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High-Grade Osteosarcoma of the Foot: Presentation, Treatment, Prognostic Factors, and Outcome of 23 Cooperative Osteosarcoma Study Group COSS Patients.

1. Introduction

Bone tumors of the foot have been reported to be rare, and reported studies are limited to case reports and very few small cohort studies [1-6]. Of these tumors, 23-26% are malignant and only 4% represent osteosarcomas, whereas only 1% of all osteosarcomas occur in the foot [6-8].

To fill the current gap in literature, we evaluated in this study all patients with an osteosarcoma of the foot registered by the COSS to identify prognostic factors and to evaluate similarities and differences in outcome compared to other osteosarcoma sites.

2. Methods

2.1. Patient Eligibility. The analysis is based on all patients registered by the Cooperative German-Austrian-Swiss Osteosarcoma Study Group (COSS) since 1980 [9-15]. The study group's primary focus has generally been on patients with primary high-grade central osteosarcoma of bone under 40 years of age, but all other patients in a different age group or diagnosed with another type of osteosarcoma were also registered and followed.

All COSS studies were approved by the appropriate ethics and/or protocol review committee. Before registration and therapy, informed consent was obtained from all patients and/or their legal guardians, depending on patients' age.

This study is based on all patients with a primary, previously untreated high-grade osteosarcoma of the foot registered between January 1980 and April 2016 with a follow-up of at least 3 months.

2.2. Diagnostics. Diagnostic procedures used to define the extension of the primary tumor included conventional radiography in all studies, whereas computed tomography (CT) scan and magnetic resonance imaging (MRI) varied over time. To exclude primary metastases, a chest X-ray and a 99mTc-methylene-diphosphonate bone scan were conducted, since 1991 a CT scan of the chest was mandatory as well. Follow-up analyses included X-rays of the chest and primary tumor site in intervals defined by the appropriate COSS protocol. In case of systemic metastases at any time after initial diagnosis, a complete restaging was performed.

2.3. Treatment. Treatment including preoperative (neoadjuvant) and postoperative chemotherapy and surgery was to be performed according to the COSS protocols active at enrolment [10-13, 15-17]. In brief, all protocols included varying combinations of high-dose methotrexate with leucovorin rescue, doxorubicin, cisplatin, and/or ifosfamide and sometimes others.

Local therapy was to be performed by surgery during weeks 9 to 11 of therapy, depending on the employed protocol. The type of resection was decided by the local surgeon but it was recommended to attempt wide or radical resections [18] and, if present, it was also recommended to completely resect all primary metastases [17].

2.4. Data Collection and Definition of Variables. All variables were collected prospectively and evaluated for distribution within the evaluated patient cohort and for possible correlations with outcome.

Patient age and sex: Self-explanatory.

Tumor site: Tumor site within the foot was classified by us into one of the three anatomic parts of the foot (phalanges, metatarsal bones, and tarsus) according to the specific bone involved.

Tumor size: Absolute tumor volume as measured by initial imaging.

Primary metastases: Primary systemic dissemination was assumed whenever metastases other than skip lesions were detected on initial staging, except when the suspicion was later excluded by surgery with negative histology. Patients with a radiologic diagnosis of primary metastases who never underwent surgery for the suspected metastases were included among those with primary dissemination.

Alkaline phosphatase (AP) and lactate dehydrogenase (LDH): Serum levels of AP and LDH were obtained at initial diagnosis. Levels were considered as elevated (E) if they exceeded the upper limit of normal (N) as stated by the local laboratory.

Symptoms and their duration: Most COSS protocols, except for those active between 1985 and 1990, included an assessment of symptom duration. The interval between the onset of pain and/or tumor-associated swelling and biopsy/primary operation was counted in days.

Delay of chemotherapy: The lag time from diagnostic procedure to the first day of chemotherapy. A treatment delay was arbitrarily defined as an interval of longer than 21 days.

Timing of surgery: Primary surgery was assumed whenever an attempt to remove the primary lesion had been performed before the initiation of chemotherapy, whether this had been done with or without the knowledge of the correct diagnosis, whereas primary chemotherapy was assumed if the start of chemotherapy had preceded surgery.

Type of local surgery: The surgical procedures were divided into amputation and foot-saving resections as final solution.

Complete surgical remission (CR): A complete surgical remission was assumed only when all detectable tumor foci were removed during first-line therapy. If no complete surgical remission could be achieved, the day after diagnostic biopsy was considered the day of the first event.

