- Email: [email protected]
Survival of osteosarcoma patients following diagnosis of synchronous skip metastases
Journal Pre-proof Survival of osteosarcoma patients following diagnosis of synchronous skip metastases Peiming Yang, Magdalena Gilg, Scott Evans, Francesca Totti, Jonathan Stevenson, Lee Jeys, Michael Parry PII:
S0972-978X(19)30539-2
DOI:
https://doi.org/10.1016/j.jor.2019.10.003
Reference:
JOR 838
To appear in:
Journal of Orthopaedics
Received Date: 2 September 2019 Accepted Date: 13 October 2019
Please cite this article as: Yang P, Gilg M, Evans S, Totti F, Stevenson J, Jeys L, Parry M, Survival of osteosarcoma patients following diagnosis of synchronous skip metastases, Journal of Orthopaedics, https://doi.org/10.1016/j.jor.2019.10.003. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier B.V. on behalf of Professor P K Surendran Memorial Education Foundation.
Survival of osteosarcoma patients following diagnosis of synchronous skip metastases
Authors: Peiming Yang MBChB, Magdalena Gilg, Scott Evans FRCS, Francesca Totti, Jonathan Stevenson FRCS, Lee Jeys FRCS, Michael Parry FRCS Royal Orthopaedic Hospital NHS Foundation Trust UK
Corresponding Author: Peiming Yang, E-mail: [email protected]
Statement of Compliance with Ethical Standards: Conflict of Interest - All authors declare that they have no conflict of interest. Funding - There is no funding source. Ethical approval - This article does not contain any studies with human participants or animals performed by any of the authors.
Survival of osteosarcoma patients following diagnosis of synchronous skip metastases
Abstract Background: We aim to investigate the prognostic implications of synchronous skip metastases in osteosarcoma by presenting the largest single centre series to date. Methods: Retrospective study of 21 osteosarcoma patients with skip metastases treated between 1983 and 2004. Results: No statistical difference in overall survival was demonstrated when comparing presence of lung metastases to those without (p=0.859). No statistical difference was found in overall survival according to age group (<18yrs vs >18yrs; p=0.126), or to percentage chemotherapy-induced bone necrosis (<90% vs >90%; p=0.056). Conclusions: The presence of skip metastases confers a very poor prognosis as an independent variable.
Key Words: Skip metastases; Synchronous; Osteosarcoma; Survival
Level of Evidence: III
This manuscript was presented as an abstract in the Doctor’s Academy 8th International Academic & Research Conference 2018.
Introduction It is well established that the presence of any clinically detectable metastatic disease at the time of initial diagnosis confers a very poor prognosis to patients with primary osteosarcoma. The 5-year survival of such patients with synchronous metastatic disease is 19-40%.1 This is significantly lower than the reported 5-year survival of 60-70% for localised osteosarcoma.1-2 Osteosarcoma with synchronous regional or distant bone metastases reportedly leads to low survival rates despite treatment with chemotherapy and surgery.3-4 Skip metastases are a specific type of regional bone metastases. They are defined by The American Joint Committee on Cancer (AJCC) as “two or more discontinuous lesions in the same bone”. Therefore, trans-articular lesions are excluded.5 Current studies suggest that skip metastases occur in 2% of high-grade osteosarcoma cases.4-6 Small case series have been reported in the literature documenting the incidence and prognosis of patients with a confirmed diagnosis of osteosarcoma and synchronous skip metastases.3-4, 7-8. The prognosis for patients with synchronous skip metastases has been reported as generally poor.3, 4, 6 Leavey et al, however, reported survival of osteosarcoma patients with skip lesions for at least three years after diagnosis, following treatment with wide local excision and chemotherapy.7 More recently, data on the use of modern chemotherapy regimens have suggested improved outcomes for patients with skip metastases when compared to previously reported figures.8 The aim of the current study, therefore, was to assess the prognostic implications of skip metastases in primary osteosarcoma patients by reporting the largest single centre series to date. The study aimed specifically to establish the effect of skip metastases as an independent variable on overall prognosis for patients with high grade osteosarcoma.
Patients and Methods All patients diagnosed and treated for a histologically confirmed osteosarcoma at a single institution between 1983 and 2014 were included in the study. The study comprised a retrospective analysis of all patients diagnosed and treated at a single tertiary referral sarcoma centre identified from the institution’s prospectively maintained database. From this cohort, all patients found to have skip metastases at initial diagnosis of primary osteosarcoma were identified. The study population comprised 1575 patients treated for an osteosarcoma at a single institution. Records relating to the grade, stage and patient demographics were available for all patients. The presence of skip metastases was confirmed through the use of plain radiography of the entire bone segment. Skeletal imaging comprised Tc99m scintigraphy was used to identify skip or distant skeletal metastases. Cross sectional imaging of the affected compartment was by means of magnetic resonance imaging (MRI). Of the 1575 patients, 56 had radiological evidence of skip metastases. Of these, 25 were excluded; 12 patients had evidence of multifocal disease (primary tumour with widespread distant metastases including visceral and osseous metastases, and so did not undergo surgical treatment of the primary tumour) at diagnosis, 4 patients did not have complete imaging or histology, 9 patients had less than 12 months follow-up, and 1 patient developed iatrogenic skip metastasis as a result of contamination following two knee arthroscopies prior to the diagnosis of osteosarcoma, and was therefore excluded. Of the 21 patients included in our study, all underwent surgical resection of the primary tumour. 9(43%) were females and 12 males. The median age at diagnosis was 14(range 4 to 42). The primary lesion was located in the femur in 17(81%) patients, the tibia in 2(9%) patients, the humerus in 1(5%), and the pelvis in 1(5%) patient. Data collected included demographic data, tumour site and size, local surgical management (limb salvage versus limb sacrifice), and margin status at resection. Oncological outcomes comprised overall survival (OS), disease free survival (DFS), and the time to local recurrence (LR) or metastases.
