the assessment of the tumours regimes [17]. This trial closed early after an interim anal - “resectability” by independent experts indicated that the ysis demonstrated no benefit in the histotype-tailored technical difficulty of surgery appeared to be similar in regimes. However, at 48  months, overall suvrival in the both cohorts. Although the cohorts were reasonably well standard cohort was 89%, which suggests a potential ben- matched, they were not randomized and we identified efit to neoadjuvant standard chemotherapy in these his - some important differences. There was a higher propor - tological subtypes. As of yet, there is consensus regarding tion of popliteal fossa and leg tumours in the ILP cohort. the role of (neo)adjuvant chemotherapy and its use is not It is generally accepted that achieving local control for considered standard in the most recent guidelines [18]. In Jakob et al. Clin Sarcoma Res (2018) 8:12 Page 6 of 9 Fig. 2 CONSORT diagram of the Standard and ILP cohorts sarcomas is more challenging in the distal than the associated with their use becomes increasingly impor- proximal extremity. Therefore, this may represent a bias tant. Induction ILP carries the risks associated with an towards patients with more challenging tumours being additional operation and short term toxicity associated referred to specialist centres providing ILP. A further with regional chemotherapy. That being said, the peri- limitation to this study is the inability to comment on operative morbidity associated with ILP is generally very the post-operative limb-function in each cohort, an addi- low. Severe regional toxicity following ILP is rare occur- tional important factor that may influence the choice of ring in 2–15% and the need for amputation even more treatment strategy in these patients. so with rates of 0–2% [28]. The long-term complications In the absence of any significant difference in out - from external beam radiotherapy, the technique used in comes between these treatment strategies, the morbidity the majority of patients in this study, are well documented Jakob et al. Clin Sarcoma Res (2018) 8:12 Page 7 of 9 Table 2 Post-operative outcomes in standard and ILP cohorts Standard N = 80 ILP N = 44 p value Complications All 25 (31%) 17 (39%) 0.43 Wound infection 12 (15%) 7 (16%) 1.0 Collection 13 (16%) 8 (18%) 0.81 Amputation 0 (0%) 2 (5%) 0.12 Resection margin R0 65 (81%) 39 (89%) 0.32 R1 15 (19%) 5 (11%) Follow‑up, months Median 31 36 0.3373 (Range) (4–194) (8–163) Local recurrence 13 (16%) 5 (11%) 0.597 Local recurrence OR post‑ operative amputation 13 (16%) 7 (16%) 1 Systemic recurrence 43 (54%) 23 (52%) 1 Fig. 3 Oncological outcomes for the ILP and Standard cohorts (logrank test was used to assess comparison) Table 3 Multivariate cox proportional hazard analysis [29]. However, during the period of this study, advances of factors effecting survival and recurrence of tumours have been made in radiotherapy techniques. When given by cohort pre-operatively, the dose of radiotherapy may be reduced and the use of intensity-modulated radiotherapy, which Local recurrence Systemic recurrence is associated with lower toxicity rates, is becoming more HR (95% CI) p value HR (95% CI) p value widespread [15, 30]. Even so, the long-term sequelae of Standard 1.66 (0.64–4.27) 0.295 1.04 (0.63–1.73) 0.867 radiotherapy, including the risk of second malignancies, ILP 1 1 remain significant and are of particular importance in Increasing Age 1.04 (1.01–1.08) 0.02 1.02 (0.99–1.03) 0.78 young patients [31]. Increasing size 0.951 (0.84–1.08) 0.44 1.04 (0.99–1.09) 0.98 Conclusion 1 Induction ILP followed by a wide resection provides an R1 3.63 (1.36–9.69) 0.01 1.56 (0.85–2.89) 0.153 alternative treatment to standard therapy in the manage- ment of locally advanced ESTS. Consideration should be R0 1 1 given to induction ILP in young patients with large, high- Grade 3 1.74 (0.56–5.35) 0.33 0.91 (0.55–1.51) 0.704 grade extremity sarcomas who would benefit most from Grade 2 1 1 avoiding radiotherapy. Jakob et al. Clin Sarcoma Res (2018) 8:12 Page 8 of 9 sarcomas of the extremities: prospective randomized evaluations of (1) Additional file limb‑sparing surgery plus radiation therapy compared with amputation and (2) the role of adjuvant chemotherapy. Ann Surg. 1982;196(3):305–15. 6. Williard WC, Hajdu SI, Casper ES, Brennan MF. Comparison of amputation Additional file 1: Figure S1. Scatter plot of individual tumour ratings with limb‑sparing operations for adult soft tissue sarcoma of the extrem‑ and median scores of resectability by cohort as assessed by MRI imaging ity. Ann Surg. 1992;215(3):269–75. (see Fig. 1) (statistical analysis was performed using Mann–Whitney test). 7. Eggermont AM, Schraffordt Koops H, Klausner JM, Kroon BB, Schlag PM, Lienard D, van Geel AN, Hoekstra HJ, Meller I, Nieweg OE, et al. Isolated limb perfusion with tumor necrosis factor and melphalan for limb salvage in 186 patients with locally advanced soft tissue extremity Authors’ contributions sarcomas. The cumulative multicenter European experience. Ann Surg. Study concept and design: JJ, AJH, JMT, PH, DS. Acquisition, analysis and inter‑ 1996;224(6):756–64 (discussion 764-755). pretation of data: HGS, MJW, TP, JJ, PUT, PH, AJH, DCS. Drafting manuscript: 8. Bazzoni F, Beutler B. The tumor necrosis factor ligand and receptor fami‑ HGS, MJW, JJ, AJH. All authors read and approved the final manuscript. lies. N Engl J Med. 1996;334(26):1717–25. 9. Locksley RM, Killeen N, Lenardo MJ. The TNF and TNF receptor superfami‑ Author details lies: integrating mammalian biology. Cell. 2001;104(4):487–501. Department of Surgery, Division of Surgical Oncology, University Hospital 10. ten Hagen TL, Eggermont AM. Changing the pathophysiology of solid Mannheim, University of Heidelberg, Mannheim, Germany. Sarcoma Unit, tumours: the potential of TNF and other vasoactive agents. Int J Hyper‑ Department of Academic Surgery, Royal Marsden Hospital NHS Foundation thermia. 