Tumor response: Response to preoperative chemotherapy was assessed histologically according to the six-grade scale of Salzer-Kuntschik et al. A good response was defined as less than 10% viable tumor residues (response grades 1-3), poor tumor response in case of more than 10% vital tumor cells (grade 4-6) [19].

2.5. Statistical Methods. All eligible patients were evaluated on an intent-to-treat basis. All parameters were investigated by univariate techniques. The Kaplan-Meier method [20] was used for survival analysis, and for analysis of the subgroups according to the defined variables, the log-rank test (Mantel-Cox test) or, if appropriate, Breslow's test (generalized Wilcoxon test) was used for comparisons [21-23]. Overall survival was calculated from the time of diagnostic biopsy until death. Event-free survival was calculated until death or first event, whatever occurred first. Patients who never achieved a complete surgical remission were assumed to have suffered an event on day one after diagnostic biopsy.

All P values are two-sided, and significant implies P < 0.05. SPSS version 22.0 (SPSS Inc., Chicago, IL) was used for statistical calculations.

3. Results

We identified 30 patients registered as having osteosarcomas of the foot within the COSS database. Seven of these were excluded from further analyses: five low-grade osteosarcomas (three low-grade central and two parosteal), one osteosarcoma occurred as a secondary malignancy (following B-cell lymphoma), and one benign bone lesion originally misdiagnosed as osteosarcoma, leaving 23 patients with primary high-grade osteosarcomas for statistical analyses (Table 1). The diagnosis of osteosarcoma was made or confirmed by a member of the COSS reference pathology panel in 19 of 23 eligible patients, while four samples were seen by local pathologists only. Patients were registered by 18 institutions from three different European countries (Germany 14, Austria 3, and Switzerland 1).

There were 13 males and ten females, and median age was 32 years (range: 6-58 years). Among 21 of the 23 patients with information on prediagnostic symptoms, eight (38%) complained of pain only, two (10%) registered swelling only, and eleven (52%) reported both, resulting in a total of 19 (90%) patients with pain and 13 (62%) with swelling. In 20 of the 23 patients with relevant data available, the median duration between first symptoms and diagnostic biopsy was 154 days (range: 21-1940 days). The patient with the longest prediagnostic interval had received multiple previous biopsies, with diagnoses ranging from bone cyst to fibrous dysplasia, prior to the diagnosis of osteosarcoma.

Localization of the primary tumor was as follows: in two patients a phalanx (9%), in five patients a metatarsal bone (21%), and in 16 patients a tarsal bone (70%). Absolute tumor volume was documented for 10 of the 23 patients, the median being 31.5 [cm.sup.3] (range: 3-54 [cm.sup.3]). All tumors were T1 tumors (<8 cm) according to AJCC staging system (Table 1). Three patients had evidence of primary metastases: one had ipsilateral inguinal lymph node involvement and two suffered from pulmonary metastases.

Among 20 of the 23 patients with appropriate information, serum alkaline phosphatase (AP) levels at diagnosis were normal in 15 (75%) and elevated in five (25%). Among 19 out of 23 patients with available information on lactate dehydrogenase (LDH) serum levels at diagnosis, these were normal in 16 (84%) and elevated in three (16%).

Eighteen of the 23 patients received preoperative chemotherapy, while five had primary surgery (three prior to receiving the correct diagnosis and two thereafter). The median duration between diagnostic biopsy/primary surgery and start of chemotherapy was 28 days (range: 1-83 days).

Twenty-one of the 23 patients (87%) achieved a macroscopically complete surgical remission of all tumor sites (Tables 1 and 2). The remaining two were not operated for pulmonary metastases, one of these had progression of primary metastases and the other developed metastases during preoperative chemotherapy. Among the 23 patients with known surgery of their primary tumor, 19 (83%) received only one surgical procedure until obtaining their best total surgical outcome and 4 (17%) received two surgical procedure (three patients received amputation after incomplete primary resection and one patient received complete resection of pulmonary metastases). In total, 19 patients (83%) underwent amputations and four (17%) foot-saving resections (Tables 1 and 3). Among these four patients, three received a resection with wide margins and one with marginal margins. The patient receiving resection with marginal margins had primary pulmonary metastases, which were not operated, and developed a large local recurrence.