Variables assessed for their influence on overall survival included patients’ age, presence of synchronous lung metastasis at initial presentation, and patients’ response to chemotherapy. Primary osteosarcoma was classified as large (>1/3 of the affected bone) or small (<1/3 of the affected bone) as originally described by Kager et al,8 as well as according to the Enneking Staging System.3 Patients with skip metastasis underwent diagnostic local and systemic staging studies including haematological and biochemical tests, plain x-rays, and MRI scan of the lesion. Staging CT scan of the chest, as well as whole body bone scan was performed. The aim of surgical treatment in all cases was to completely remove both the primary and skip lesions with an appropriate margin of resection. The decision regarding limb salvage versus amputation was carefully discussed by a supra-regional sarcoma multidisciplinary team. Amputation was offered to all patients with tumours that involved critical neurovascular structures, where a clear resection margin was not achievable by limb salvage surgery. Adjuvant chemotherapy was administered to all patients before or after surgery according to national guidelines active at the time of diagnosis. Postoperative surveillance comprised clinical examination for local recurrence with subsequent magnetic resonance imaging (MRI) on the basis of examination findings, and chest radiography with subsequent computerized tomography (CT) on the basis of radiography findings for systemic disease. Follow-up occurred at 3 monthly intervals for the first 2 years, 6 monthly until 5 years, and annually thereafter, according to UK guidelines for bone sarcoma management.10 Overall survival was assessed using the Kaplan-Meier method with differences in survivorship between cohorts assessed with the log-rank method. Differences were considered significant at a p value<0.05.
Results Skip metastases were diagnosed pre-operatively in 3 of 21(14%) patients using plain x-ray, in 14(66%) patients using magnetic resonance imaging (MRI), and in the remaining 4(19%) patients using bone scan. (Table 2)
All patients with skip metastases underwent surgical resection of the primary tumour including the skip metastases (N=21). Seventeen (81%) patients underwent limb salvage, and the remaining 4(19%) underwent amputation. The overall median follow-up period for all 21 patients was 73(range 7-158) months. All patients who underwent amputation died at a median time of 15(range 5-32) months. Of the 17 patients who underwent limb salvage surgery, 11(65%) patients were alive at a median follow-up of 76 months. All 11 patients were disease free at the time of latest follow up, and none had evidence of local recurrence or metastatic disease. The remaining 6 patients succumbed to disease at a median of 18(range 4-66) months. Of these, 3 developed local recurrence prior to death, at a median of 8(range 6-11) months. One patient had local recurrence in the humerus, and 2 in distal femur. All 3 patients had clear margins at the time of initial resection, but all 3 had a poor histological response to chemotherapy (<90% tumour necrosis). All 3 patients developed synchronous, irresectable lung metastases at the time of local recurrence. The median survival from the diagnosis of local recurrence was 9(range 7-15) months. Overall survival for the whole cohort was 81% at 12 months, 60% at 24 months, and 31% at 36 months (Figure 1). Five of 21 primary osteosarcomas with associated skip lesions were classified as small (<1/3 of the affected bone), and 16 of 21 lesions were large (>1/3 of the affected bone). According to Enneking Staging System, 12 of 21 (57%) patients had Grade IIB lesions, and the remaining 9 patients had Grade III lesions (Table 2). The median survival time for large lesions with skip metastases was 13(range 8-17) months, compared to the median survival time of 27(range 25-31) months for small lesions (P=0.042). Nine patients (43%) had lung metastases at diagnosis, and the remaining 12 patients had no other (than skip mets) sites of metastasis (Table 1). Only 2 of 9 osteosarcoma patients with skip lesions and synchronous lung metastasis were alive following initial treatment within the median follow-up period of
61(range 5-86) months. Both patients have undergone surgical resection of their isolated lung metastases. Both these patients were found to have no evidence of local recurrence or distant metastases within this follow-up period. No statistical difference in overall survival was demonstrated when comparing the presence of lung metastasis on initial presentation to those without (p=0.859) (Figure 2). No statistical difference in overall survival was demonstrated according to the age at presentation between patients below 18 years of age to those above 18 years old (p=0.126) (Figure 3). Following histological analysis of post-resection specimens for response to chemotherapy, 14(67%) patients had <90% tumour necrosis and 7(33%) patients had >90% tumour necrosis. There was no statistical difference in survival when comparing those with >90% necrosis to those with <90% necrosis to chemotherapy (p=0.056) (Figure 4).