2006;22(3):241–6. Trust, Fulham Road, London SW3 6JJ, UK. Department of Orthopedic Oncol‑ 11. O’Donnell PW, Griffin AM, Eward WC, Sternheim A, Catton CN, Chung PW, ogy, Helios Klinikum Berlin‑Buch, Sarcoma Center Berlin‑Brandenburg, Berlin, O’Sullivan B, Ferguson PC, Wunder JS. The effect of the setting of a posi‑ Germany. Medical Faculty Mannheim, University of Heidelberg, Mannheim, tive surgical margin in soft tissue sarcoma. Cancer. 2014;120(18):2866–75. Germany. Department of Surgery, Division of Surgical Oncology and Thoracic 12. Coindre JM. Grading of soft tissue sarcomas: review and update. Arch Surgery, University Hospital Mannheim, University of Heidelberg, Mannheim, Pathol Lab Med. 2006;130(10):1448–53. Germany. 13. Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Acknowledgements Surg Oncol. 2010;17(6):1471–4. JJ was granted a research fellowship by the Royal Marsden NHS foundation 14. Pitcher ME, Thomas JM. Functional compartmental resection for soft tis‑ trust. The authors acknowledge financial support by Deutsche Forschungsge ‑ sue sarcomas. Eur J Surg Oncol. 1994;20(4):441–5. meinschaft and Ruprecht‑Karls‑Universität Heidelberg within the funding 15. O’Sullivan B, Davis AM, Turcotte R, Bell R, Catton C, Chabot P, Wunder programme Open Access Publishing. No other funding was received for this J, Kandel R, Goddard K, Sadura A, et al. Preoperative versus postopera‑ study. tive radiotherapy in soft‑tissue sarcoma of the limbs: a randomised trial. Lancet. 2002;359(9325):2235–41. Competing interests 16. Woll PJ, Reichardt P, Le Cesne A, Bonvalot S, Azzarelli A, Hoekstra HJ, Leahy Peter Hohenberger and Jens Jakob received honoraria from Boehringer M, Van Coevorden F, Verweij J, Hogendoorn PC, et al. Adjuvant chemo‑ Ingelheim. therapy with doxorubicin, ifosfamide, and lenograstim for resected soft‑ tissue sarcoma (EORTC 62931): a multicentre randomised controlled trial. Availability of data and materials Lancet Oncol. 2012;13(10):1045–54. The datasets used and analysed during the current study are available from 17. Gronchi A, Ferrari S, Quagliuolo V, Broto JM, Pousa AL, Grignani G, Basso the corresponding author on reasonable request. U, Blay JY, Tendero O, Beveridge RD, et al. Histotype‑tailored neoadju‑ vant chemotherapy versus standard chemotherapy in patients with Consent for publication high‑risk soft ‑tissue sarcomas (ISG‑STS 1001): an international, open‑ Not applicable. label, randomised, controlled, phase 3, multicentre trial. Lancet Oncol. 2017;18(6):812–22. Ethics approval and consent to participate 18. Group ESESNW. Soft tissue and visceral sarcomas: ESMO clinical Ethical approval for this study was obtained from an institutional review board. practice guidelines for diagnosis, treatment and follow‑up. Ann Oncol. 2014;25(Suppl 3):102–12. Publisher’s Note 19. Bonvalot S, Laplanche A, Lejeune F, Stoeckle E, Le Pechoux C, Vanel D, Springer Nature remains neutral with regard to jurisdictional claims in pub‑ Terrier P, Lumbroso J, Ricard M, Antoni G, et al. Limb salvage with isolated lished maps and institutional affiliations. perfusion for soft tissue sarcoma: could less TNF‑alpha be better? Ann Oncol. 2005;16(7):1061–8. Received: 17 October 2017 Accepted: 17 March 2018 20. Cherix S, Speiser M, Matter M, Raffoul W, Lienard D, Theumann N, Mouh‑ sine E, Mirimanoff RO, Leyvraz S, Lejeune FJ, et al. Isolated limb perfusion with tumor necrosis factor and melphalan for non‑resectable soft tissue sarcomas: long‑term results on efficacy and limb salvage in a selected group of patients. J Surg Oncol. 2008;98(3):148–55. 21. Deroose JP, Eggermont AM, van Geel AN, Burger JW, den Bakker MA, de References Wilt JH, Verhoef C. Long‑term results of tumor necrosis factor alpha‑ and 1. Grimer R, Judson I, Peake D, Seddon B. Guidelines for the management of melphalan‑based isolated limb perfusion in locally advanced extremity soft tissue sarcomas. Sarcoma. 2010;2010:506182. soft tissue sarcomas. J Clin Oncol. 2011;29(30):4036–44. 2. Rastrelli M, Tropea S, Basso U, Roma A, Maruzzo M, Rossi CR. Soft tissue 22. Gutman M, Inbar M, Lev‑Shlush D, Abu‑Abid S, Mozes M, Chaitchik S, Mel‑ limb and trunk sarcomas: diagnosis, treatment and follow‑up. Anticancer ler I, Klausner JM. High dose tumor necrosis factor‑alpha and melphalan Res. 2014;34(10):5251–62. administered via isolated limb perfusion for advanced limb soft tissue 3. Casali PG, Blay JY. experts ECECPo: soft tissue sarcomas: ESMO clinical sarcoma results in a > 90% response rate and limb preservation. Cancer. practice guidelines for diagnosis, treatment and follow‑up. Ann Oncol. 1997;79(6):1129–37. 2010;21(Suppl 5):v198–203. 23. Pennacchioli E, Deraco M, Mariani L, Fiore M, Mussi C, Collini P, Olmi 4. Alamanda VK, Crosby SN, Archer KR, Song Y, Schwartz HS, Holt GE. Ampu‑ P, Casali PG, Santinami M, Gronchi A. Advanced extremity soft tissue tation for extremity soft tissue sarcoma does not increase overall survival: sarcoma: prognostic effect of isolated limb perfusion in a series of 88 a retrospective cohort study. Eur J Surg Oncol. 2012;38(12):1178–83. patients treated at a single institution. Ann Surg Oncol. 2007;14(2):553–9. 5. Rosenberg SA, Tepper J, Glatstein E, Costa J, Baker A, Brennan M, DeMoss 24. Jakob J, Tunn PU, Hayes AJ, Pilz LR, Nowak K, Hohenberger P. Oncologi‑ EV, Seipp C, Sindelar WF, Sugarbaker P, et al. The treatment of soft‑tissue cal outcome of primary non‑metastatic soft tissue sarcoma treated by Jakob et al. Clin Sarcoma Res (2018) 8:12 Page 9 of 9 neoadjuvant isolated limb perfusion and tumor resection. J Surg Oncol. 