Adult-Type Soft Tissue Sarcomas in Pediatric-Age Patients: Experience at the Istituto Nazionale Tumori in Milan
http://www.100md.com
《临床肿瘤学》
the Pediatric Oncology Unit, Departments of Pathology and Radiotherapy, Melanoma Sarcoma Surgical Unit, and Division of Medical Statistics and Biometry, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milano, Italy
ABSTRACT
PURPOSE: Nonrhabdomyosarcoma soft tissue sarcomas are a heterogeneous group of tumors for which optimal treatment remains controversial. We report on a large group of 182 patients younger than 18 years old treated at a single institution over a 25-year period.
PATIENTS AND METHODS: In this relatively homogeneous subgroup of adult-type histotypes, surgery was the mainstay of treatment; radiotherapy was administered to 73 patients, and chemotherapy was administered to 114 patients (70 received chemotherapy as adjuvant therapy).
RESULTS: Overall survival at 5 years was 89% in patients who underwent complete resection at diagnosis, 79% in patients who had marginal resection, 52% in initially unresected patients, and 17% in patients with metastases at onset. Outcome was unsatisfactory in patients with large and high-grade tumors, even after gross resection; adjuvant chemotherapy seemed to improve the results in this group. Initially unresected patients who responded well to chemotherapy and subsequently underwent complete resection had an event-free survival rate of approximately 70%. The rate of response to chemotherapy was 58%.
CONCLUSION: The identification of prognostic variables should enable risk-adapted therapies to be planned. Patients with initially unresectable disease and patients with resected large and high-grade tumors are at high risk of metastases and treatment failure. Although the limits of this retrospective analysis are self-evident, our data would suggest that intensive chemotherapy (with an ifosfamide-doxorubicin regimen) might have a more significant role in these patients than what is generally assumed.
INTRODUCTION
Soft tissue sarcomas are rare, with an annual incidence of approximately two to three per 100,000 persons, and they account for less than 1% of all malignant tumors and 2% of all cancer-related deaths.1 In pediatric age, however, approximately 8% of malignancies are soft tissue sarcomas, with rhabdomyosarcoma (RMS) representing approximately 55% to 60% of the soft tissue sarcomas.2 The so-called nonrhabdomyosarcoma soft tissue sarcomas (NRSTS) account for approximately 3% of pediatric cancers and constitute a very heterogeneous group of tumors with a variety of histotypes with different origin, biology, and natural history, some of which are more common in adults and many of which are rare in children. Most of the experience gained in the treatment of pediatric NRSTS either derives from managing soft tissue sarcomas in adults or relies on the principles derived from the management of RMS.
NRSTS usually arise in the extremities (although they can develop anywhere in the body), and they are characterized by local aggressiveness and a propensity to metastasize that is correlated to their grade of malignancy. NRSTS management is complex and necessarily multidisciplinary.3,4 Although surgery is known to be the mainstay of treatment, our knowledge of the role of adjuvant treatments is clearly incomplete and needs to be improved. In particular, there is no general agreement concerning the use of chemotherapy.3 NRSTS are generally considered scarcely chemosensitive, but data emerging recently from some adult studies seem to suggest that patients with high-risk extremity sarcomas can benefit from intensified adjuvant chemotherapy.5
Given the heterogeneity of these tumors, clinical studies should target diagnostic subgroups as specifically as possible, but the rarity of each histotype prevents the performance of clinical trials on a single tumor type, and consequently, NRSTS have to be analyzed as a group. To create a more homogeneous group, we focused on NRSTS that are typical of adulthood (excluding infantile fibrosarcoma) and definitely malignant (excluding borderline tumors, ie, hemangioendothelioma) and that have morphologic features resembling differentiated/mature tissues (excluding small round-cell tumors, ie, RMS, extraosseus peripheral primitive neuroectodermal tumor and Ewing's sarcoma, and desmoplastic small round-cell tumor). We defined these tumors as adult-type soft tissue sarcomas. This report is a retrospective analysis of 182 consecutive patients seen at our institution in a 25-year period.
PATIENTS AND METHODS
In all, 634 consecutive cases of previously untreated patients younger than 18 years who were diagnosed with soft tissue sarcoma between 1977 and 2003 were collected from the Pediatric Oncology Unit's database at the Istituto Nazionale Tumori (Milan, Italy). Three hundred forty-one of the patients (54%) were classified as having RMS, and 293 were classified as having NRSTS.
We used the term adult type to describe definitely malignant soft tissue sarcomas occurring mainly in adult age and characterized by a closer morphologic resemblance of differentiated/mature tissues (usually with a spindle-cell and pleomorphic morphology) and an uncertain response to chemotherapy. Sarcomas belonging to the group of small round-cell tumors, including RMS, desmoplastic small round-cell tumor (n = 6), and extraosseus peripheral primitive neuroectodermal tumor and Ewing's sarcoma (n = 48) were excluded, as were cases of infantile fibrosarcoma and hemangiopericytoma (n = 8) and tumors with uncertain malignancy (ie, hemangioendothelioma, n = 28; and myofibroblastic lesions as fibromatosis and desmoid tumors, n = 21).
As a result, 182 patients were included in this study and analyzed for survival. Complete details on clinical features, treatment, and outcome were available for all patients. The histologic diagnosis was made by pathologists at our institution before starting any treatment. Most of the histologic features were reviewed for the purposes of this study; in detail, 141 patients (77%) were reviewed, whereas for 41 patients, the tumor specimens or slides were not available (most of these patients were in the older of the series and treated in the 1970s period). The tumor grade was assigned in 125 patients. Grading evaluation was not performed for 16 of the 141 reviewed patients because the biopsy slides were unavailable, whereas the specimens of the delayed surgery were reviewed but were not proper for grading evaluation because of the primary chemotherapy. Tumor grade was assigned according to the French Federation of Cancer Centers Sarcoma Group's grading system.6 This is a three-grade classification system that defines a score in relation to tumor differentiation, mitotic index, and tumoral necrosis; it was chosen for its high reproducibility and the opportunity for a valid comparison with adult series.6
Clinical Grouping
Before starting treatment, data were available for most patients on the physical examination, the local extent of disease as assessed by computed tomography and/or magnetic resonance imaging, chest x-ray and/or chest computed tomography scan, abdominal ultrasound, and whole-body bone scan. Disease was staged according to the clinical tumor-node-metastases classification7 and the Intergroup Rhabdomyosarcoma Study (IRS) postsurgical grouping system.8 According to the former, T1 are tumors confined to the organ or tissue of origin, whereas T2 lesions invade contiguous structures; T1 and T2 groups are further classified as a or b depending on whether tumor diameter is 5 cm or more than 5 cm, respectively. Regional node involvement is indicated as N0 or N1 and distant metastases at onset is indicated as M0 or M1 based on histologic or clinical and radiologic assessments.7 The IRS system categorizes patients in four groups based on the amount and extent of residual tumor after initial surgery. Group I includes completely excised tumors with negative microscopic margins; group II indicates grossly resected tumors with microscopic residual disease and/or regional lymph nodal spread; group III patients have macroscopic residual disease after incomplete resection or biopsy; and group IV patients have metastases at onset.8
Treatment
Patients were treated using a multimodality therapeutic approach, including surgery, chemotherapy, and radiotherapy, based on the ongoing protocols at the time of diagnosis. Treatment strategies did not change substantially over the years; primary excision was generally attempted if complete and nonmutilating resection was considered feasible; if not, a biopsy was taken, and chemotherapy (and/or radiotherapy) was administered to shrink the tumor and make it more amenable to subsequent surgery.