Discussion Incidence, Demographics, and Diagnosis of Skip Lesions: We have demonstrated that the incidence of skip metastases in patients presenting with osteosarcoma is 1.3%. This is comparable to the incidence reported by Kager et al.7 It is important to appreciate, however, that due to our long study period (1983 to 2014), it is possible that some patients with skip metastasis in the earlier years were missed due to lack of available imaging modalities. Consequently, our incidence of skip metastasis may have to be interpreted with a degree of caution. The incidence of skip metastasis reported in existing literature ranges from 0.7% (n= 2 of 282 patients) to 25% (n= 10 of 40 patients).3-6, 9, 11. These large variations are likely related to the different study inclusion criteria and recruitment periods used. Enneking et al observed a high incidence of skip metastasis of 25%.4 Wuisman et al, however, reported an incidence of only 6.1% in 1990 from the same institute.6 This most likely represents an evolution in the understanding of the presentation of osteosarcoma and improvements in diagnostic imaging.
Our findings of age range at diagnosis, gender ratio, and distribution of primary tumour sites, were all similar to that reported by Enneking et al and Kager et al.3, 9 Consistent with reports from Panicek et al and Saifuddin et al, we also found that MRI of the whole bone segment was the most reliable imaging modality to detect skip metastases.13, 14 Overall and Disease-Free Survival: We have demonstrated that the survival rate at 36 months for osteosarcoma patients with skip lesions was only 31%. This is significantly lower than the estimated 5-year survival of 70% for isolated nonmetastatic osteosarcomas.1, 2. Our figures for survival correspond to the findings of a number of existing studies. Sajadi et al have reported an average survival of 32.5 months (range 15 to 44 months) for osteosarcoma patients with skip metastases.11 Malawer et al and Sajadi et al have both described in separate studies a series of 13 patients with skip metastases, 5 of whom had synchronous metastases elsewhere at presentation, all of whom died within 75 months of diagnosis. 11, 12 In contrast, Kager et al reported that the 5-year survival for patients with skip lesions was 50%.9 The reason for this discrepancy is uncertain, considering the similarities in study population and management options between Kager et al and other studies. Prognostic Factors: The majority of skip metastases (76%) were in association with large primary osteosarcomas affecting >1/3 of the affected bone. Whether the development of skip metastases is a reflection of the initial tumour volume or a unique characteristic of the tumour itself remains unclear but the relative size of the tumours presenting with skip metastases appears to be larger than those treated in the same institution without skip metastases. Bielack et al have also reported similar findings.1 Whether the poor prognosis seen in this population is reflective of the presence of these skip lesions or is attributable to the initial tumour size, or indeed a composite function of both this variables remains to be accurately assessed, largely due to the low incidence of skip metastases in osteosarcoma.
The presence of synchronous lung metastases also conferred a survival disadvantage, as one would expect. Although poor prognosis of concomitant synchronous lung metastasis was also reported by Malawer et al,12 our results showed no statistical difference between those with skip metastases and lung metastases at presentation and those with skip metastases alone. This suggests a trend towards skip metastases being an independent predictor of poor survival. The effect of the histological response of the tumour to neo-adjuvant chemotherapy in osteosarcoma on overall disease-free survival is well established.1 However, we have demonstrated for patients with skip metastases at diagnosis, the response to chemotherapy had no significant effect on overall survival. Although there is no clear explanation for this finding, this would suggest that the underlying biological nature of osteosarcomas with skip metastases enables the tumour to behave in an aggressive way that is independent of variables such as chemotherapy treatment. Four of 21 patients underwent amputation. In all, wide margins were achieved but despite this, none of these patients survived. This was likely related to the large size and invasiveness of the primary tumour, which increased risks of disease recurrence. Of the 17 patients who underwent limb salvage surgery, 10(58%) patients survived at a median follow-up of 21(range 14-30) months, with 6 of these patients showing no evidence of local or distant recurrence. Our results therefore illustrate that limb salvage surgery in selected patients with skip metastases can achieve satisfactory survival rates. However, patients who require amputation carry a poor prognosis likely due to large tumour size. Limitations: We acknowledge the limitations of this study. The study was conducted retrospectively. This may increase risks of inaccuracies in patient level data collection. However, we believe our data to be accurate as it was collected from a prospectively maintained database recorded in real time at the point of referral and treatment. The period of study spanned three decades. During this period the quality and range of imaging studies available have improved whilst there has also been an evolution in
oncological management. These may have had an effect on our results. However, these are necessary potential limitations when studying extremely rare tumours.
Conclusion We have demonstrated in the largest single centre study to date that skip metastasis acts as an independent variable, which confers a poor prognosis in osteosarcoma patients. New treatment strategies for this subset of patients are urgently required in order to improve overall survival, particularly in those who are not suitable for limb salvage surgery.
Data Availability Statement: Data used to support findings of this study are included in the study
Funding Statement: There is no funding source Conflict of Interest: All authors declare that they have no conflict of interest.