28. Smith HG, Hayes AJ. The role of regional chemotherapy in the 2014;109(8):786–90. management of extremity soft tissue malignancies. Eur J Surg Oncol. 25. Yang JC, Chang AE, Baker AR, Sindelar WF, Danforth DN, Topalian SL, 2016;42(1):7–17. DeLaney T, Glatstein E, Steinberg SM, Merino MJ, et al. Randomized 29. Davis AM, O’Sullivan B, Turcotte R, Bell R, Catton C, Chabot P, Wunder J, prospective study of the benefit of adjuvant radiation therapy in Hammond A, Benk V, Kandel R, et al. Late radiation morbidity following the treatment of soft tissue sarcomas of the extremity. J Clin Oncol. randomization to preoperative versus postoperative radiotherapy in 1998;16(1):197–203. extremity soft tissue sarcoma. Radiother Oncol. 2005;75(1):48–53. 26. Bonvalot S, Gronchi A. ILP and RT: the study that will never be. Ann Surg 30. Folkert MR, Singer S, Brennan MF, Kuk D, Qin LX, Kobayashi WK, Crago Oncol. 2011;18(2):303–5. AM, Alektiar KM. Comparison of local recurrence with conventional and 27. Deroose JP, Burger JW, van Geel AN, den Bakker MA, de Jong JS, Egger‑ intensity‑modulated radiation therapy for primary soft ‑tissue sarcomas of mont AM, Verhoef C. Radiotherapy for soft tissue sarcomas after isolated the extremity. J Clin Oncol. 2014;32(29):3236–41. limb perfusion and surgical resection: essential for local control in all 31. Hall EJ, Wuu CS. Radiation‑induced second cancers: the impact of 3D ‑ CRT patients? Ann Surg Oncol. 2011;18(2):321–7. and IMRT. Int J Radiat Oncol Biol Phys. 2003;56(1):83–8. Submit your next manuscript to BioMed Central and we will help you at every step: • We accept pre-submission inquiries • Our selector tool helps you to find the most relevant journal • We provide round the clock customer support • Convenient online submission • Thorough peer review • Inclusion in PubMed and all major indexing services • Maximum visibility for your research Submit your manuscript at www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical Sarcoma Research Springer Journals

Regional chemotherapy by isolated limb perfusion prior to surgery compared with surgery and post-operative radiotherapy for primary, locally advanced extremity sarcoma: a comparison of matched cohorts

Loading next page...
 
/lp/springer-journals/regional-chemotherapy-by-isolated-limb-perfusion-prior-to-surgery-mo0dK20ViP
Publisher
Springer Journals
Copyright
Copyright © 2018 by The Author(s)
Subject
Biomedicine; Cancer Research; Oncology; Surgical Oncology
eISSN
2045-3329
DOI
10.1186/s13569-018-0098-6
Publisher site
See Article on Publisher Site

Abstract

Background: Induction chemotherapy by isolated limb perfusion (ILP) with melphalan and tumour necrosis factor‑ α is an effective strategy to facilitate limb ‑ conserving surgery in locally advanced extremity sarcoma. In a comparison of cohorts matched for grade, size and surgical resectability, we compared the outcome of patients undergoing induc‑ tion ILP prior to limb‑ conserving surgery and selective post‑ operative radiotherapy with patients undergoing limb‑ conserving surgery and routine post‑ operative radiotherapy. Methods: Patients with primary, grade 2/3 sarcomas of the lower limbs over 10 cm in size were identified from prospectively maintained databases at 3 centres. Patients treated at a UK centre underwent limb‑ conserving surgery and post‑ operative radiotherapy (Standard cohort). Patients at two German centres underwent induction ILP, limb‑ conserving surgery and selective post‑ operative radiotherapy (ILP cohort). Results: The Standard cohort comprised 80 patients and the ILP cohort 44 patients. Both cohorts were closely matched in terms of tumour size, grade, histological subtype and surgical resectability. The median age was greater in the Standard vs the ILP cohort (60.5 years vs 56 years, p = 0.033). The median size was 13 cm in both cohorts. 5‑ year local‑ recurrence (ILP 12.2%, Standard 20.1%, p = 0.375) and distant metastases‑ free survival rates (ILP 49.6%, Standard 46.0% p = 0.821) did not differ significantly between cohorts. Fewer patients received post ‑ operative radiotherapy in the ILP cohort compared with the Standard cohort (27% vs 82%, p < 0.001). Conclusion: In comparative cohorts, the outcomes of patients undergoing induction ILP prior to surgery did not differ from those undergoing standard management, although induction ILP was associated with a reduced need for adjuvant radiation. Keywords: Soft tissue sarcoma, Isolated limb perfusion, Adjuvant radiotherapy, Postoperative complications *Correspondence: andrew.hayes@rmh.nhs.uk Jens Jakob and Henry George Smith contributed equally to this work Sarcoma Unit, Department of Academic Surgery, Royal Marsden Hospital NHS Foundation Trust, Fulham Road, London SW3 6JJ, UK Full list of author information is available at the end of the article © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Jakob et al. Clin Sarcoma Res (2018) 8:12 Page 2 of 9 oncological outcomes differed between these alternative Background multi-modality approaches to large high-grade sarcoma Extremity soft tissue sarcomas (ESTS) are rare tumours of the lower limb. comprising over 50 different histological subtypes [1, 2]. Optimal management of locally advanced ESTS requires Patients and methods multimodal therapy and the precise role of isolated limb Patient selection perfusion (ILP) in the overall treatment strategy remains Patients were identified from 1996 to 2010 using pro - to be fully defined. For small or superficial ESTS, treat - spectively maintained databases at the Royal Marsden ment usually involves surgery alone, gaining wide sur- Hospital London, UK (defined as the Standard cohort) gical margins while preserving function. Adjuvant and the Sarcoma Center Berlin-Brandenburg and the radiotherapy is reserved for high-grade tumours greater University Medical Center Mannheim, Germany (defined than 5 cm or small tumours