Four of 17 (25%) tumors which were resected following preoperative chemotherapy and for whom information on histological response was available responded well to preoperative chemotherapy (<10% viable tumor), and thirteen (75%) responded poorly (Tables 1 and 4).

Twenty-two patients received systemic chemotherapy for their primary disease; information on the drugs used was available for 21. Among these, all 21 received doxorubicin, 21 received cisplatin (100%) (two additional carboplatin), 19 ifosfamide (90%), 16 high-dose methotrexate (76%), and five etoposide (24%) (Table 1).

After a median follow-up of 4.2 years (range: 0.4-18.5 years) for all 23 patients and 4.8 years (range: 0.4-18.45 years) for the 15 survivors, three- and five-year survival estimates were 84% (standard error (SE) 8.6%) and 64% (SE 12%), respectively (Figure 1). Among the 15 survivors, thirteen were in first complete remission, one was lost to follow-up while in first recurrence, and another one was alive with his third recurrence. Of the eight patients who died, six suffered from progressive disease (two without ever having achieved a complete remission, one in first, one in second, and two after third recurrence), one of a secondary malignancy (Ewing sarcoma), and one of an unknown cause during first recurrence (Tables 1 and 5).

Among 21 patients in whom complete surgical remission was achieved, thirteen remained event free and eight experienced an event. Among these, five developed lung metastases (de novo, 1 following complete removal of primary lung metastases), one de novo ipsilateral inguinal lymph node metastases, and one a recurrence in the ipsilateral proximal lower leg following complete surgery of both the primary tumor and primary (inguinal) lymph node metastases. In addition, one patient died from a secondary malignancy (Ewing sarcoma) (Table 1). Three- and five-year event-free survival estimates were 62% (SE 12%) and 54% (SE 13%), respectively. There was no significant difference in overall and event-free survival between the first 18 years of patient recruitment and the second 18 years.

Event-free survival (EFS) and overall survival (OAS) correlated with primary metastatic status and best surgical remission status (Table 6).

4. Discussion

Osteosarcoma of the foot is exceedingly rare, and consequently the available information on patient and tumor characteristics, optimal management, and outcome is very limited. Therefore, we decided to investigate the greatest time span possible (36 years) using the data prospectively collected by the Cooperative German-Austrian-Swiss Osteosarcoma Study Group. We were able to analyze 23 eligible patients with primary high-grade osteosarcoma of the foot, which represents one of the largest cohorts of such patients reported to date.

While recommended diagnostic and therapeutic procedures have varied to some extent during this prolonged period, the overall results of osteosarcoma therapy have not [24-27], so we believe our findings hold true even for today. Low-grade as well as secondary osteosarcomas were excluded, as their biology and/or treatment differs from the more common primary high-grade central osteosarcomas.

Concerning patient-related variables, we observed the same slight male predominance as known for extremity osteosarcoma [28], but, similar to others [1, 2], a considerably older median age of 32 years. As in osteosarcoma, in general [13], pain was the most frequent presenting symptom. The median duration between first symptoms and diagnostic biopsy was 154 days (range: 21-1940 days), which is shorter than that described in other series of osteosarcomas of the feet [2,4] but longer than that we have observed for other extremity osteosarcomas (median: 69 days) [13].

Like others [1, 5], we observed the tarsal bones to be the most frequently affected site within the foot. In our 23 patient cohort, three had evidence of primary metastases upon imaging, comparable to the situation in osteosarcoma of other sites [13, 29]. Two had lung metastases and one had lymph node metastases, the latter being rather unusual for osteosarcoma [30]. Compared to osteosarcoma in general [31], fewer patients from our series presented with elevated alkaline phosphatase levels, probably correlating with their smaller tumor volumes, while the rate of elevated lactate dehydrogenase was similar [32].

Our patients with osteosarcoma of the foot received the same multimodal therapy including chemotherapy and surgery as patients with osteosarcoma in general. While the more frequent osteosarcomas of long extremity bones have witnessed a major shift from amputation towards limb-saving surgery over the past several decades [14], we did not observe such a trend in this series, where three quarters of all affected feet were either completely or partially amputated.

Compared to osteosarcoma in general, where approximately half of all tumors respond well to preoperative chemotherapy [13, 28, 33], only one quarter of 16 evaluable pedal osteosarcomas from our series did so. We were not able to extract information regarding response from other published series, so that this disparity must probably be considered a novel finding for which there is no immediate explanation besides the small cohort size. The biology underlying this apparent difference remains to be elucidated.