References 1) Bielack SS, Kempf-Bielack B, Delling G, Prognostic factors in high-grade osteosarcoma of the extremities or trunk: An analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J Clin Oncol 2002, 20:776-790 2) Bacci G, Longhi A, Versari M, Mercuri M, Briccoli A, Picci P, Prognostic factors for Osteosarcoma of the extremity treated with neoadjuvant chemotherapy, Cancer 2006, Vol1:1154-1161 3) Enneking WF, Kagan A, “Skip” metastases in osteosarcoma. Cancer 1975, 36:2192-2205
4) Enneking WF, Kagan A, The implications of “skip” metastases in osteosarcoma. Clin Orthop Relat Res 1975, 111:33-41 5) Greene F, Page DL, Fleming ID, AJCC Cancer Staging Manual (ed 6). New York, NY, Springer, 2002 6) Wuisman P, Enneking WF, Prognosis for patients who have osteosarcoma with skip metastasis. J Bone Joint Surg Am 1990, 72:60-68 7) Leavey PJ, Day MD, Booth T, et al, Skip metastasis in osteosarcoma. J Pediatr Hematol Oncol 2003, 25:806-808 8) Jaffe N, Pearson P, Eftekhari F, et al, Skip metastases in pediatric osteosarcoma. Proc Am Soc Clin Oncol 2002, 21:277b 9) Kager L, Zoubek A, Kastner U, Kempf-Bielack B, Potratz J, Kotz R, G. Exner U, Franzius C, Lang S, Maas R, Jurgens H, Gadner H, and Bielack S, Skip Metastases in Osteosarcoma: Experience of the Cooperative Osteosarcoma Study Group, J Clin Oncol 2006, vol 24(10) 10) Grimer R, Athanasou N, Gerrand C, Judson I, Lewis I, Morland B, Peake D, Seddon B, Whelan J, UK Guidelines for the management of Bone Sarcomas, Sarcoma, vol 2010: 1-14 11) Sajadi KR, Heck RK, Neel MD, et al, The incidence and prognosis of osteosarcoma skip metastases. Clin. Orthop Relat Res 2004, 426:92-96 12) Malawer MM, Dunham WK, Skip metastases in osteosarcoma: Recent experience. J Surg Oncol 1983, 22:236-245 13) Panicek DM, Gatsonis C, Rosenthal DI, et al: CT and MR imaging in the local staging of primary malignant musculoskeletal neoplasms: Report of the Radiology Diagnostic Oncology Group. Radiology 1997, 202:237-246 14) Saifuddin A: The accuracy of imaging in the local staging of appendicular osteosarcoma. Skeletal Radiol 2002, 31:191-201
Table 1) Table showing demographic and clinical details of all 21 patients with primary osteosarcoma and skip metastases involved in the study. NED= no evidence of disease, AWD= alive with disease, DOD= dead of disease;
Patients' characteristics N (%) Sex
female
9 (42.9)
male
12 (57.1)
Age at initial diagnosis median 14 years (range, 4- 42) Localisation primary osteosaracoma
femur
17 (81.0)
tibia
2 (9.5)
humerus
1 (4.8)
pelvis
1 (4.8)
small
11 (47.6)
large
10 (42.9)
none
2 (9.5)
limb salvage
15 (71.4)
amputation
4 (19.0)
NED
4 (19.0)
DOD
12 (57.1)
AWD
5 (23.8)
Lung metastasis at initial diagnosis
yes
9 (42.9)
no
12 (57.1)
Margins
wide
8 (38.1)
marginal
11 (52.4)
unknown
2 (9.5)
< 95 %
14 (66.7)
> 95 %
4 (19.0)
unknown
3 (14.3)
Size of primary osteosarcoma
Surgery
Status at last FU
Necrosis
Table 2) Table showing patient and tumour characteristics of all 21 patients with osteosarcoma and skip metastases Primary Tumour
Skip Metastases
Lung Metastases
Patient No.
Gender
Age
Site
Size
Site
Number
Enneking
Site
Number
Diagnostics of skip metastases
Staging System
1
F
14
Femur
Large
Femur
1
IIB
-
-
XR, BSC
2
M
42
Pelvis
Small
Pelvis
1
IIB
-
-
XR, BSC
3
F
12
Femur
Small
Femur
1
IIB
-
-
XR, MRI
4
M
35
Tibia
Small
Tibia
1
IIB
-
-
XR, MRI
5
M
4
Femur
Small
Femur
1
IIB
-
-
MRI
6
F
12
Humerus
Small
Humerus
1
IIB
-
-
MRI
7
M
15
Femur
Small
Femur
1
IIB
-
-
XR, BSC
8
F
16
Femur
Small
Femur
1
IIB
-
-
XR, MRI
9
M
20
Tibia
Large
Tibia
2
IIB
-
-
XR, MRI
10
M
40
Tibia
Small
Tibia
1
IIB
-
-
XR, MRI
11
M
30
Femur
Small
Femur
2
IIB
-
-
XR, MRI
12
M
12
Femur
Small
Femur
1
IIB
-
-
MRI
13
F
7
Femur
Large
Femur
2
III
Bil
4
XR
14
M
27
Femur
Large
Femur
3
III
Uni
1
XR, MRI
15
M
11
Femur
Small
Femur
1
III
Bil
5
MRI
16
M
16
Femur
Large
Femur
1
III
Bil
2
XR, MRI
17
F
14
Femur
Large
Femur
1
III
Uni
2
XR, BSC
18
F
6
Femur
Large
Femur
2
III
Bil
1
XR, MRI
19
M
5
Femur
Large
Femur
1
III
Uni
2
XR, MRI
20
F
22
Femur
Large
Femur
2
III
Bil
4
XR, MRI
21
F
17
Femur
Large
Femur
1
III
Bil
1
XR, MRI
Abbreviations: Bil: Bilateral; M: Male; F: Female; MRI: Magnetic Resonance Imaging; Uni: Unilateral; XR: Plain Radiograph
Figure 1) Overall survival for whole cohort of osteosarcoma patients with skip metastasis was 81% at 12 months, 60% at 24 months and 31% at 36 months
Figure 2) No statistical difference in overall survival according to the presence of lung metastases at initial diagnosis with log rank test (p=0.859)
Figure 3) No statistical difference in overall survival according to age group (<18/>=18 years) (p=0.126)
Figure 4) No significant difference in OS according to percentage of necrosis (<90%, >90% rate of necrosis) (p=0.056)
S0972-978X(19)30539-2
DOI:
https://doi.org/10.1016/j.jor.2019.10.003
Reference:
JOR 838
To appear in:
Journal of Orthopaedics
Received Date: 2 September 2019 Accepted Date: 13 October 2019
Please cite this article as: Yang P, Gilg M, Evans S, Totti F, Stevenson J, Jeys L, Parry M, Survival of osteosarcoma patients following diagnosis of synchronous skip metastases, Journal of Orthopaedics, https://doi.org/10.1016/j.jor.2019.10.003. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier B.V. on behalf of Professor P K Surendran Memorial Education Foundation.