that focally involve margins as the ILP cohort). In the ILP cohort, all patients with a adjacent to a critical structure [3]. When sarcomas attain primary, unifocal, intermediate or high-grade (G2 and even greater dimensions, such as over 10 cm, it becomes G3) ESTS of the lower limb with a maximum dimension increasingly difficult to achieve negative margins with - of over 10  cm who underwent an induction ILP prior out recourse to amputation or function-limiting surgery. to a surgical resection were included. In the Standard While amputation for ESTS does not improve survival cohort, all patients with the same characteristics but who for sarcoma over limb-conserving surgery, it may still had undergone limb-conserving surgery were included. be considered for large sarcomas when the risk for local Patients with disseminated disease at diagnosis or who recurrence is viewed as significant [4–6]. had received pre-operative systemic chemotherapy were Induction chemotherapy by ILP using melphalan excluded. with recombinant human tumour necrosis factor alpha Grading was according to the FNCLCC system [12]. (TNFα) prior to a limb-conserving surgical resection Each tumour was staged as T2b N0 MO G2 or G3, corre- was introduced as a strategy for locally advanced sar- sponding to stage IIb or III in the AJCC system [13]. Size comas considered irresectable other than by an ampu- was defined by pre-operative cross sectional imaging (CT tation [7]. TNFα is a multifunctional cytokine, which or MRI) and confirmed after pathological analysis. The causes increased vascular permeability, associated with administration of adjuvant radiotherapy in either cohort increased extravasation of cytotoxic agents and selective was not an inclusion criterion and all decisions relating destruction of tumour-associated vessels by endothelial to radiotherapy were made on an individual patient basis. apoptosis and inflammation [8–10]. A multi-institutional case series of patients with locally advanced sarcomas, Treatment considered to be irresectable with limb-conserving sur- The ILP cohort underwent induction ILP with TNFα gery and adjuvant radiotherapy, which were treated using (Beromun , Boehringer Ingelheim, Germany) and mel- ILP with TNFα reported a limb salvage rate of 84% [7]. phalan followed by a wide or compartmental resection In light of these results, TNFα has been licensed for this of the tumour 6–10  weeks later. Adjuvant radiation was indication since 2006. not given routinely but considered in case of R1 resec- ILP is now used more widely in large, high-grade tions or where the rate of necrosis post-ILP was consid- tumours that are compatible with limb-conserving sur- ered suboptimal. The Standard cohort underwent a wide gery but risk positive resection margins. Such patients or compartmental resection, with radiotherapy offered at would undergo an induction ILP prior to a wide resection 6–12 weeks post-operatively [14]. of the primary tumour, with the aim of gaining as wide a margin as is compatible with preserving limb function. Isolated limb perfusion Post-operative radiotherapy is then typically only offered ILP has been described in detail before [7]. The proce - if the pathology specimen demonstrates viable tumour dure was performed under general anaesthesia. The per - at a compromised margin. The alternative, which might fusions were hyperthermic, with a target temperature of be considered the standard management, would be a 38–39.5  °C. TNFα was administered after a stable limb function-preserving wide resection with adjuvant radio- circuit without leakage had been established, at a dose of therapy to compromised margins. It is known that with 2–4 mg. Melphalan was applied 15 min later, at a dose of adjuvant radiotherapy, planned microscopic positive 10  mg/L of perfused limb volume. Total perfusion time margins over a critical structure are fully compatible with was 90 min. The extremity was then rinsed with hydroxyl long-term local control [11]. ethyl starch. In a retrospective cohort analysis, we sought to determine whether the peri-operative morbidity and Jakob et al. Clin Sarcoma Res (2018) 8:12 Page 3 of 9 Surgical resection the images based on resectability from 1 to 10, with 1 The surgical approach in both cohorts was to achieve being easily resectable by limb-conserving surgery and negative surgical histopathological margins where pos- 10 indicating that limb conservation was impossible and sible in the context of a limb-conserving operation. En- amputation was required (Fig. 1). bloc resections with wide margins (1–2 cm of uninvolved tissue or an intact adjacent fascial layer) were performed Statistical analysis whenever possible. When the tumour abutted major ves- To identify risk factors for local recurrence, metastasis sels or motor nerves, the adventitia or epineurium was and death from disease, stepwise Cox proportional-haz- taken as the margin of resection. When vessels were ards regression analyses were performed using SPSS ver- encased, they were resected and reconstructed. When sion 20. The influence of age (< 65 vs. ≥ 65 years), tumour the tumour abutted the bone, the periosteum was taken size, tumour grade (2 vs. 3), resection margin (R0 vs. R1), en-bloc with the tumour. Soft tissue reconstruction post-operative irradiation (yes vs. no), and local recur- with pedicled or free-flaps was performed whenever rence were assessed. Overall survival, systemic and local necessary. recurrences were calculated using Kaplan–Meier method and compared using the logrank test (Graphpad Prism, Adjuvant radiotherapy Version 6.0). Post-operative radiotherapy was administered 6–10  weeks post-surgery. In the Standard cohort, post- Results operative radiotherapy was considered for all cases. How- Patient characteristics ever, the final decision was made by a multi-disciplinary Details of patient demographics are shown in Table  1. team in light of post-operative histology, the surgical 80 patients were identified in the Standard cohort and margins and the patient’s age and co-morbidities. In the compared to 44 patients in the ILP cohort (Fig.  2). The ILP cohort, radiotherapy was administered in selected median age of patients in the Standard cohort was cases when there was a suboptimal histopathological 60.5  years (range 18–92), which was significantly older response (less than 90% necrosis or viable tumour pre- than the ILP cohort with a median age of 56 years (range sent at a surgical margin). 