Surgery was defined as complete (IRS group I) when histologic margins were free, thus including ablative surgeries, compartment resections (en bloc resection of the tumor and the entire compartment of origin, where tumor was entirely anatomically confined), and wide excisions (en bloc excisions through normal tissue, beyond the reactive zone but within the muscular compartment, removing the tumor with its pseudocapsule). We chose to consider as marginal (IRS group II) any resections coming just outside the pseudocapsule, with suspected microscopic residual disease (marginal resection according to Enneking's criteria) and cases with microscopically infiltrated margins (considered by Enneking as intralesional).9 We defined as primary re-excision any resurgery performed up to 2 months after an initially inadequate resection and before any other treatment. Delayed surgery is defined as surgery performed after primary chemotherapy or radiotherapy.
Radiotherapy was administered to patients considered at risk of local failure. External-beam irradiation was delivered using megavoltage photon or electron beam energies, with conventional fractionation (1.8 to 2.0 Gy daily for 5 days a week). The radiation fields included the initial tumor volume plus 2- to 3-cm margins.
In most cases, systemic chemotherapy was part of the treatment program. Different chemotherapeutic regimens were used over the years, according to ongoing protocols. All patients received a multidrug regimen, including cyclophosphamide or ifosfamide, plus anthracyclines (doxorubicin or epirubicin); dactinomycin and vincristine were added in several cases. In patients with measurable disease, response to chemotherapy was recorded according to the radiologically assessed reduction in the sum of the products of the perpendicular diameters of all measurable lesions and defined as follows: complete response (CR), complete disappearance of disease; partial response (PR), maximal tumor reduction more than 50%; and minor response (MR), maximal tumor reduction more than 25%. Stable disease or a maximal tumor reduction less than 25% was classified as no response, whereas an increase in tumor size or the detection of new lesions was called progression of disease. Because even an MR could be significant in these tumors (which are generally regarded as poor responders to chemotherapy), chemotherapy response rate was evaluated also considering CR, PR, and MR.
Statistical Methods
Event-free survival (EFS) and overall survival (OS) were estimated according to the Kaplan-Meier method.10 Patients were evaluated from histologic diagnosis to latest uneventful follow-up, disease progression, relapse, or death from any cause for EFS and to death for OS. The local relapse-free survival (LRFS) was calculated from diagnosis to local progression or relapse. Patients who died of their tumor after distant failure and before local progression or relapse were excluded at the time of death in the analysis of LRFS. Metastases-free survival (MFS) was calculated from diagnosis to the onset of distant metastases.
The log-rank test was used to compare the survival curves of patient subgroups in a univariate analysis to ascertain the potential value of various prognostic factors.11 2 tests were used to compare the frequency of certain clinical characteristics in the different patient subgroups. Multivariate analysis of EFS in patients with grossly resected tumors was carried out by means of the Cox regression model.12 The number of events for the other end points (and in patients with initially unresected tumors) was too small to allow such an analysis. To describe the results obtained with the Cox model, we report hazard ratio estimates and corresponding 95% CIs, together with the likelihood ratio P values, for testing the overall association between each covariate and EFS. Patient follow-up, as of January 2004, ranged from 6 to 256 months (median, 110 months).
RESULTS
Table 1 lists the patients' clinical features. The most frequent histotype was synovial sarcoma (32% of patients). Histologic grades were available for 125 patients; 24 were classified as grade 1, 33 were classified as grade 2, and 68 were classified as grade 3.
Thirteen patients had hereditary syndromes; 11 had neurofibromatosis type 1 (malignant peripheral nerve sheath tumor [MPNST], n = 10; and malignant hemangiopericytoma, n = 1), one had Li Fraumeni syndrome (leiomyosarcoma), and one had xeroderma pigmentosum (angiosarcoma). In one patient, soft part sarcoma (synovial sarcoma) developed as a second tumor 6 years after a lymphoblastic leukemia.
Six patients (3%) had lymph node involvement at diagnosis. The histotypes included two clear-cell sarcomas and one case each of MPNST, angiosarcoma, epithelioid sarcoma, and alveolar soft part sarcoma; they were all grade 3 tumors, and four of the six patients had T2b tumors.
Six patients had distant metastases at onset. The metastatic sites were the lung in five patients and the bones in one patient. All patients had T2b and grade 3 tumors, and the histotypes were alveolar soft part sarcoma in three patients and synovial sarcoma, MPNST, and sarcoma not otherwise specified in one patient each.
One hundred patients underwent complete resection at diagnosis (70 of them throughout primary re-excision), 36 had marginal resection, and 13 had incomplete resection with macroscopic residual tumor. Biopsy was the initial surgery in 33 patients. In 22 patients, delayed surgery was performed after chemotherapy, with complete tumor excision in 19 of these patients. Surgery was mutilating in nine patients (eight at diagnosis and one at delayed surgery).
Seventy-three patients had radiotherapy (72 patients postoperatively and only one patient as a presurgical procedure). The total dose of radiotherapy ranged from 45 to 70 Gy (median, 58 Gy).
Systemic chemotherapy was used in 114 patients. It was administered as primary treatment to all but two of the IRS group III to IV patients. Adjuvant chemotherapy was administered to 70 (51%) of 136 of the IRS group I to II patients; chemotherapy was usually required for patients with high-grade or large tumors, although during the 25-year study period, the decision of whether to administer chemotherapy was sometimes individualized. All the patients who received adjuvant chemotherapy had large or high-grade tumors; but among the 95 group I to II patients with a tumor size more than 5 cm or grade 3 histology, 70 received chemotherapy, and 25 did not receive chemotherapy. Eighty-one patients received a regimen of vincristine, doxorubicin, cyclophosphamide, and dactinomycin; 22 patients received vincristine, doxorubicin, ifosfamide, and dactinomycin; and 10 patients received ifosfamide plus doxorubicin or epirubicin (plus cisplatin in four patients). One metastatic patient received vincristine, doxorubicin, ifosfamide, and dactinomycin plus high-dose chemotherapy with stem-cell rescue.