Survival of osteosarcoma patients following diagnosis of synchronous skip metastases
Authors: Peiming Yang MBChB, Magdalena Gilg, Scott Evans FRCS, Francesca Totti, Jonathan Stevenson FRCS, Lee Jeys FRCS, Michael Parry FRCS Royal Orthopaedic Hospital NHS Foundation Trust UK
Corresponding Author: Peiming Yang, E-mail: [email protected]
Statement of Compliance with Ethical Standards: Conflict of Interest - All authors declare that they have no conflict of interest. Funding - There is no funding source. Ethical approval - This article does not contain any studies with human participants or animals performed by any of the authors.
Survival of osteosarcoma patients following diagnosis of synchronous skip metastases
Abstract Background: We aim to investigate the prognostic implications of synchronous skip metastases in osteosarcoma by presenting the largest single centre series to date. Methods: Retrospective study of 21 osteosarcoma patients with skip metastases treated between 1983 and 2004. Results: No statistical difference in overall survival was demonstrated when comparing presence of lung metastases to those without (p=0.859). No statistical difference was found in overall survival according to age group (<18yrs vs >18yrs; p=0.126), or to percentage chemotherapy-induced bone necrosis (<90% vs >90%; p=0.056). Conclusions: The presence of skip metastases confers a very poor prognosis as an independent variable.
Key Words: Skip metastases; Synchronous; Osteosarcoma; Survival
Level of Evidence: III
This manuscript was presented as an abstract in the Doctor’s Academy 8th International Academic & Research Conference 2018.
Introduction It is well established that the presence of any clinically detectable metastatic disease at the time of initial diagnosis confers a very poor prognosis to patients with primary osteosarcoma. The 5-year survival of such patients with synchronous metastatic disease is 19-40%.1 This is significantly lower than the reported 5-year survival of 60-70% for localised osteosarcoma.1-2 Osteosarcoma with synchronous regional or distant bone metastases reportedly leads to low survival rates despite treatment with chemotherapy and surgery.3-4 Skip metastases are a specific type of regional bone metastases. They are defined by The American Joint Committee on Cancer (AJCC) as “two or more discontinuous lesions in the same bone”. Therefore, trans-articular lesions are excluded.5 Current studies suggest that skip metastases occur in 2% of high-grade osteosarcoma cases.4-6 Small case series have been reported in the literature documenting the incidence and prognosis of patients with a confirmed diagnosis of osteosarcoma and synchronous skip metastases.3-4, 7-8. The prognosis for patients with synchronous skip metastases has been reported as generally poor.3, 4, 6 Leavey et al, however, reported survival of osteosarcoma patients with skip lesions for at least three years after diagnosis, following treatment with wide local excision and chemotherapy.7 More recently, data on the use of modern chemotherapy regimens have suggested improved outcomes for patients with skip metastases when compared to previously reported figures.8 The aim of the current study, therefore, was to assess the prognostic implications of skip metastases in primary osteosarcoma patients by reporting the largest single centre series to date. The study aimed specifically to establish the effect of skip metastases as an independent variable on overall prognosis for patients with high grade osteosarcoma.
Patients and Methods All patients diagnosed and treated for a histologically confirmed osteosarcoma at a single institution between 1983 and 2014 were included in the study. The study comprised a retrospective analysis of all patients diagnosed and treated at a single tertiary referral sarcoma centre identified from the institution’s prospectively maintained database. From this cohort, all patients found to have skip metastases at initial diagnosis of primary osteosarcoma were identified. The study population comprised 1575 patients treated for an osteosarcoma at a single institution. Records relating to the grade, stage and patient demographics were available for all patients. The presence of skip metastases was confirmed through the use of plain radiography of the entire bone segment. Skeletal imaging comprised Tc99m scintigraphy was used to identify skip or distant skeletal metastases. Cross sectional imaging of the affected compartment was by means of magnetic resonance imaging (MRI). Of the 1575 patients, 56 had radiological evidence of skip metastases. Of these, 25 were excluded; 12 patients had evidence of multifocal disease (primary tumour with widespread distant metastases including visceral and osseous metastases, and so did not undergo surgical treatment of the primary tumour) at diagnosis, 4 patients did not have complete imaging or histology, 9 patients had less than 12 months follow-up, and 1 patient developed iatrogenic skip metastasis as a result of contamination following two knee arthroscopies prior to the diagnosis of osteosarcoma, and was therefore excluded. Of the 21 patients included in our study, all underwent surgical resection of the primary tumour. 9(43%) were females and 12 males. The median age at diagnosis was 14(range 4 to 42). The primary lesion was located in the femur in 17(81%) patients, the tibia in 2(9%) patients, the humerus in 1(5%), and the pelvis in 1(5%) patient. Data collected included demographic data, tumour site and size, local surgical management (limb salvage versus limb sacrifice), and margin status at resection. Oncological outcomes comprised overall survival (OS), disease free survival (DFS), and the time to local recurrence (LR) or metastases.