17–82), (Mann–Whitney test p = 0.033). There was no difference in tumour size between the two cohorts with Histopathological analysis both having a median tumour size of 13  cm (Standard Histopathologic analysis included assessment of resec- range 10–29, ILP range 10–34), (p = 0.915 Mann–Whit- tion margins and pathological response. A macroscopi- ney test). The proportion of grade 2 and 3 tumours was cally positive margin was defined as R2 resection. If the also similar with the Standard cohort having 52 (65%) tumour extended into the resection margin (< 1 mm) on of patients with grade 3 tumours and the ILP cohort 31 microscopic examination, the margin was defined as R1 patients (70.5%) (p = 0.840 Fisher’s exact test). No sig- resection and margins without actual involvement of the nificant difference was found in the score of resectability resection margin (> 1 mm or an intact fascial plane) were between the two groups (Standard Cohort vs ILP median considered microscopically negative (R0). 4.45 vs 5.05 p = 0.314, mean 5.12 vs 4.23 p = 0.112) although the ILP cohort had slightly higher absolute Follow‑up scores (Additional file 1: Figure S1). Patients were followed up every 3–4 month intervals for the first 3 years, then twice a year for up to 5  years, and Treatment annually thereafter. Details of operative characteristics, complications, resec- tion margins, final tumour histology and follow-up are Cohort comparison for resectability shown in Table  2. Patients in the ILP cohort were sig- To ensure that the tumours in both cohorts were equiva- nificantly more likely to undergo vascular reconstruction. lent in terms of resectability, three independent sarcoma The use of flaps was also more common in this cohort. surgeons working at major European sarcoma centres No significant difference in significant complications, reviewed anonymised MRI’s from patients within each defined as wound infections or collections requiring sur - cohort and scored the compatibility of the tumours with gical or radiological intervention, was noted between the limb-conserving surgery and adjuvant radiotherapy two cohorts. Two patients (5%) in the ILP cohort required alone. Twenty patients were randomly selected from an amputation. One amputation was performed in the each cohort. The anonymised images, together with basic peri-operative period due to procedure-related complica- patient details (gender, age, histopathology and tumour tions. The other amputation was performed 18  months size), were then distributed to the assessors who ranked after surgery due to chronic ulceration following a Jakob et al. Clin Sarcoma Res (2018) 8:12 Page 4 of 9 Fig. 1 Examples of MRI imaging of patients used for comparison of tumour resectability in cohorts wound infection. No patients in the Standard cohort Standard cohort 20.1%, p = 0.375 log-rank test) and dis- required amputation. In the Standard cohort 66 (82%) of tant metastases-free survival (ILP cohort 49.6%, Standard patients received adjuvant radiotherapy compared to 12 cohort 46.0%, p = 0.821 log-rank test) did not signifi - (27%) patients in the ILP cohort (p < 0.001, Chi square). cantly differ between cohorts (Fig.  3). Furthermore, at the The reasons for omitting radiotherapy in the Standard time of writing, the local failure rate (i.e. patients devel- cohort were age and associated performance status (4 oping local recurrence or requiring amputation) for both patients, median age 87.3 years), a compartmental resec- treatment arms was identical at 16%. Treatment strategy tion achieving negative margins in all planes (6 patients, was not predictive of local or distant recurrence, with the median age 57.7 years) or the rapid development of pul- only factors found to increase the risk of local recurrence monary metastases in the early post-operative period (4 on multivariate analysis being age and a positive (R1) patients). In the ILP cohort, the local recurrence rate in resection margin (Table  3). The 5-year overall survival patients not receiving adjuvant radiotherapy was not sig- was worse in the Standard cohort compared to the ILP nificantly different to those who did (12.5% vs 8%, p = 1.0 cohort (46.8% vs 63.8%, p = 0.020 log-rank test). How- unpaired t-test). ever, in a Cox proportional hazard model, when the dif- ferences in age between the two cohorts were accounted Oncological Outcomes for, the overall survival on multivariate analysis between The median follow-up for the Standard and ILP cohorts the ILP and Standard cohorts was virtually identical (HR was 31 (4–194) months and 36 (8–163) months, respec- 1.02, 95% CI 1.00–1.04, p = 0.043). tively. The 5-year local recurrence-free (ILP cohort 12.2%, Jakob et al. Clin Sarcoma Res (2018) 8:12 Page 5 of 9 Table 1 Patient and tumour characteristics contrast, induction chemotherapy with ILP is widely rec- ognised to produce markedly better response rates than Standard cohort ILP cohort Overall systemic chemotherapy and has a well-established role Number of patients 80 44 124 in facilitating function-preserving resections in locally Age at operation (median), 60.5 56 57.5 advanced ESTS that would