Overall, 112 patients were in first complete remission, and 17 were in second, third, or fourth remission at the time of the analysis. Four patients were alive with disease, 48 died of their tumor (3 to 138 months from diagnosis), and one died of a second malignancy (postirradiation osteogenic sarcoma, which developed 10 years after MPNST).
Overall, survival rates were as follows. EFS rate was 64.0% (SE, 3.7%) and 59.0% (SE, 3.9%) at 5 and 10 years, respectively; LRFS rate was 75.4% (SE, 3.3%) and 72.0% (SE, 3.6%) at 5 and 10 years, respectively; MFS rate was 72.5% (SE, 3.5%) and 68.1% (SE, 3.8%) at 5 and 10 years, respectively; and OS rate was 76.1% (SE, 3.3%) and 71.8% (SE, 3.7%) at 5 and 10 years, respectively.
Over the years, 5-year EFS and OS rates increased from 56% and 67% in the 1970s and 1980s to 77% and 87% after 1990, respectively (Table 2). As shown in Tables 3 and 4, this improvement was more significant in the subset of patients with surgically resected tumor than in patients who were considered unresectable at diagnosis.
Table 2 lists the survival rates according to the variables considered in the univariate analysis. In the whole series of patients, tumor invasiveness and size were the most important prognostic factors; patients with T2b tumor had 5-year EFS and OS rates of 28.8% and 48.2%, respectively. Female sex, older age, high-grade tumor, MPNST histology, and tumor sites other than extremities correlated with a worse outcome.
Tumor size was correlated strongly with local invasiveness and high-grade histology. T2 and grade 3 tumors occurred in 17 (20%) of 86 and 15 (33%) of 45 patients with tumors 5 cm, respectively, and in 75 (78%) of 96 and 52 (65%) of 80 patients with tumors greater than 5 cm (P < .01).
Patients With Grossly Resected Disease
Macroscopic resection at diagnosis was performed in 136 patients (IRS group I, n = 100; and IRS group II, n = 36). Survival rates at 5 years were as follow: EFS, 71.7% (SE, 4.0%); LRFS, 82.5% (SE, 3.4%); MFS, 78.6% (SE, 3.7%); and OS, 86.1% (SE, 3.2%).
Local invasiveness and tumor size were still the most significant prognostic factors (Table 3). T2b patients had an unsatisfactory outcome (5-year EFS, 30.2%; 5-year OS, 60.3%). Figure 1 shows that survival rates differed significantly according to the state of the surgical margins (5-year OS, 88.7% in group I v 78.7% in group II). It is worth noting that local invasiveness particularly affected the quality of surgery. T2 tumors were present in 26 (26%) of 100 and 25 (69%) of 36 patients in group I and II, respectively (P < .01); tumors more than 5 cm were present in 36 (36%) of 100 and 20 (55%) of 36 patients in group I and II, respectively (P = not significant [NS]); and grade 3 tumors were present in 25 (42%) of 60 and 14 (54%) of 26 patients in group I and II, respectively (P = NS).
Local invasiveness and tumor size strongly influenced the local control. Five-year LRFS rate was 91.1% in patients with T1 tumors and 67.1% in patients with T2 tumors (P = .0004); LRFS rate was 89.5% in patients with tumors 5 cm and 71.3% in patients with tumors greater than 5 cm (P = .0012); and LRFS rate was 86.9% in IRS group I patients and 70.1% in IRS group II patients (P = .0584). Tumor grade did not correlate with local failure; 5-year LRFS rate was 88.1% in patients with grade 1 tumors, 91.6% in patients with grade 2 tumors, and 80.1% in patients with grade 3 tumors (P = .5455).
In the subset of completely resected patients (IRS group I, n = 100), postoperative radiotherapy was administered to 22 patients. In this group, 5-year LRFS rate was 95.2% in patients treated with radiotherapy and 84.4% in patients who did not receive postoperative irradiation (P = NS).
Concerning only patients considered at high risk of local failure because of large tumor size (> 5 cm), radiotherapy seemed to have an impact on local control and outcome. The 5-year LRFS and OS rates were 91.7% and 90.0%, respectively, for patients treated with postoperative radiotherapy (n = 13) and 69.8% and 53.8%, respectively, for patients who were treated without radiotherapy (n = 23; P = .4747 for LRFS and P = .0248 for OS). In these two groups, there was a balance in the tumor grade distribution (ie, grade 3 tumors were present in 38% of the subset of patients treated with radiotherapy and in 43% of the patients not treated with radiotherapy); however, the percentage of patients who also received chemotherapy was higher in patients who received radiation compared with patients who did not (77% v 56%, respectively), and this could have influenced the better LRFS and OS rates.
In patients who underwent marginal resection (IRS group II, n = 36), radiotherapy was administered to 27 patients (75%). LRFS rate at 5 years was 75.7% in patients administered radiotherapy and 55.6% in patients who did not received radiotherapy (P = .1403). Three patients with grade 1 tumors received marginal resection; two were treated with postoperative radiotherapy, and one was treated with surgery alone. The patient who did not receive irradiation had local relapse.
Adjuvant chemotherapy was administered to 70 (51%) of 136 patients. Seventy-two percent of these patients (36 of 50 patients) had synovial sarcoma, and 39% (34 of 86 patients) had other histotypes; the majority of these patients had grade 3 tumors (71%) and tumors greater than 5 cm (60%).
The possible benefit of adjuvant chemotherapy was evaluated in patients considerable at high risk of metastases because of high-grade (grade 3) and large tumor size (> 5 cm). This group included 27 patients (considering all histotypes first), and the 5-year EFS rate was 45.6%. If synovial sarcoma patients (generally considered more chemosensitive)13 were excluded from the analysis, the group included 15 patients, and the 5-year EFS and MFS rates were 27.7% and 35.8%, respectively. In this subset of patients (grade 3, size > 5 cm, and synovial sarcomas excluded), 5-year MFS rate was 53% in the patients who received adjuvant chemotherapy (n = 11) and 0% in patients who did not receive adjuvant chemotherapy (n = 4; all patients treated without chemotherapy experienced distant metastases; P = .2041).
Patients With Initially Unresected Disease
Forty patients were classified as IRS group III after biopsy (n = 27) or macroscopically incomplete resection (n = 13). The clinical findings of IRS group III patients were substantially different from those of group I to II patients; the percentages of patients were higher for MPNST (30% v 12%, respectively; P < .05) and high-grade tumor (70% v 45%, respectively; P < .05), as well as for tumor at sites other than the limbs (65% v 29%, respectively; P < .01), locally invasive tumor (90% v 38%, respectively; P < .01), and tumor larger than 5 cm (85% v 41%, respectively; P < .01).