Variables assessed for their influence on overall survival included patients’ age, presence of synchronous lung metastasis at initial presentation, and patients’ response to chemotherapy. Primary osteosarcoma was classified as large (>1/3 of the affected bone) or small (<1/3 of the affected bone) as originally described by Kager et al,8 as well as according to the Enneking Staging System.3 Patients with skip metastasis underwent diagnostic local and systemic staging studies including haematological and biochemical tests, plain x-rays, and MRI scan of the lesion. Staging CT scan of the chest, as well as whole body bone scan was performed. The aim of surgical treatment in all cases was to completely remove both the primary and skip lesions with an appropriate margin of resection. The decision regarding limb salvage versus amputation was carefully discussed by a supra-regional sarcoma multidisciplinary team. Amputation was offered to all patients with tumours that involved critical neurovascular structures, where a clear resection margin was not achievable by limb salvage surgery. Adjuvant chemotherapy was administered to all patients before or after surgery according to national guidelines active at the time of diagnosis. Postoperative surveillance comprised clinical examination for local recurrence with subsequent magnetic resonance imaging (MRI) on the basis of examination findings, and chest radiography with subsequent computerized tomography (CT) on the basis of radiography findings for systemic disease. Follow-up occurred at 3 monthly intervals for the first 2 years, 6 monthly until 5 years, and annually thereafter, according to UK guidelines for bone sarcoma management.10 Overall survival was assessed using the Kaplan-Meier method with differences in survivorship between cohorts assessed with the log-rank method. Differences were considered significant at a p value<0.05.
Results Skip metastases were diagnosed pre-operatively in 3 of 21(14%) patients using plain x-ray, in 14(66%) patients using magnetic resonance imaging (MRI), and in the remaining 4(19%) patients using bone scan. (Table 2)
All patients with skip metastases underwent surgical resection of the primary tumour including the skip metastases (N=21). Seventeen (81%) patients underwent limb salvage, and the remaining 4(19%) underwent amputation. The overall median follow-up period for all 21 patients was 73(range 7-158) months. All patients who underwent amputation died at a median time of 15(range 5-32) months. Of the 17 patients who underwent limb salvage surgery, 11(65%) patients were alive at a median follow-up of 76 months. All 11 patients were disease free at the time of latest follow up, and none had evidence of local recurrence or metastatic disease. The remaining 6 patients succumbed to disease at a median of 18(range 4-66) months. Of these, 3 developed local recurrence prior to death, at a median of 8(range 6-11) months. One patient had local recurrence in the humerus, and 2 in distal femur. All 3 patients had clear margins at the time of initial resection, but all 3 had a poor histological response to chemotherapy (<90% tumour necrosis). All 3 patients developed synchronous, irresectable lung metastases at the time of local recurrence. The median survival from the diagnosis of local recurrence was 9(range 7-15) months. Overall survival for the whole cohort was 81% at 12 months, 60% at 24 months, and 31% at 36 months (Figure 1). Five of 21 primary osteosarcomas with associated skip lesions were classified as small (<1/3 of the affected bone), and 16 of 21 lesions were large (>1/3 of the affected bone). According to Enneking Staging System, 12 of 21 (57%) patients had Grade IIB lesions, and the remaining 9 patients had Grade III lesions (Table 2). The median survival time for large lesions with skip metastases was 13(range 8-17) months, compared to the median survival time of 27(range 25-31) months for small lesions (P=0.042). Nine patients (43%) had lung metastases at diagnosis, and the remaining 12 patients had no other (than skip mets) sites of metastasis (Table 1). Only 2 of 9 osteosarcoma patients with skip lesions and synchronous lung metastasis were alive following initial treatment within the median follow-up period of
61(range 5-86) months. Both patients have undergone surgical resection of their isolated lung metastases. Both these patients were found to have no evidence of local recurrence or distant metastases within this follow-up period. No statistical difference in overall survival was demonstrated when comparing the presence of lung metastasis on initial presentation to those without (p=0.859) (Figure 2). No statistical difference in overall survival was demonstrated according to the age at presentation between patients below 18 years of age to those above 18 years old (p=0.126) (Figure 3). Following histological analysis of post-resection specimens for response to chemotherapy, 14(67%) patients had <90% tumour necrosis and 7(33%) patients had >90% tumour necrosis. There was no statistical difference in survival when comparing those with >90% necrosis to those with <90% necrosis to chemotherapy (p=0.056) (Figure 4).
Discussion Incidence, Demographics, and Diagnosis of Skip Lesions: We have demonstrated that the incidence of skip metastases in patients presenting with osteosarcoma is 1.3%. This is comparable to the incidence reported by Kager et al.7 It is important to appreciate, however, that due to our long study period (1983 to 2014), it is possible that some patients with skip metastasis in the earlier years were missed due to lack of available imaging modalities. Consequently, our incidence of skip metastasis may have to be interpreted with a degree of caution. The incidence of skip metastasis reported in existing literature ranges from 0.7% (n= 2 of 282 patients) to 25% (n= 10 of 40 patients).3-6, 9, 11. These large variations are likely related to the different study inclusion criteria and recruitment periods used. Enneking et al observed a high incidence of skip metastasis of 25%.4 Wuisman et al, however, reported an incidence of only 6.1% in 1990 from the same institute.6 This most likely represents an evolution in the understanding of the presentation of osteosarcoma and improvements in diagnostic imaging.