Like in extremity osteosarcoma in general [28], most patients from our series achieved a first complete surgical remission. The recurrence rate and the time to recurrence were also similar to that which our group has observed for extremity osteosarcoma in general [13, 34]. Interestingly, there were no local recurrences as first event, a result which may have been favored by the aggressive, mostly ablative surgical approach employed. Given that wide margins may be difficult to achieve by foot-salvaging procedures, margins correlate with the local recurrence risk [35], prognosis following local osteosarcoma recurrence is very poor [36] and gait performance is often quite good following partial or even complete amputation of the foot [37]; we believe that such an aggressive surgical approach is well justified.

The recurrences we observed were mostly lung metastases, again as well known for osteosarcoma in general [28, 34]. Two patients had either primary or secondary lymph node involvement, which is rather unusual for this particular malignancy [30]. However, the small numbers prohibit making definitive statements about whether the risk for lymphatic spread is truly higher than for osteosarcomas of other sites. Metastases in other published series were usually pulmonary [1]. Nevertheless, we would recommend careful assessment of the ipsilateral lymphatic drainage as part of staging and follow-up of patients with an osteosarcoma of the foot.

Given the very similar recurrence rates already discussed above, it comes as no surprise that the 5-year event-free and overall survival rates are also similar to those observed in other series which included both localized and primary metastatic osteosarcomas [14, 26, 38]. Even though tumor size is a very well-established prognostic factor and osteosarcomas of the foot are more likely to be detected at smaller size, the obtained results are certainly not superior to those our group has achieved in other long-bone extremity osteosarcomas [13]. We can only assume that this may be due to a somewhat different tumor biology which also manifests in the low response rate to preoperative chemotherapy. As a note of caution, some papers on foot osteosarcomas have reported higher cure rates, albeit based upon even smaller patient numbers [4].

Patients with primary metastases are known to be associated with inferior event-free and overall survival rates [13, 30, 39, 40], which was also seen in our cohort, where none of the three patients with primary metastases survived. Complete surgical remission, mostly achieved by amputation, was the strongest positive predictive factor for EFS and OS in our cohort. In this context, we have to emphasize that the subgroup of patients not receiving complete surgical remission consisted of only 2 of the 23 patients and these patients had inoperable primary metastases, respectively, progressive disease under chemotherapy. Nonetheless, our finding is in accordance with the general osteosarcoma literature [13, 28]. When investigating other factors for potential correlations with prognosis, such as tumor site within the foot, size, elevated serum LDH or AP levels, or response to preoperative chemotherapy [1,13,32,41-43], we did not observe significant correlations with either event-free or overall survival, which may of course have been due to the limited number of patients included in our study.

5. Conclusion

Our study is one of the largest cohorts of patients with osteosarcoma of the foot reported to date despite the relatively small collection of only 23 patients. Using the same treatment strategy as employed in extremity osteosarcomas in general, we also achieved similar results. Primary metastatic status and surgical outcome correlated with prognosis. These results argue in favor of treating osteosarcomas of the foot like other extremity osteosarcomas and further highlight the importance of achieving complete surgical remission, especially regarding the poor response of the tumors to neoadjuvant chemotherapy.

https://doi.org/10.1155/2018/1632978

Disclosure

Peter Reichardt reports grants/personal fees from Novartis, Pfizer Bayer, PharmaMar, Amgen, AstraZeneca, Clinigen, Lilly, and Deciphera outside the submitted work; S. Bielack reports grants from Deutsche Krebshilfe, Forderkreis krebskranke Kinder Stuttgart e.V., and AXIS Forschungsstiftung during the conduct of the study and from Lilly, Bayer, Pfizer, Novartis, and Isofol outside the submitted work; Reinhard Windhager reports grants from Boehringer Ingelheim, Pfizer, Stryher, Taheda, and DePuy outside the submitted work. All other authors disclose that they have no financial or personal relationships with other people or organizations that could inappropriately influence (bias) their work.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Acknowledgments

The authors thank all patients who contributed to the COSS studies and acknowledge the physicians, nurses, data managers, and support staff of the collaborating centers for their active participation and Joachim Gerss for his support with the interpretation of survival analyses. Thanks are due to German Cancer Aid (Deutsche Krebshilfe) and sponsorship association for raising funds for children with cancer Stuttgart (Forderkreis krebskranke Kinder Stuttgart e.V.) for funding the work in question.