For patients with initially unresected disease, 5-year EFS, LRFS, MFS, and OS rates were 45.2%, 55.6%, 59.0%, and 51.8%, respectively. Table 4 lists the survival rates according to different variables. The small number of patients in some subsets (ie, T1 tumor or size 5 cm) limited the statistical value of univariate analysis, but female sex, older age, and MPNST histotype were statistically significant adverse factors.
Neoadjuvant chemotherapy was administered to 38 patients. Two patients did not receive chemotherapy. The first patient had a huge MPNST of the gluteus; he received radiotherapy, but he had local and systemic spread 2 months after diagnosis and died of his tumor 1 month later. The second patient had a 2-cm, grade 1 fibrosarcoma of the gum; he was treated with radiotherapy and then complete tumor resection, and he was alive without evidence of disease at the time of the report (15 years after diagnosis).
Response to chemotherapy was as follows: one CR, 14 PRs, and seven MRs (16 patients had no response), for an overall response rate of 39% in terms of CR + PR and 58% when MR was included too. The response rate was 58% for CR + PR and 82% for CR + PR + MR in patients treated with regimens including ifosfamide and anthracyclines; and the response rate was 34% for CR + PR and 48% for CR + PR + MR in patients treated with vincristine, doxorubicin, cyclophosphamide, and dactinomycin. When patients with synovial sarcoma were excluded from the analysis, the rate of response to chemotherapy was still 55%.
Outcome was directly influenced by response to primary chemotherapy. Five-year OS rate was 71.4% in patients who responded well (CR + PR), 50.0% in patients with MR, and 36.5% in patients with no response.
After chemotherapy, 19 patients underwent complete delayed surgery (gross total resection with negative microscopic margins), which had been considered unfeasible at diagnosis. The definitive local treatment was complete delayed surgery alone in 11 patients, complete delayed surgery plus radiotherapy in eight patients (seven patients postoperatively and one patient preoperatively), radiotherapy alone in 14 patients, and incomplete surgery in seven patients. The outcome correlated with the achievement of complete tumor resection; 5-year OS rate was 80.0% in patients who had complete delayed surgery, 85.7% in patients who had complete delayed surgery plus radiotherapy, 35.7% in patients treated with radiotherapy without adequate resection, and 14.3% in incompletely resected patients who did not receive radiotherapy.
Twenty-three patients experienced tumor progression or relapse. Treatment failure was local in 13 patients, local and with distant metastases in four patients, nodal in one patient, and metastatic in four patients. Among the 13 patients who relapsed locally, six successively developed distant spread. If local progression or relapse was the major cause of treatment failure, metastatic disease represented the predominant cause of death; 13 patients died from metastatic disease, and seven died from local tumor progression.
DISCUSSION
This study retrospectively analyzes the clinical features, treatment, and outcome of a large single-institution series of pediatric patients with NRSTS, focusing on a relatively homogeneous group of adult-type histotypes. Our series is comparable with other reported studies,14,15 particularly the two recently published series from the St Jude Children's Research Hospital,16,17 which describe the prognostic variables that can predict survival and that should be used to stratify patients for a risk-adapted therapy.
The relatively small number of patients in some treatment subsets and the retrospective nature of our analysis prevent any certain conclusions from being drawn on the role of adjuvant therapies, which remains controversial. Nevertheless, our data (like other recent reports) would suggest that chemotherapy might have a more significant role in high-risk patients (ie, large tumor and high grade) than is generally believed.3,5,18-20
In the last two decades, treatment strategies for these tumors have changed to some degree, and multimodalities have been used increasingly.18 Although the effectiveness of radiotherapy is now appreciated,21,22 systemic chemotherapy still represents an open question for oncologists3,18; adult soft tissue sarcomas continue to be considered scarcely chemosensitive.
To date, only a minority of the several randomized adjuvant chemotherapy trials on adults soft tissue sarcomas has shown a significant survival advantage for chemotherapy,5,19,20,23-25 whereas the only trial performed in patients of pediatric age failed in its aim because the majority of patients refused randomization.26 Fourteen randomized trials comprising 1,568 adult patients were nonetheless included in a meta-analysis that demonstrated a lower risk of local and distant failures in patients treated with intensified doxorubicin-based chemotherapy.19,20 Moreover, an Italian randomized trial on high-risk patients (high grade and large, deep tumor) was concluded in advance because of an early striking improvement in EFS and OS among patients who received intensive ifosfamide-doxorubicin chemotherapy versus patients treated with local therapy alone.5 This trial has been defined as the first modern study on adjuvant chemotherapy in soft tissue sarcoma.18 The ifosfamide-doxorubicin regimen currently needs to be considered the regimen with the higher response rate, and several reports suggest that dose intensification (with hematopoietic growth factor support) has been associated with an improved response rate and disease-free survival.23-25, 27-30
Some of the negative results recorded in previous chemotherapy randomized studies probably need to be considered with caution. Future clinical trials should target high-risk patients properly, with accurate patient selection, and should deliver intensive chemotherapy including the most active drugs. In other words, adjuvant ifosfamide-doxorubicin chemotherapy cannot yet be considered as the standard of care in high-risk resected soft tissue sarcomas; however, recent suggestions would seem to support the beneficial impact of this approach.
Our subset of adult-type sarcomas arising in a pediatric population is comparable to the various reported series on soft tissue sarcoma in adult age. Some pediatric patients' clinical features are similar to those observed in adults (ie, the most frequent localization at extremities). Our findings confirm the known epidemiologic data that describe synovial sarcoma and MPNST as the most frequent histotypes in adolescents and young adults (in contrast, liposarcoma and malignant fibrous histiocytoma are the most frequent histotypes in adult series, with picks of incidence in the fifth and sixth decades).1 The prognostic factors of adult sarcomas (ie, large tumor size, local invasiveness, high-grade tumors, older age, and sites other than the extremities) confirm their value in our series, but the proportion of pediatric patients with unfavorable features seems quite lower than in adults (ie, tumors larger than 5 cm and high-grade tumors are present in approximately one half of the patients in our series, whereas they usually are present in two thirds of patients in adult series).13-16,21,26,31-35
As for adult series, this study emphasizes that outcome in patients with grossly resected NRSTS was good enough for low-grade, small, and noninvasive tumors, but not high-grade, large, and invasive tumors, to be treated with surgery alone. In our small subset of patients with group I to II, grade 3, and more than 5 cm tumors (synovial sarcoma excluded), the 5-year MFS rate was 35.8%; it was 53.0% for patients treated with chemotherapy, whereas it decreased to 0% for the few patients who were not administered chemotherapy (the P value was not significant, given also the small number of patients in this comparison). The high rate of metastatic spread would suggest the use of systemic chemotherapy in such patients, given also that the high mitotic rate of grade 3 tumors might, in principle, be indicative of some chance of response to chemotherapy.