Our findings of age range at diagnosis, gender ratio, and distribution of primary tumour sites, were all similar to that reported by Enneking et al and Kager et al.3, 9 Consistent with reports from Panicek et al and Saifuddin et al, we also found that MRI of the whole bone segment was the most reliable imaging modality to detect skip metastases.13, 14 Overall and Disease-Free Survival: We have demonstrated that the survival rate at 36 months for osteosarcoma patients with skip lesions was only 31%. This is significantly lower than the estimated 5-year survival of 70% for isolated nonmetastatic osteosarcomas.1, 2. Our figures for survival correspond to the findings of a number of existing studies. Sajadi et al have reported an average survival of 32.5 months (range 15 to 44 months) for osteosarcoma patients with skip metastases.11 Malawer et al and Sajadi et al have both described in separate studies a series of 13 patients with skip metastases, 5 of whom had synchronous metastases elsewhere at presentation, all of whom died within 75 months of diagnosis. 11, 12 In contrast, Kager et al reported that the 5-year survival for patients with skip lesions was 50%.9 The reason for this discrepancy is uncertain, considering the similarities in study population and management options between Kager et al and other studies. Prognostic Factors: The majority of skip metastases (76%) were in association with large primary osteosarcomas affecting >1/3 of the affected bone. Whether the development of skip metastases is a reflection of the initial tumour volume or a unique characteristic of the tumour itself remains unclear but the relative size of the tumours presenting with skip metastases appears to be larger than those treated in the same institution without skip metastases. Bielack et al have also reported similar findings.1 Whether the poor prognosis seen in this population is reflective of the presence of these skip lesions or is attributable to the initial tumour size, or indeed a composite function of both this variables remains to be accurately assessed, largely due to the low incidence of skip metastases in osteosarcoma.
The presence of synchronous lung metastases also conferred a survival disadvantage, as one would expect. Although poor prognosis of concomitant synchronous lung metastasis was also reported by Malawer et al,12 our results showed no statistical difference between those with skip metastases and lung metastases at presentation and those with skip metastases alone. This suggests a trend towards skip metastases being an independent predictor of poor survival. The effect of the histological response of the tumour to neo-adjuvant chemotherapy in osteosarcoma on overall disease-free survival is well established.1 However, we have demonstrated for patients with skip metastases at diagnosis, the response to chemotherapy had no significant effect on overall survival. Although there is no clear explanation for this finding, this would suggest that the underlying biological nature of osteosarcomas with skip metastases enables the tumour to behave in an aggressive way that is independent of variables such as chemotherapy treatment. Four of 21 patients underwent amputation. In all, wide margins were achieved but despite this, none of these patients survived. This was likely related to the large size and invasiveness of the primary tumour, which increased risks of disease recurrence. Of the 17 patients who underwent limb salvage surgery, 10(58%) patients survived at a median follow-up of 21(range 14-30) months, with 6 of these patients showing no evidence of local or distant recurrence. Our results therefore illustrate that limb salvage surgery in selected patients with skip metastases can achieve satisfactory survival rates. However, patients who require amputation carry a poor prognosis likely due to large tumour size. Limitations: We acknowledge the limitations of this study. The study was conducted retrospectively. This may increase risks of inaccuracies in patient level data collection. However, we believe our data to be accurate as it was collected from a prospectively maintained database recorded in real time at the point of referral and treatment. The period of study spanned three decades. During this period the quality and range of imaging studies available have improved whilst there has also been an evolution in
oncological management. These may have had an effect on our results. However, these are necessary potential limitations when studying extremely rare tumours.
Conclusion We have demonstrated in the largest single centre study to date that skip metastasis acts as an independent variable, which confers a poor prognosis in osteosarcoma patients. New treatment strategies for this subset of patients are urgently required in order to improve overall survival, particularly in those who are not suitable for limb salvage surgery.
Data Availability Statement: Data used to support findings of this study are included in the study
Funding Statement: There is no funding source Conflict of Interest: All authors declare that they have no conflict of interest.