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Anne J. Schuster (ID), (1) Leo Kager, (2) Peter Reichardt, (3) Daniel Baumhoer, (4) Monika Csoka, (5) Stefanie Hecker-Nolting, (1) Susanna Lang, (6) Sylvie Lorenzen, (7) Regine Mayer-Steinacker, (8) Thekla von Kalle, (9) Matthias Kevric, (1) Mathias Werner, (3) Reinhard Windhager (ID), (10) Thomas Wirth, (11) and Stefan S. Bielack (1,12)

(l) Center for Pediatric, Adolescent and Women's Medicine, Olgahospital, Department of Pediatrics 5 (Oncology, Hematology, Immunology), Klinikum Stuttgart, Stuttgart, Germany

(2) St. Anna Children's Hospital, Department of Paediatrics, Medical University of Vienna and Children's Cancer Research Institute (CCRI), Vienna, Austria

(3) Department of Interdisciplinary Oncology, HELIOS Klinikum Berlin-Buch, Berlin, Germany

(4) Bone Tumour Reference Centre (BTRC), Institute of Pathology, University Hospital of Basel and University of Basel, Basel, Switzerland

(5) 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary

(6) Department of Pathology, Vienna General Hospital, Medical University of Vienna, Vienna, Austria

(7) Department of Hematology and Oncology, Klinikum rechts der Isar Technische Universitat Munchen, Munich, Germany

(8) Department of Internal Medicine III, University of Ulm, Ulm, Germany

(9) Center for Pediatric, Adolescent and Women's Medicine, Olgahospital, Department of Pediatric Radiology, Klinikum Stuttgart, Stuttgart, Germany

(10) Department of Orthopaedics, Medical University of Vienna, Vienna, Austria

(11) Center for Pediatric, Adolescent and Women's Medicine, Olgahospital, Department of Pediatrics, Division of Pediatric Orthopedics, Klinikum Stuttgart, Stuttgart, Germany

(12) Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster, Muenster, Germany

Correspondence should be addressed to Anne J. Schuster; anne.schuster@klinikum- stuttgart.de

Received 21 November 2017; Revised 15 February 2018; Accepted 18 March 2018; Published 2 May 2018

Academic Editor: Valerae O. Lewis

Caption: Figure 1: Overall survival (---) (95% confidence interval: 0.0-10.8) and event-free survival (---) (95% confidence interval: 3.6-14.3) of the 23 patients with high-grade osteosarcoma of the foot.
Table 1: Patient and tumor characteristics, treatment, and outcome.

Pat.   Age   Sex        Tumor site          Tumor size (ml)
no.

1      10     F     Tarsus (calcaneus)        40.56 max.;
                                           dimension: 6.5 cm

2      12     F         Tarsus (os        5.5 max.; dimension
                   cuneiforme lateral)           2.5 cm

3      12     M       Tarsus (talus:          12.08 max.;
                     position in the         dimension 3 cm
                     extensor aspect)

4      13     M    Tarsus (talus medial   31.2 max.; dimension
                          part)                   5 cm

5      13     M     Tarsus (calcaneus)        36.11 max.;
                                            dimension 6.5 cm

6      13     M     Tarsus (calcaneus)    54 max.; dimension 8
                                                   cm

7      23     M     Tarsus (calcaneus)             --

8      25     F     Tarsus (calcaneus)             --

9      25     F     Tarsus (calcaneus)             --

10     29     F     Tarsus (calcaneus)             --

11     32     M         Tarsus (os                 --
                       naviculare +
                     cuneiforme III)

12     33     F         Tarsus (os                 --
                       naviculare)

13     38     M     Tarsus (calcaneus)    32 (5 x 5 x 2.5 cm)

14     38     F     Tarsus (calcaneus)    51 max.; dimension 7
                                                   cm

15     56     M       Tarsus (talus)               --

16     58     M     Tarsus (calcaneus)             --

17     11     F      Metatarsale IV:               --
                   proximal right part

18     39     F      Metatarsale IV:      3.31 max.; dimension
                       mediocranial              3.5 cm

19     44     M     Metatarsale II, os             --
                    cuneiforme II and
                           III

20     44     M       Metatarsale V                --

21     45     M       Metatarsale I                --

22     45     F    Phalanx I: proximal             --
                           part