otherwise require amputation years [7, 19–24]. Gender With induction ILP increasingly used for ESTS that may Male 46 (57.5%) 24 (54.5%) 70 (56.5%) be amenable to standard surgical management, the ques- Female 34 (42.5%) 20 (45.5%) 54 (43.5%) tion as to which strategy, if either, is superior has arisen. Tumour site Previous case series have clearly shown that induction Thigh 74 (92.5%) 30 (68.2%) 104 (83.9%) ILP prior to surgery is an effective approach to deal with Popliteal fossa 1 (1.3%) 5 (11.4%) 6 (4.8%) compromised surgical margins, as wide surgical resec- Leg 5 (6.3%) 9 (20.5%) 14 (11.3%) tions were not possible. Similarly adjuvant radiotherapy Median tumour size (cm) 13 13 13 has been shown to be effective in preventing local relapse Tumour grade after positive surgical margins [25]. The ability to directly II 28 (35.0%) 13 (29.5%) 41 (33.1%) compare these treatment strategies is hampered by the III 52 (65.0%) 31 (70.5%) 83 (66.9%) rarity of locally advanced non-metastatic primary ESTS Histology and the scarcity of specialist centres performing ILP. As Pleomorphic 35 (43.8%) 20 (45.5%) 55 (44.4%) such, a randomized study comparing these strategies is not Liposarcoma 13 (16.3%) 10 (22.7%) 23 (18.5%) feasible [26]. Although subject to the limitations of any ret- Leiomyosarcoma 9 (11.3%) 5 (11.4%) 14 (11.3%) rospective study, this comparison of matched cohorts pro- Solitary fibrous tumour 3 (3.8%) 1 (2.3%) 4 (3.2%) vides valuable evidence to compare these two approaches. MPNST 2 (2.5%) 2 (4.5%) 4 (3.2%) The present study has found that the peri-operative and Other 18 (23.8%) 6 (13.6%) 24 (19.4%) oncological outcomes of patients undergoing induction MPNST malignant peripheral nerve sheath tumour ILP prior to surgical resection are very similar to those undergoing standard surgical management. No signifi - cant difference was found in the rate of peri-operative complications between cohorts. Although two patients in Discussion the ILP cohort required amputations, only one was due Standard treatment for locally advanced ESTS consists to procedure-related complications. Similarly, no signifi - of limb-conserving surgery with adjuvant radiotherapy cant difference was found in the rates of local recurrence that may be delivered pre or post-operatively [15]. The between these treatment arms, despite the use of adju- role of (neo)adjuvant chemotherapy outside of specific vant radiotherapy being significantly less frequent in the chemo-sensitive subtypes in ESTS is controversial. In the ILP cohort. There are no clear guidelines regarding the EORTC 62931 study, Woll et al. randomised patients with use of radiotherapy following ILP, although it is typically localised, grade II or III extremity sarcoma to receive considered following an inadequate response on histo- adjuvant cheomotherapy in the form of doxorubicin, ifos- logical assessment of the specimen. However, following a famide and lenogastrim in addition to surgery, radiother- microscopically complete resection with over 50% necro- apy and, if appropriate, ILP [16]. No benefit in terms of sis in the specimen, adjuvant radiotherapy is unlikely to relapse-free or overall survival with this adjuvant regime be of additional benefit [27]. compared to the control cohort were identified (5-year As a retrospective study, this series is subject to the OS 66.5% vs 67.8%). More recently, in the ISG-STS 1001 bias inherent with this methodology. However, analysis study, Gronchi et al. randomised patients with localised, of the tumour characteristics in terms of grade, size and high-grade extremity sarcoma of 5 specified subtypes histological subtype showed that the cohorts were well to receive neoadjuvant standard chemotherapy, in the matched and this is reflected in the identical rate of met - form of epirubicin and ifosfamide, or histotype-tailored astatic spread. Similarly the assessment of the tumours regimes [17]. This trial closed early after an interim anal - “resectability” by independent experts indicated that the ysis demonstrated no benefit in the histotype-tailored technical difficulty of surgery appeared to be similar in regimes. However, at 48  months, overall suvrival in the both cohorts. Although the cohorts were reasonably well standard cohort was 89%, which suggests a potential ben- matched, they were not randomized and we identified efit to neoadjuvant standard chemotherapy in these his - some important differences. There was a higher propor - tological subtypes. As of yet, there is consensus regarding tion of popliteal fossa and leg tumours in the ILP cohort. the role of (neo)adjuvant chemotherapy and its use is not It is generally accepted that achieving local control for considered standard in the most recent guidelines [18]. In Jakob et al. Clin Sarcoma Res (2018) 8:12 Page 6 of 9 Fig. 2 CONSORT diagram of the Standard and ILP cohorts sarcomas is more challenging in the distal than the associated with their use becomes increasingly impor- proximal extremity. Therefore, this may represent a bias tant. Induction ILP carries the risks associated with an towards patients with more challenging tumours being additional operation and short term toxicity associated referred to specialist centres providing ILP. A further with regional chemotherapy. That being said, the peri- limitation to this study is the inability to comment on operative morbidity associated with ILP is generally very the post-operative limb-function in each cohort, an addi- low. Severe regional toxicity following ILP is rare occur- tional important factor that may influence the choice of ring in 2–15% and the need for amputation even more treatment strategy in these patients. so with rates of 0–2% [28]. The long-term complications In the absence of any significant difference in out - from external beam radiotherapy, the