An intensified treatment in high-risk resected patients would also include radiotherapy. Our data seem to confirm that the local recurrence rate was lower in group II patients (5-year LRFS, 75.7% in patients not treated with radiotherapy v 55.6% in patients treated with radiotherapy) and group I patients with large tumors (5-year LRFS, 91.7% in patients not treated with radiotherapy v 69.8% in patients treated with radiotherapy) when radiotherapy was delivered, although the small number of patients hindered significant P values and certain conclusions. However, these suggestions would be comparable to the hints available from larger adult series that prompt a possible role of radiotherapy after marginal resection and after wide excision of large tumors.21,22
The beneficial effect of radiotherapy on LRFS (in completely resected tumors > 5 cm) seemed to influence OS too, although there was an imbalance in the proportion of patients who received chemotherapy in the subsets of patients who received and who did not receive irradiation, and this nonrandom use of chemotherapy could have influenced the survival rates. It is known, in fact, that data from larger series have questioned the real impact of local control on survival.22 Regardless, the morbidity of radiotherapy is a more important matter in dealing with children than with adults.
As for the patients with initially unresected tumors, the 5-year OS rate remained approximately 50%. Few improvements have been seen in the results obtained over the years in this group. As reported elsewhere,34 MPNST was the most frequent histotype and was associated with a poor outcome. Age under 10 years was confirmed as a favorable prognostic factor,31 despite our excluding infantile fibrosarcomas from this study, whereas the unfavorable effect of female sex remains unexplained. Our analysis showed that a better chance of cure coincided with the chance to ensure adequate surgery after shrinking the tumor with chemotherapy17,29,30; patients who responded well to neoadjuvant chemotherapy and underwent delayed complete resection had a 5-year EFS rate of approximately 70%. This would suggest the need to increase the intensity of primary chemotherapy. Although several patients in our series were administered chemotherapy regimens definable as mild by comparison with protocols used today for adult sarcomas or pediatric small round-cell sarcomas, the overall response rate was 58% in terms of CR + PR + MR and increased to 82% when only regimens including ifosfamide and anthracyclines were considered. These results are questionable, given the small group of patients and the decision to include MR in calculating the response rate; nonetheless, together with the suggestion of a possible benefit of adjuvant chemotherapy in high-risk resected patients, these findings would point to a more important role for chemotherapy than what has been hitherto reported.
In conclusion, unlike RMS (for which numerous cooperative trials over the years have yielded great improvements in our knowledge and the results of treatment), the management of pediatric adult-type soft tissue sarcomas still poses several unsolved questions, although pediatricians can draw important information from the experience of adult oncologists. The identification of prognostic variables strongly influencing outcome would enable us to plan risk-adapted therapies. Considering the unsatisfactory outcome in patients with advanced unresectable disease and in patients with high-grade and/or large tumors even after complete surgery, more intensive therapies and new strategies are needed. The success of the antityrosine kinase imatinib mesylate in the treatment of c-kit–positive gastrointestinal mesenchymal tumors provides important insight for the development of new molecular therapies specifically designed for targets critical to a tumor's biology.36 While awaiting new therapies directed against the product of some of the several chromosomal translocations occurring in sarcomas, a better use of the standard therapies has to be sought. Although chemotherapy cannot be considered a standard treatment for these malignancies as of yet, we are getting glimpses of its efficacy, particularly when intensive ifosfamide-doxorubicin regimens have been delivered to patients with high-grade and high-risk tumors.5 Large international cooperative trials are needed to define the best treatment for each risk group of NRSTS patients.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
Supported in part by the Associazione Bianca Garavaglia.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Spunt SL, Ashley Hill D, Motosue AM, et al: Clinical features and outcome of initially unresected nonmetastatic pediatric nonrhabdomyosarcoma soft tissue sarcoma. J Clin Oncol 20:3225-3235, 2002
Spunt SL, Poquette CA, Hurt YS, et al: Prognostic factors for children and adolescents with surgically resected nonrhabdomyosarcoma soft tissue sarcoma: An analysis of 121 patients treated at St Jude Children's Research Hospital. J Clin Oncol 17:3697-3705, 1999
Demetri GD: Highlights of sarcoma research. J Clin Oncol Classic Papers and Current Comments 7:681-684, 2002
Sarcoma Meta-Analysis Collaboration: Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: Meta-analysis of individual data. Lancet 350:1647-1654, 1997
Sarcoma Meta-Analysis Collaboration (SMAC): Adjuvant chemotherapy for localised soft-tissue sarcoma in adults. Cochrane Database Syst Rev 4:CD001419, 2000
Coindre JM, Terrie P, Bui NB, et al: Prognostic factors in adult patients with locally controlled soft tissue sarcoma: A study of 546 patients from the French Federation of Cancer Centers Sarcoma Group. J Clin Oncol 14:869-877, 1996
Yang JC, Chang AE, Baker AR, et al: Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity. J Clin Oncol 16:197-203, 1998
Edmonson JH, Ryan LM, Blum RH, et al: Randomized comparison of doxorubicin alone versus ifosfamide plus doxorubicin or mitomycin, doxorubicin, and cisplatin against advanced soft tissue sarcomas. J Clin Oncol 11:1269-1275, 1993
Bramwell V, Rouesse J, Steward W, et al: Adjuvant CYVADIC chemotherapy for adult soft tissue sarcoma: Reduced local recurrence but no improvement in survival—A study of the European Organization for Research and Treatment of Cancer Soft Tissue Sarcoma and Bone Sarcoma Group. J Clin Oncol 12:1137-1149, 1994
Antman K, Crowley J, Balcerzak SP, et al: An intergroup phase III randomized study of doxorubicin and dacarbazine with or without ifosfamide and mesna in advanced soft tissue and bone sarcomas. J Clin Oncol 11:1276-1285, 1993
Pratt CB, Pappo AS, Gieser P, et al: Role of adjuvant chemotherapy in the treatment of surgically resected pediatric nonrhabdomyosarcomatous soft tissue sarcomas: A Pediatric Oncology Group Study. J Clin Oncol 17:1219-1226, 1999
Patel SR, Vadhan-Raj S, Papadopolous N, et al: High-dose ifosfamide in bone and soft tissue sarcomas: Results of phase II and pilot studies—Dose-response and schedule dependence. J Clin Oncol 15:2378-2384, 1997