23     57     M     Phalanx distalis I    31 max.; dimension 5
                                                   cm

Pat.    Primary mets.     AP   LDH       Pre-op       Surgical
no.                                   chemotherapy    remission

1            None         N     N      A, M, I, P        CR

2            None         N     N      A, M, I, P        CR

3            None         --   --      A, M, I, P        CR

4          2-5 lung       E     E      A, M, I, P        No

5            None         E     N      A, M, I, P        CR

6            None         E     N       A, M, P          CR

7            None         N     N       A, M, P          CR

8            None         N     N    COSS 96, n.f.s      CR

9            None         N     N      A, M, I, P        CR

10           None         E     N       A, M, P          No

11     Lymph node; left   N     E      A, M, I, P        CR
            groin

12           None         E     E      A, M, I, P        CR

13           None         N     N      A, M, I, P        CR

14           None         N    --      A, M, I, P        CR

15           None         N     N       A, P, I          CR

16           None         N     N                        CR

17           None         N     N       A, P, M          CR

18           None         --   --          --            CR

19           None         N     N       A, I, P          CR

20           Lung         N     N       A, P, I          CR

21           None         N     N       A, P, I          CR

22           None         --   --    None; patient       CR
                                      disbelieved
                                       diagnosis

23           None         N     N          --            CR

Pat.     Type of surgery       Tumor response     Postoperative
no.                                               chemotherapy

1      Amputation lower leg         Poor           A, M, I, E
            below knee

2      Amputation forefoot          Good             A, I, P
         in Chopart joint

3      Resection of talus,          Poor           A, M, I, P
       half os naviculare,
        and distal part of
        lateral calcaneus
        inch sinus tarsi;
        reimplantation of
         proximal talus:
          tumor in 1 cm
             distance

4       En bloc resection           Poor          A, P, E, HD-I
          distal part of
        tibia, fibula and
              talus

5      Amputation of foot:          Poor           A, M, I, P
       exarticulation upper
           ankle joint

6      Amputation lower leg         Poor             A, M, P
            below knee

7      Amputation lower leg         Poor             A, M, P
            below knee

8      Amputation lower leg          --              n.f.s.
            below knee

9        First operation:           Poor           A, M, I, P
         excochleation of
           cyst; second
            operation:
       amputation of lower
          leg below knee

10     Amputation lower leg         Poor          A, M, I, P, E
              n.f.s

11       Amputation: foot           Poor           A, M, I, P
        through calcaneus;
        resection of groin
            metastases

12        Amputation of             Good          A, I, P, E, M
             forefoot

13       First operation:     N.A. (primary OP)    A, M, I, P
          intralesional
        excochleation of a
          "cyst" second
            operation:
       amputation lower leg
            below knee

14     Amputation lower leg         Poor           A, M, I, P
            below knee

15      Amputation distal           Good             A, P, I
            lower leg

16       First operation:     N.A. (primary OP)      A, P, I
           resection of
         calcaneal cyst:
        second operation:
       amputation lower leg
            below knee

17      Resection ray IV,           Poor          A, P, M, E, I
       metatarsale III and
       V reconstruction of
       axis III with fibula

18     Partial resection of   N.A. (primary OP)    A, I, P, M
        ray III-V through
            cuboid and
          cuneiforme III

19     Amputation forefoot          Poor             A, P, I
         in Chopart joint

20       First operation:           Good           I, P, M, A
       amputation atypical
        in Chopart joint;
        second operation:
       wedge resection left
            lower lobe

21     Amputation ray I and         Poor             A, P, I
       II and os naviculare

22     Amputation ray I and   N.A. (primary OP)       None
             II right

23     Amputation phalanx I   N.A. (primary OP)      A, P, I

Pat.          Event             Further therapy        EFS       OAS
no.                                                  (years)   (years)

1      SMD (Ewing sarcoma)                             8.9       8.9

2              None                                    13        13

3              None                                    11        11

4       No CR progressive            n.f.s.             0        0.7
        lung mets., local
               rec.

5              None                                    7.6       7.6

6              None                                   0.86      0.86

7              None                                    0.9       0.9

8              None                                    4.8       4.8

9          Lymph node          Second- and third-      0.8       1.4
           metastases          line chemotherapy
        ipsilateral groin