technique used in comes between these treatment strategies, the morbidity the majority of patients in this study, are well documented Jakob et al. Clin Sarcoma Res (2018) 8:12 Page 7 of 9 Table 2 Post-operative outcomes in standard and ILP cohorts Standard N = 80 ILP N = 44 p value Complications All 25 (31%) 17 (39%) 0.43 Wound infection 12 (15%) 7 (16%) 1.0 Collection 13 (16%) 8 (18%) 0.81 Amputation 0 (0%) 2 (5%) 0.12 Resection margin R0 65 (81%) 39 (89%) 0.32 R1 15 (19%) 5 (11%) Follow‑up, months Median 31 36 0.3373 (Range) (4–194) (8–163) Local recurrence 13 (16%) 5 (11%) 0.597 Local recurrence OR post‑ operative amputation 13 (16%) 7 (16%) 1 Systemic recurrence 43 (54%) 23 (52%) 1 Fig. 3 Oncological outcomes for the ILP and Standard cohorts (logrank test was used to assess comparison) Table 3 Multivariate cox proportional hazard analysis [29]. However, during the period of this study, advances of factors effecting survival and recurrence of tumours have been made in radiotherapy techniques. When given by cohort pre-operatively, the dose of radiotherapy may be reduced and the use of intensity-modulated radiotherapy, which Local recurrence Systemic recurrence is associated with lower toxicity rates, is becoming more HR (95% CI) p value HR (95% CI) p value widespread [15, 30]. Even so, the long-term sequelae of Standard 1.66 (0.64–4.27) 0.295 1.04 (0.63–1.73) 0.867 radiotherapy, including the risk of second malignancies, ILP 1 1 remain significant and are of particular importance in Increasing Age 1.04 (1.01–1.08) 0.02 1.02 (0.99–1.03) 0.78 young patients [31]. Increasing size 0.951 (0.84–1.08) 0.44 1.04 (0.99–1.09) 0.98 Conclusion 1 Induction ILP followed by a wide resection provides an R1 3.63 (1.36–9.69) 0.01 1.56 (0.85–2.89) 0.153 alternative treatment to standard therapy in the manage- ment of locally advanced ESTS. Consideration should be R0 1 1 given to induction ILP in young patients with large, high- Grade 3 1.74 (0.56–5.35) 0.33 0.91 (0.55–1.51) 0.704 grade extremity sarcomas who would benefit most from Grade 2 1 1 avoiding radiotherapy. Jakob et al. Clin Sarcoma Res (2018) 8:12 Page 8 of 9 sarcomas of the extremities: prospective randomized evaluations of (1) Additional file limb‑sparing surgery plus radiation therapy compared with amputation and (2) the role of adjuvant chemotherapy. Ann Surg. 1982;196(3):305–15. 6. Williard WC, Hajdu SI, Casper ES, Brennan MF. Comparison of amputation Additional file 1: Figure S1. Scatter plot of individual tumour ratings with limb‑sparing operations for adult soft tissue sarcoma of the extrem‑ and median scores of resectability by cohort as assessed by MRI imaging ity. Ann Surg. 1992;215(3):269–75. (see Fig. 1) (statistical analysis was performed using Mann–Whitney test). 7. Eggermont AM, Schraffordt Koops H, Klausner JM, Kroon BB, Schlag PM, Lienard D, van Geel AN, Hoekstra HJ, Meller I, Nieweg OE, et al. Isolated limb perfusion with tumor necrosis factor and melphalan for limb salvage in 186 patients with locally advanced soft tissue extremity Authors’ contributions sarcomas. The cumulative multicenter European experience. Ann Surg. Study concept and design: JJ, AJH, JMT, PH, DS. Acquisition, analysis and inter‑ 1996;224(6):756–64 (discussion 764-755). pretation of data: HGS, MJW, TP, JJ, PUT, PH, AJH, DCS. Drafting manuscript: 8. Bazzoni F, Beutler B. The tumor necrosis factor ligand and receptor fami‑ HGS, MJW, JJ, AJH. All authors read and approved the final manuscript. lies. N Engl J Med. 1996;334(26):1717–25. 9. Locksley RM, Killeen N, Lenardo MJ. The TNF and TNF receptor superfami‑ Author details lies: integrating mammalian biology. Cell. 2001;104(4):487–501. Department of Surgery, Division of Surgical Oncology, University Hospital 10. ten Hagen TL, Eggermont AM. Changing the pathophysiology of solid Mannheim, University of Heidelberg, Mannheim, Germany. Sarcoma Unit, tumours: the potential of TNF and other vasoactive agents. Int J Hyper‑ Department of Academic Surgery, Royal Marsden Hospital NHS Foundation thermia. 2006;22(3):241–6. Trust, Fulham Road, London SW3 6JJ, UK. Department of Orthopedic Oncol‑ 11. O’Donnell PW, Griffin AM, Eward WC, Sternheim A, Catton CN, Chung PW, ogy, Helios Klinikum Berlin‑Buch, Sarcoma Center Berlin‑Brandenburg, Berlin, O’Sullivan B, Ferguson PC, Wunder JS. The effect of the setting of a posi‑ Germany. Medical Faculty Mannheim, University of Heidelberg, Mannheim, tive surgical margin in soft tissue sarcoma. Cancer. 2014;120(18):2866–75. Germany. Department of Surgery, Division of Surgical Oncology and Thoracic 12. Coindre JM. Grading of soft tissue sarcomas: review and update. Arch Surgery, University Hospital Mannheim, University of Heidelberg, Mannheim, Pathol Lab Med. 2006;130(10):1448–53. Germany. 13. Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Acknowledgements Surg Oncol. 2010;17(6):1471–4. JJ was granted a research fellowship by the Royal Marsden NHS foundation 14. Pitcher ME, Thomas JM. Functional compartmental resection for soft tis‑ trust. The authors acknowledge financial support by Deutsche Forschungsge ‑ sue sarcomas. Eur J Surg Oncol. 1994;20(4):441–5. meinschaft and Ruprecht‑Karls‑Universität Heidelberg within the funding 15. O’Sullivan B, Davis AM, Turcotte R, Bell R, Catton C, Chabot P, Wunder programme Open Access Publishing. No other funding was received for this J, Kandel R, Goddard K, Sadura A, et al. Preoperative versus postopera‑ study. tive radiotherapy in soft‑tissue sarcoma of the limbs: a randomised trial. Lancet. 2002;359(9325):2235–41. Competing interests 16. Woll PJ, Reichardt P, Le Cesne A, Bonvalot S, Azzarelli A, Hoekstra HJ, Leahy Peter Hohenberger and Jens Jakob received honoraria from Boehringer M, Van Coevorden F, Verweij J, Hogendoorn PC, et al. Adjuvant chemo‑ Ingelheim. therapy with doxorubicin, ifosfamide, and lenograstim for resected soft‑ tissue sarcoma (EORTC 62931): a multicentre randomised controlled trial. Availability of data and materials Lancet Oncol. 