Rosen G, Forscher C, Lowenbraun S, et al: Synovial sarcoma: Uniform response of metastases to high dose ifosfamide. Cancer 73:2506-2511, 1994
Walter AW, Shearer PD, Pappo AS, et al: A pilot study of vincristine, ifosfamide, and doxorubicin in the treatment of pediatric non-rhabdomyosarcoma soft tissue sarcomas. Med Pediatr Oncol 30:210-216, 1998
Pratt CB, Maurer HM, Gieser P, et al: Treatment of unresectable or metastatic pediatric soft tissue sarcomas with surgery, irradiation, and chemotherapy: A Pediatric Oncology Group Study. Med Pediatr Oncol 30:201-209, 1998
Hayes-Jordan AA, Spunt SL, Poquette CA, et al: Nonrhabdomyosarcoma soft tissue sarcomas in children: Is age at diagnosis an important variable J Pediatr Surg 35:948-954, 2000
Kattan MW, Leung DHY, Brennan MF: Postoperative nomogram for 12-year sarcoma-specific death. J Clin Oncol 20:791-796, 2002
Pisters PW, Leung DH, Woodruff J, et al: Analysis of prognostic factors in 1,041 patients with localized soft tissue sarcomas of the extremities. J Clin Oncol 14:1679-1689, 1996
Koea JB, Leung D, Lewis JJ, et al: Histopathologic type: An independent prognostic factor in primary soft tissue sarcoma of the extremity Ann Surg Oncol 10:432-440, 2003
Weitz J, Antonescu CR, Brennan MF: Localized extremity soft tissue sarcoma: Improved knowledge with unchanged survival over time. J Clin Oncol 21:2719-2725, 2003
DeMatteo R: The GIST of targeted cancer therapy: A tumor (gastrointestinal stromal tumor), a mutated gene (c-kit), and a molecular inhibitor (ST1571). Ann Surg Oncol 9:831-839, 2002(Andrea Ferrari, Michela C)
ABSTRACT
PURPOSE: Nonrhabdomyosarcoma soft tissue sarcomas are a heterogeneous group of tumors for which optimal treatment remains controversial. We report on a large group of 182 patients younger than 18 years old treated at a single institution over a 25-year period.
PATIENTS AND METHODS: In this relatively homogeneous subgroup of adult-type histotypes, surgery was the mainstay of treatment; radiotherapy was administered to 73 patients, and chemotherapy was administered to 114 patients (70 received chemotherapy as adjuvant therapy).
RESULTS: Overall survival at 5 years was 89% in patients who underwent complete resection at diagnosis, 79% in patients who had marginal resection, 52% in initially unresected patients, and 17% in patients with metastases at onset. Outcome was unsatisfactory in patients with large and high-grade tumors, even after gross resection; adjuvant chemotherapy seemed to improve the results in this group. Initially unresected patients who responded well to chemotherapy and subsequently underwent complete resection had an event-free survival rate of approximately 70%. The rate of response to chemotherapy was 58%.
CONCLUSION: The identification of prognostic variables should enable risk-adapted therapies to be planned. Patients with initially unresectable disease and patients with resected large and high-grade tumors are at high risk of metastases and treatment failure. Although the limits of this retrospective analysis are self-evident, our data would suggest that intensive chemotherapy (with an ifosfamide-doxorubicin regimen) might have a more significant role in these patients than what is generally assumed.
INTRODUCTION
Soft tissue sarcomas are rare, with an annual incidence of approximately two to three per 100,000 persons, and they account for less than 1% of all malignant tumors and 2% of all cancer-related deaths.1 In pediatric age, however, approximately 8% of malignancies are soft tissue sarcomas, with rhabdomyosarcoma (RMS) representing approximately 55% to 60% of the soft tissue sarcomas.2 The so-called nonrhabdomyosarcoma soft tissue sarcomas (NRSTS) account for approximately 3% of pediatric cancers and constitute a very heterogeneous group of tumors with a variety of histotypes with different origin, biology, and natural history, some of which are more common in adults and many of which are rare in children. Most of the experience gained in the treatment of pediatric NRSTS either derives from managing soft tissue sarcomas in adults or relies on the principles derived from the management of RMS.
NRSTS usually arise in the extremities (although they can develop anywhere in the body), and they are characterized by local aggressiveness and a propensity to metastasize that is correlated to their grade of malignancy. NRSTS management is complex and necessarily multidisciplinary.3,4 Although surgery is known to be the mainstay of treatment, our knowledge of the role of adjuvant treatments is clearly incomplete and needs to be improved. In particular, there is no general agreement concerning the use of chemotherapy.3 NRSTS are generally considered scarcely chemosensitive, but data emerging recently from some adult studies seem to suggest that patients with high-risk extremity sarcomas can benefit from intensified adjuvant chemotherapy.5
Given the heterogeneity of these tumors, clinical studies should target diagnostic subgroups as specifically as possible, but the rarity of each histotype prevents the performance of clinical trials on a single tumor type, and consequently, NRSTS have to be analyzed as a group. To create a more homogeneous group, we focused on NRSTS that are typical of adulthood (excluding infantile fibrosarcoma) and definitely malignant (excluding borderline tumors, ie, hemangioendothelioma) and that have morphologic features resembling differentiated/mature tissues (excluding small round-cell tumors, ie, RMS, extraosseus peripheral primitive neuroectodermal tumor and Ewing's sarcoma, and desmoplastic small round-cell tumor). We defined these tumors as adult-type soft tissue sarcomas. This report is a retrospective analysis of 182 consecutive patients seen at our institution in a 25-year period.
PATIENTS AND METHODS
In all, 634 consecutive cases of previously untreated patients younger than 18 years who were diagnosed with soft tissue sarcoma between 1977 and 2003 were collected from the Pediatric Oncology Unit's database at the Istituto Nazionale Tumori (Milan, Italy). Three hundred forty-one of the patients (54%) were classified as having RMS, and 293 were classified as having NRSTS.
We used the term adult type to describe definitely malignant soft tissue sarcomas occurring mainly in adult age and characterized by a closer morphologic resemblance of differentiated/mature tissues (usually with a spindle-cell and pleomorphic morphology) and an uncertain response to chemotherapy. Sarcomas belonging to the group of small round-cell tumors, including RMS, desmoplastic small round-cell tumor (n = 6), and extraosseus peripheral primitive neuroectodermal tumor and Ewing's sarcoma (n = 48) were excluded, as were cases of infantile fibrosarcoma and hemangiopericytoma (n = 8) and tumors with uncertain malignancy (ie, hemangioendothelioma, n = 28; and myofibroblastic lesions as fibromatosis and desmoid tumors, n = 21).