10      No CR: pulmonary      Corporectomy of HWK4      0        2.1
          filiae during       and BWK3, mets. Os
       preoperative chemo,     pubis, fourth rib
       mets. HWK4 and BWK 3

11      Rec. lower leg and    Resection of distal      2.2       4.2
            lung mets.               fibula

12          Lung mets.          High-dose chemo        4.9       5.0
                                    rejected

13        Lung mets. 3x       2 x metastasectomies     2.2       4.1

14             None                                    1.1       1.1

15             None                                    2.0       2.0

16             None                                    0.4       0.4

17             None                                    4.0       4.0

18          Lung mets.          Rec. I-III: 3 x        5.3      18.45
                               wedge resection of
                               affected pulmonary
                                      site

19             None                                    1.6       1.6

20     Lung mets. bilateral   No further therapy:      1.5      4.72
                                  patient will

21             None                                     2         2

22     Rec. 1: lung mets.,    2x wedge resection,      1.5       6.6
         Rec. 2: lung +       amputation right leg
       popliteal fossa, and
       Rec. 3: lymph node
          mets.: lung,
        mediastinal, and
            abdominal

23             None                                    1.6       1.6

Pat.     Status
no.

1        DOC-SMD

2        LFU-CR1

3        LFU-CR1

4      DOD-primary
         disease

5        LFU-CR1

6          CR1

7        LFU-CR1

8        LFU-CR1

9       DOD-Rec1

10     DOD-primary
         disease

11      DOD-Rec2

12      LFU-Rec1

13      DOD-Rec3

14       LFU-CR1

15       LFU-CR1

16       LFU-CR1

17       LFU-CR1

18         CR3

19         CR1

20      DUC-Rec1

21       LFU-CR1

22      DOD-Rec3

23       LFU-CR1

Pat. = patient; No. = number; status = status at the last available
follow-up; F = female; M = male; N = normal; E = elevated; N = normal;
A = doxorubicin; M = methotrexate; I = ifosfamide; HD = high dose; P =
cisplatin; E = etoposide; CR = complete surgical remission (primary
tumor and metastases); good-poor tumor response = <-[greater than or
equal to] 10% viable tumor following pre-op. chemotherapy; SMD =
secondary malignant disease; n.f.s. = not further specified; mets. =
metastases; OP = operation; N.A. = not applicable; DOC = death of
other cause; LFU = lost to follow-up; DOD = death of disease; Rec. =
recurrence.

Table 2: Complete surgical remission in localized and metastatic
disease.

Surgical remission                    Number of patients with
                                         localized disease

Number of patients                              20
Complete resection of primary tumor             20
Complete resection of metastases                0*
Complete surgical remission                     19

Surgical remission                    Number of patients with
                                        metastatic disease

Number of patients                               3
Complete resection of primary tumor              3
Complete resection of metastases                 2
Complete surgical remission                      2

Surgical remission                     Number of
                                      all patients

Number of patients                         23
Complete resection of primary tumor        23
Complete resection of metastases           2
Complete surgical remission                21

One patient with localized disease developed pulmonary metastases
during preoperative chemotherapy and did not receive metastasectomy
because of progressive disease.

Table 3: Type of surgery.

Type of surgery     Number of patients       Number of patients
                  with localized disease   with metastatic disease

Amputation                  17                        2
Resection                   3                         1

Type of surgery    Number of
                  all patients

Amputation             19
Resection              4


Table 4: Tumor response to preoperative chemotherapy.

Tumor response                            Number of patients with
                                             localized disease

Good (less than 10% viable tumor cells)              3
Poor (more than 10% viable tumor cells)             11
Not applicable (primary surgery)                     5
Not documented                                       1

Tumor response                              Number of patients
                                          with metastatic disease

Good (less than 10% viable tumor cells)              1
Poor (more than 10% viable tumor cells)              2
Not applicable (primary surgery)                     0
Not documented                                       0

Tumor response                             Number of
                                          all patients

Good (less than 10% viable tumor cells)        4
Poor (more than 10% viable tumor cells)        13
Not applicable (primary surgery)               5
Not documented                                 1

Table 5: Outcome at the last follow-up.