2012;13(10):1045–54. The datasets used and analysed during the current study are available from 17. Gronchi A, Ferrari S, Quagliuolo V, Broto JM, Pousa AL, Grignani G, Basso the corresponding author on reasonable request. U, Blay JY, Tendero O, Beveridge RD, et al. Histotype‑tailored neoadju‑ vant chemotherapy versus standard chemotherapy in patients with Consent for publication high‑risk soft ‑tissue sarcomas (ISG‑STS 1001): an international, open‑ Not applicable. label, randomised, controlled, phase 3, multicentre trial. Lancet Oncol. 2017;18(6):812–22. Ethics approval and consent to participate 18. Group ESESNW. Soft tissue and visceral sarcomas: ESMO clinical Ethical approval for this study was obtained from an institutional review board. practice guidelines for diagnosis, treatment and follow‑up. Ann Oncol. 2014;25(Suppl 3):102–12. Publisher’s Note 19. Bonvalot S, Laplanche A, Lejeune F, Stoeckle E, Le Pechoux C, Vanel D, Springer Nature remains neutral with regard to jurisdictional claims in pub‑ Terrier P, Lumbroso J, Ricard M, Antoni G, et al. Limb salvage with isolated lished maps and institutional affiliations. perfusion for soft tissue sarcoma: could less TNF‑alpha be better? Ann Oncol. 2005;16(7):1061–8. Received: 17 October 2017 Accepted: 17 March 2018 20. Cherix S, Speiser M, Matter M, Raffoul W, Lienard D, Theumann N, Mouh‑ sine E, Mirimanoff RO, Leyvraz S, Lejeune FJ, et al. Isolated limb perfusion with tumor necrosis factor and melphalan for non‑resectable soft tissue sarcomas: long‑term results on efficacy and limb salvage in a selected group of patients. J Surg Oncol. 2008;98(3):148–55. 21. Deroose JP, Eggermont AM, van Geel AN, Burger JW, den Bakker MA, de References Wilt JH, Verhoef C. Long‑term results of tumor necrosis factor alpha‑ and 1. Grimer R, Judson I, Peake D, Seddon B. Guidelines for the management of melphalan‑based isolated limb perfusion in locally advanced extremity soft tissue sarcomas. Sarcoma. 2010;2010:506182. soft tissue sarcomas. J Clin Oncol. 2011;29(30):4036–44. 2. Rastrelli M, Tropea S, Basso U, Roma A, Maruzzo M, Rossi CR. Soft tissue 22. Gutman M, Inbar M, Lev‑Shlush D, Abu‑Abid S, Mozes M, Chaitchik S, Mel‑ limb and trunk sarcomas: diagnosis, treatment and follow‑up. Anticancer ler I, Klausner JM. High dose tumor necrosis factor‑alpha and melphalan Res. 2014;34(10):5251–62. administered via isolated limb perfusion for advanced limb soft tissue 3. Casali PG, Blay JY. experts ECECPo: soft tissue sarcomas: ESMO clinical sarcoma results in a > 90% response rate and limb preservation. Cancer. practice guidelines for diagnosis, treatment and follow‑up. Ann Oncol. 1997;79(6):1129–37. 2010;21(Suppl 5):v198–203. 23. Pennacchioli E, Deraco M, Mariani L, Fiore M, Mussi C, Collini P, Olmi 4. Alamanda VK, Crosby SN, Archer KR, Song Y, Schwartz HS, Holt GE. Ampu‑ P, Casali PG, Santinami M, Gronchi A. Advanced extremity soft tissue tation for extremity soft tissue sarcoma does not increase overall survival: sarcoma: prognostic effect of isolated limb perfusion in a series of 88 a retrospective cohort study. Eur J Surg Oncol. 2012;38(12):1178–83. patients treated at a single institution. Ann Surg Oncol. 2007;14(2):553–9. 5. Rosenberg SA, Tepper J, Glatstein E, Costa J, Baker A, Brennan M, DeMoss 24. Jakob J, Tunn PU, Hayes AJ, Pilz LR, Nowak K, Hohenberger P. Oncologi‑ EV, Seipp C, Sindelar WF, Sugarbaker P, et al. The treatment of soft‑tissue cal outcome of primary non‑metastatic soft tissue sarcoma treated by Jakob et al. Clin Sarcoma Res (2018) 8:12 Page 9 of 9 neoadjuvant isolated limb perfusion and tumor resection. J Surg Oncol. 28. Smith HG, Hayes AJ. The role of regional chemotherapy in the 2014;109(8):786–90. management of extremity soft tissue malignancies. Eur J Surg Oncol. 25. Yang JC, Chang AE, Baker AR, Sindelar WF, Danforth DN, Topalian SL, 2016;42(1):7–17. DeLaney T, Glatstein E, Steinberg SM, Merino MJ, et al. Randomized 29. Davis AM, O’Sullivan B, Turcotte R, Bell R, Catton C, Chabot P, Wunder J, prospective study of the benefit of adjuvant radiation therapy in Hammond A, Benk V, Kandel R, et al. Late radiation morbidity following the treatment of soft tissue sarcomas of the extremity. J Clin Oncol. randomization to preoperative versus postoperative radiotherapy in 1998;16(1):197–203. extremity soft tissue sarcoma. Radiother Oncol. 2005;75(1):48–53. 26. Bonvalot S, Gronchi A. ILP and RT: the study that will never be. Ann Surg 30. Folkert MR, Singer S, Brennan MF, Kuk D, Qin LX, Kobayashi WK, Crago Oncol. 2011;18(2):303–5. AM, Alektiar KM. Comparison of local recurrence with conventional and 27. Deroose JP, Burger JW, van Geel AN, den Bakker MA, de Jong JS, Egger‑ intensity‑modulated radiation therapy for primary soft ‑tissue sarcomas of mont AM, Verhoef C. Radiotherapy for soft tissue sarcomas after isolated the extremity. J Clin Oncol. 2014;32(29):3236–41. limb perfusion and surgical resection: essential for local control in all 31. Hall EJ, Wuu CS. Radiation‑induced second cancers: the impact of 3D ‑ CRT patients? Ann Surg Oncol. 2011;18(2):321–7. and IMRT. Int J Radiat Oncol Biol Phys. 2003;56(1):83–8. Submit your next manuscript to BioMed Central and we will help you at every step: • We accept pre-submission inquiries • Our selector tool helps you to find the most relevant journal • We provide round the clock customer support • Convenient online submission • Thorough peer review • Inclusion in PubMed and all major indexing services • Maximum visibility for your research Submit your manuscript at www.biomedcentral.com/submit

Journal

Clinical Sarcoma ResearchSpringer Journals

Published: Jul 2, 2018

References