As a result, 182 patients were included in this study and analyzed for survival. Complete details on clinical features, treatment, and outcome were available for all patients. The histologic diagnosis was made by pathologists at our institution before starting any treatment. Most of the histologic features were reviewed for the purposes of this study; in detail, 141 patients (77%) were reviewed, whereas for 41 patients, the tumor specimens or slides were not available (most of these patients were in the older of the series and treated in the 1970s period). The tumor grade was assigned in 125 patients. Grading evaluation was not performed for 16 of the 141 reviewed patients because the biopsy slides were unavailable, whereas the specimens of the delayed surgery were reviewed but were not proper for grading evaluation because of the primary chemotherapy. Tumor grade was assigned according to the French Federation of Cancer Centers Sarcoma Group's grading system.6 This is a three-grade classification system that defines a score in relation to tumor differentiation, mitotic index, and tumoral necrosis; it was chosen for its high reproducibility and the opportunity for a valid comparison with adult series.6
Clinical Grouping
Before starting treatment, data were available for most patients on the physical examination, the local extent of disease as assessed by computed tomography and/or magnetic resonance imaging, chest x-ray and/or chest computed tomography scan, abdominal ultrasound, and whole-body bone scan. Disease was staged according to the clinical tumor-node-metastases classification7 and the Intergroup Rhabdomyosarcoma Study (IRS) postsurgical grouping system.8 According to the former, T1 are tumors confined to the organ or tissue of origin, whereas T2 lesions invade contiguous structures; T1 and T2 groups are further classified as a or b depending on whether tumor diameter is 5 cm or more than 5 cm, respectively. Regional node involvement is indicated as N0 or N1 and distant metastases at onset is indicated as M0 or M1 based on histologic or clinical and radiologic assessments.7 The IRS system categorizes patients in four groups based on the amount and extent of residual tumor after initial surgery. Group I includes completely excised tumors with negative microscopic margins; group II indicates grossly resected tumors with microscopic residual disease and/or regional lymph nodal spread; group III patients have macroscopic residual disease after incomplete resection or biopsy; and group IV patients have metastases at onset.8
Treatment
Patients were treated using a multimodality therapeutic approach, including surgery, chemotherapy, and radiotherapy, based on the ongoing protocols at the time of diagnosis. Treatment strategies did not change substantially over the years; primary excision was generally attempted if complete and nonmutilating resection was considered feasible; if not, a biopsy was taken, and chemotherapy (and/or radiotherapy) was administered to shrink the tumor and make it more amenable to subsequent surgery.
Surgery was defined as complete (IRS group I) when histologic margins were free, thus including ablative surgeries, compartment resections (en bloc resection of the tumor and the entire compartment of origin, where tumor was entirely anatomically confined), and wide excisions (en bloc excisions through normal tissue, beyond the reactive zone but within the muscular compartment, removing the tumor with its pseudocapsule). We chose to consider as marginal (IRS group II) any resections coming just outside the pseudocapsule, with suspected microscopic residual disease (marginal resection according to Enneking's criteria) and cases with microscopically infiltrated margins (considered by Enneking as intralesional).9 We defined as primary re-excision any resurgery performed up to 2 months after an initially inadequate resection and before any other treatment. Delayed surgery is defined as surgery performed after primary chemotherapy or radiotherapy.
Radiotherapy was administered to patients considered at risk of local failure. External-beam irradiation was delivered using megavoltage photon or electron beam energies, with conventional fractionation (1.8 to 2.0 Gy daily for 5 days a week). The radiation fields included the initial tumor volume plus 2- to 3-cm margins.
In most cases, systemic chemotherapy was part of the treatment program. Different chemotherapeutic regimens were used over the years, according to ongoing protocols. All patients received a multidrug regimen, including cyclophosphamide or ifosfamide, plus anthracyclines (doxorubicin or epirubicin); dactinomycin and vincristine were added in several cases. In patients with measurable disease, response to chemotherapy was recorded according to the radiologically assessed reduction in the sum of the products of the perpendicular diameters of all measurable lesions and defined as follows: complete response (CR), complete disappearance of disease; partial response (PR), maximal tumor reduction more than 50%; and minor response (MR), maximal tumor reduction more than 25%. Stable disease or a maximal tumor reduction less than 25% was classified as no response, whereas an increase in tumor size or the detection of new lesions was called progression of disease. Because even an MR could be significant in these tumors (which are generally regarded as poor responders to chemotherapy), chemotherapy response rate was evaluated also considering CR, PR, and MR.
Statistical Methods
Event-free survival (EFS) and overall survival (OS) were estimated according to the Kaplan-Meier method.10 Patients were evaluated from histologic diagnosis to latest uneventful follow-up, disease progression, relapse, or death from any cause for EFS and to death for OS. The local relapse-free survival (LRFS) was calculated from diagnosis to local progression or relapse. Patients who died of their tumor after distant failure and before local progression or relapse were excluded at the time of death in the analysis of LRFS. Metastases-free survival (MFS) was calculated from diagnosis to the onset of distant metastases.
The log-rank test was used to compare the survival curves of patient subgroups in a univariate analysis to ascertain the potential value of various prognostic factors.11 2 tests were used to compare the frequency of certain clinical characteristics in the different patient subgroups. Multivariate analysis of EFS in patients with grossly resected tumors was carried out by means of the Cox regression model.12 The number of events for the other end points (and in patients with initially unresected tumors) was too small to allow such an analysis. To describe the results obtained with the Cox model, we report hazard ratio estimates and corresponding 95% CIs, together with the likelihood ratio P values, for testing the overall association between each covariate and EFS. Patient follow-up, as of January 2004, ranged from 6 to 256 months (median, 110 months).
RESULTS
Table 1 lists the patients' clinical features. The most frequent histotype was synovial sarcoma (32% of patients). Histologic grades were available for 125 patients; 24 were classified as grade 1, 33 were classified as grade 2, and 68 were classified as grade 3.
Thirteen patients had hereditary syndromes; 11 had neurofibromatosis type 1 (malignant peripheral nerve sheath tumor [MPNST], n = 10; and malignant hemangiopericytoma, n = 1), one had Li Fraumeni syndrome (leiomyosarcoma), and one had xeroderma pigmentosum (angiosarcoma). In one patient, soft part sarcoma (synovial sarcoma) developed as a second tumor 6 years after a lymphoblastic leukemia.
Six patients (3%) had lymph node involvement at diagnosis. The histotypes included two clear-cell sarcomas and one case each of MPNST, angiosarcoma, epithelioid sarcoma, and alveolar soft part sarcoma; they were all grade 3 tumors, and four of the six patients had T2b tumors.