Outcome           Number of patients        Number of patients
                 with localized disease   with metastatic disease

Died                       5                         3
Alive                      15                        0
Alive CR1                  13                        0
Alive Rec1-LFU             1                         0
Alive CR3                  1                         0

Outcome           Number of
                 all patients

Died                  8
Alive                 15
Alive CR1             13
Alive Rec1-LFU        1
Alive CR3             1

CR = complete surgical remission (primary tumor and metastases); CR1 =
first complete surgical remission; CR3 = third complete surgical
remission; Rec. 1 = first recurrence; LFU = lost to follow-up.

Table 6: Univariate analysis of overall and event-free survival.

Survival                            Number of   Percent
Variable                            patients

Total                                  23
Age
  <32 years (median)                   12         52
  >32 years                            11         48
Sex
  Male                                 13         57
  Female                               10         43
Tumor site
  Tarsus                               16         70
  Other                                 7         30
Tumor size
  <31.5 [cm.sup.3] (median)             5         50
  >31.5 [cm.sup.3]                      5         50
Primary metastases
  No                                   20         87
  Yes                                   3         13
AP
  Normal                               15         75
  Elevated                              5         25
LDH
  Normal                               16         84
  Elevated                              3         16
Duration of symptoms
  <154 days (median)                   11         55
  >154 days                             9         45
Delay of chemotherapy
  <21 days                              8         35
  >21 days                             15         65
Timing of operation
  After preoperative chemotherapy      18         78
  Primary surgery                       5         22
Type of surgery
  Resection                             4         17
  Amputation                           19         83
Surgical remission
  Complete remission                   21         95
  Macroscopic residual                  2          9
Tumor response
  Good                                  4         24
  Poor                                 13         76

Survival                                    Event-free survival
Variable
                                    5 year (%)   SE (%)   P (log-rank)

Total
Age
  <32 years (median)                    64         15        0.438
  >32 years                             39         21
Sex
  Male                                  44         18        0.791
  Female                                63         18
Tumor site
  Tarsus                                49         16        0.903
  Other                                 71         17
Tumor size
  <31.5 [cm.sup.3] (median)             80         18        0.786
  >31.5 [cm.sup.3]                      67         27
Primary metastases
  No                                    66         13        0.005
  Yes                                   0          0
AP
  Normal                                60         16        0.216
  Elevated                              30         24
LDH
  Normal                                68         14        0.076
  Elevated                              0          0
Duration of symptoms
  <154 days (median)                    76         16        0.188
  >154 days                             29         22
Delay of chemotherapy
  <21 days                              58         19        0.532
  >21 days                              52         17
Timing of operation
  After preoperative chemotherapy       52         14        0.929
  Primary surgery                       67         27
Type of surgery
  Resection                             75         22        0.660
  Amputation                            45         15
Surgical remission
  Complete remission                    60         13        0.000
  Macroscopic residual                  0          0
Tumor response
  Good                                  38         29        0.980
  Poor                                  64         15

Survival                                      Overall survival
Variable
                                    5 year (%)   SE (%)   P (log-rank)

Total
Age
  <32 years (median)                    61         15        0.828
  >32 years                             67         20
Sex
  Male                                  39        17.5       0.235
  Female                                89        10.5
Tumor site
  Tarsus                                57         15        0.503
  Other                                 80         18
Tumor size
  <31.5 [cm.sup.3] (median)             80         18        0.366
  >31.5 [cm.sup.3]                      67         27
Primary metastases
  No                                    78         11        0.008
  Yes                                   0          0
AP
  Normal                                57         16        0.568
  Elevated                              53         25
LDH
  Normal                                62         15        0.291
  Elevated                              33         27
Duration of symptoms
  <154 days (median)                    76         16        0.463
  >154 days                             51         20
Delay of chemotherapy
  <21 days                              73         17        0.441
  >21 days                              57         17
Timing of operation
  After preoperative chemotherapy       64         13        0.587
  Primary surgery                       67         27
Type of surgery
  Resection                             75         22        0.347
  Amputation                            60         14
Surgical remission
  Complete remission                    72         12        0.000
  Macroscopic residual                  0          0
Tumor response
  Good                                  67         27        0.435
  Poor                                  59         16

5-year event-free and overall survival and P values in the log-rank
test for all variables (see Data collection and Definition of
Variables). SE = standard error; P = two-sided P values.
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Title Annotation:Research Article
Author:Schuster, Anne J.; Kager, Leo; Reichardt, Peter; Baumhoer, Daniel; Csoka, Monika; Hecker-Nolting, St
Publication:Sarcoma
Article Type:Report
Date:Jan 1, 2018
Words:6801
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