References 1) Bielack SS, Kempf-Bielack B, Delling G, Prognostic factors in high-grade osteosarcoma of the extremities or trunk: An analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J Clin Oncol 2002, 20:776-790 2) Bacci G, Longhi A, Versari M, Mercuri M, Briccoli A, Picci P, Prognostic factors for Osteosarcoma of the extremity treated with neoadjuvant chemotherapy, Cancer 2006, Vol1:1154-1161 3) Enneking WF, Kagan A, “Skip” metastases in osteosarcoma. Cancer 1975, 36:2192-2205
4) Enneking WF, Kagan A, The implications of “skip” metastases in osteosarcoma. Clin Orthop Relat Res 1975, 111:33-41 5) Greene F, Page DL, Fleming ID, AJCC Cancer Staging Manual (ed 6). New York, NY, Springer, 2002 6) Wuisman P, Enneking WF, Prognosis for patients who have osteosarcoma with skip metastasis. J Bone Joint Surg Am 1990, 72:60-68 7) Leavey PJ, Day MD, Booth T, et al, Skip metastasis in osteosarcoma. J Pediatr Hematol Oncol 2003, 25:806-808 8) Jaffe N, Pearson P, Eftekhari F, et al, Skip metastases in pediatric osteosarcoma. Proc Am Soc Clin Oncol 2002, 21:277b 9) Kager L, Zoubek A, Kastner U, Kempf-Bielack B, Potratz J, Kotz R, G. Exner U, Franzius C, Lang S, Maas R, Jurgens H, Gadner H, and Bielack S, Skip Metastases in Osteosarcoma: Experience of the Cooperative Osteosarcoma Study Group, J Clin Oncol 2006, vol 24(10) 10) Grimer R, Athanasou N, Gerrand C, Judson I, Lewis I, Morland B, Peake D, Seddon B, Whelan J, UK Guidelines for the management of Bone Sarcomas, Sarcoma, vol 2010: 1-14 11) Sajadi KR, Heck RK, Neel MD, et al, The incidence and prognosis of osteosarcoma skip metastases. Clin. Orthop Relat Res 2004, 426:92-96 12) Malawer MM, Dunham WK, Skip metastases in osteosarcoma: Recent experience. J Surg Oncol 1983, 22:236-245 13) Panicek DM, Gatsonis C, Rosenthal DI, et al: CT and MR imaging in the local staging of primary malignant musculoskeletal neoplasms: Report of the Radiology Diagnostic Oncology Group. Radiology 1997, 202:237-246 14) Saifuddin A: The accuracy of imaging in the local staging of appendicular osteosarcoma. Skeletal Radiol 2002, 31:191-201
Table 1) Table showing demographic and clinical details of all 21 patients with primary osteosarcoma and skip metastases involved in the study. NED= no evidence of disease, AWD= alive with disease, DOD= dead of disease;
Patients' characteristics N (%) Sex
female
9 (42.9)
male
12 (57.1)
Age at initial diagnosis median 14 years (range, 4- 42) Localisation primary osteosaracoma
femur
17 (81.0)
tibia
2 (9.5)
humerus
1 (4.8)
pelvis
1 (4.8)
small
11 (47.6)
large
10 (42.9)
none
2 (9.5)
limb salvage
15 (71.4)
amputation
4 (19.0)
NED
4 (19.0)
DOD
12 (57.1)
AWD
5 (23.8)
Lung metastasis at initial diagnosis
yes
9 (42.9)
no
12 (57.1)
Margins
wide
8 (38.1)
marginal
11 (52.4)
unknown
2 (9.5)
< 95 %
14 (66.7)
> 95 %
4 (19.0)
unknown
3 (14.3)
Size of primary osteosarcoma
Surgery
Status at last FU
Necrosis
Table 2) Table showing patient and tumour characteristics of all 21 patients with osteosarcoma and skip metastases Primary Tumour
Skip Metastases
Lung Metastases
Patient No.
Gender
Age
Site
Size
Site
Number
Enneking
Site
Number
Diagnostics of skip metastases
Staging System
1
F
14
Femur
Large
Femur
1
IIB
-
-
XR, BSC
2
M
42
Pelvis
Small
Pelvis
1
IIB
-
-
XR, BSC
3
F
12
Femur
Small
Femur
1
IIB
-
-
XR, MRI
4
M
35
Tibia
Small
Tibia
1
IIB
-
-
XR, MRI
5
M
4
Femur
Small
Femur
1
IIB
-
-
MRI
6
F
12
Humerus
Small
Humerus
1
IIB
-
-
MRI
7
M
15
Femur
Small
Femur
1
IIB
-
-
XR, BSC
8
F
16
Femur
Small
Femur
1
IIB
-
-
XR, MRI
9
M
20
Tibia
Large
Tibia
2
IIB
-
-
XR, MRI
10
M
40
Tibia
Small
Tibia
1
IIB
-
-
XR, MRI
11
M
30
Femur
Small
Femur
2
IIB
-
-
XR, MRI
12
M
12
Femur
Small
Femur
1
IIB
-
-
MRI
13
F
7
Femur
Large
Femur
2
III
Bil
4
XR
14
M
27
Femur
Large
Femur
3
III
Uni
1
XR, MRI
15
M
11
Femur
Small
Femur
1
III
Bil
5
MRI
16
M
16
Femur
Large
Femur
1
III
Bil
2
XR, MRI
17
F
14
Femur
Large
Femur
1
III
Uni
2
XR, BSC
18
F
6
Femur
Large
Femur
2
III
Bil
1
XR, MRI
19
M
5
Femur
Large
Femur
1
III
Uni
2
XR, MRI
20
F
22
Femur
Large
Femur
2
III
Bil
4
XR, MRI
21
F
17
Femur
Large
Femur
1
III
Bil
1
XR, MRI
Abbreviations: Bil: Bilateral; M: Male; F: Female; MRI: Magnetic Resonance Imaging; Uni: Unilateral; XR: Plain Radiograph
Figure 1) Overall survival for whole cohort of osteosarcoma patients with skip metastasis was 81% at 12 months, 60% at 24 months and 31% at 36 months
Figure 2) No statistical difference in overall survival according to the presence of lung metastases at initial diagnosis with log rank test (p=0.859)
Figure 3) No statistical difference in overall survival according to age group (<18/>=18 years) (p=0.126)
Figure 4) No significant difference in OS according to percentage of necrosis (<90%, >90% rate of necrosis) (p=0.056)