Six patients had distant metastases at onset. The metastatic sites were the lung in five patients and the bones in one patient. All patients had T2b and grade 3 tumors, and the histotypes were alveolar soft part sarcoma in three patients and synovial sarcoma, MPNST, and sarcoma not otherwise specified in one patient each.
One hundred patients underwent complete resection at diagnosis (70 of them throughout primary re-excision), 36 had marginal resection, and 13 had incomplete resection with macroscopic residual tumor. Biopsy was the initial surgery in 33 patients. In 22 patients, delayed surgery was performed after chemotherapy, with complete tumor excision in 19 of these patients. Surgery was mutilating in nine patients (eight at diagnosis and one at delayed surgery).
Seventy-three patients had radiotherapy (72 patients postoperatively and only one patient as a presurgical procedure). The total dose of radiotherapy ranged from 45 to 70 Gy (median, 58 Gy).
Systemic chemotherapy was used in 114 patients. It was administered as primary treatment to all but two of the IRS group III to IV patients. Adjuvant chemotherapy was administered to 70 (51%) of 136 of the IRS group I to II patients; chemotherapy was usually required for patients with high-grade or large tumors, although during the 25-year study period, the decision of whether to administer chemotherapy was sometimes individualized. All the patients who received adjuvant chemotherapy had large or high-grade tumors; but among the 95 group I to II patients with a tumor size more than 5 cm or grade 3 histology, 70 received chemotherapy, and 25 did not receive chemotherapy. Eighty-one patients received a regimen of vincristine, doxorubicin, cyclophosphamide, and dactinomycin; 22 patients received vincristine, doxorubicin, ifosfamide, and dactinomycin; and 10 patients received ifosfamide plus doxorubicin or epirubicin (plus cisplatin in four patients). One metastatic patient received vincristine, doxorubicin, ifosfamide, and dactinomycin plus high-dose chemotherapy with stem-cell rescue.
Overall, 112 patients were in first complete remission, and 17 were in second, third, or fourth remission at the time of the analysis. Four patients were alive with disease, 48 died of their tumor (3 to 138 months from diagnosis), and one died of a second malignancy (postirradiation osteogenic sarcoma, which developed 10 years after MPNST).
Overall, survival rates were as follows. EFS rate was 64.0% (SE, 3.7%) and 59.0% (SE, 3.9%) at 5 and 10 years, respectively; LRFS rate was 75.4% (SE, 3.3%) and 72.0% (SE, 3.6%) at 5 and 10 years, respectively; MFS rate was 72.5% (SE, 3.5%) and 68.1% (SE, 3.8%) at 5 and 10 years, respectively; and OS rate was 76.1% (SE, 3.3%) and 71.8% (SE, 3.7%) at 5 and 10 years, respectively.
Over the years, 5-year EFS and OS rates increased from 56% and 67% in the 1970s and 1980s to 77% and 87% after 1990, respectively (Table 2). As shown in Tables 3 and 4, this improvement was more significant in the subset of patients with surgically resected tumor than in patients who were considered unresectable at diagnosis.
Table 2 lists the survival rates according to the variables considered in the univariate analysis. In the whole series of patients, tumor invasiveness and size were the most important prognostic factors; patients with T2b tumor had 5-year EFS and OS rates of 28.8% and 48.2%, respectively. Female sex, older age, high-grade tumor, MPNST histology, and tumor sites other than extremities correlated with a worse outcome.
Tumor size was correlated strongly with local invasiveness and high-grade histology. T2 and grade 3 tumors occurred in 17 (20%) of 86 and 15 (33%) of 45 patients with tumors 5 cm, respectively, and in 75 (78%) of 96 and 52 (65%) of 80 patients with tumors greater than 5 cm (P < .01).
Patients With Grossly Resected Disease
Macroscopic resection at diagnosis was performed in 136 patients (IRS group I, n = 100; and IRS group II, n = 36). Survival rates at 5 years were as follow: EFS, 71.7% (SE, 4.0%); LRFS, 82.5% (SE, 3.4%); MFS, 78.6% (SE, 3.7%); and OS, 86.1% (SE, 3.2%).
Local invasiveness and tumor size were still the most significant prognostic factors (Table 3). T2b patients had an unsatisfactory outcome (5-year EFS, 30.2%; 5-year OS, 60.3%). Figure 1 shows that survival rates differed significantly according to the state of the surgical margins (5-year OS, 88.7% in group I v 78.7% in group II). It is worth noting that local invasiveness particularly affected the quality of surgery. T2 tumors were present in 26 (26%) of 100 and 25 (69%) of 36 patients in group I and II, respectively (P < .01); tumors more than 5 cm were present in 36 (36%) of 100 and 20 (55%) of 36 patients in group I and II, respectively (P = not significant [NS]); and grade 3 tumors were present in 25 (42%) of 60 and 14 (54%) of 26 patients in group I and II, respectively (P = NS).
Local invasiveness and tumor size strongly influenced the local control. Five-year LRFS rate was 91.1% in patients with T1 tumors and 67.1% in patients with T2 tumors (P = .0004); LRFS rate was 89.5% in patients with tumors 5 cm and 71.3% in patients with tumors greater than 5 cm (P = .0012); and LRFS rate was 86.9% in IRS group I patients and 70.1% in IRS group II patients (P = .0584). Tumor grade did not correlate with local failure; 5-year LRFS rate was 88.1% in patients with grade 1 tumors, 91.6% in patients with grade 2 tumors, and 80.1% in patients with grade 3 tumors (P = .5455).
In the subset of completely resected patients (IRS group I, n = 100), postoperative radiotherapy was administered to 22 patients. In this group, 5-year LRFS rate was 95.2% in patients treated with radiotherapy and 84.4% in patients who did not receive postoperative irradiation (P = NS).
Concerning only patients considered at high risk of local failure because of large tumor size (> 5 cm), radiotherapy seemed to have an impact on local control and outcome. The 5-year LRFS and OS rates were 91.7% and 90.0%, respectively, for patients treated with postoperative radiotherapy (n = 13) and 69.8% and 53.8%, respectively, for patients who were treated without radiotherapy (n = 23; P = .4747 for LRFS and P = .0248 for OS). In these two groups, there was a balance in the tumor grade distribution (ie, grade 3 tumors were present in 38% of the subset of patients treated with radiotherapy and in 43% of the patients not treated with radiotherapy); however, the percentage of patients who also received chemotherapy was higher in patients who received radiation compared with patients who did not (77% v 56%, respectively), and this could have influenced the better LRFS and OS rates.
In patients who underwent marginal resection (IRS group II, n = 36), radiotherapy was administered to 27 patients (75%). LRFS rate at 5 years was 75.7% in patients administered radiotherapy and 55.6% in patients who did not received radiotherapy (P = .1403). Three patients with grade 1 tumors received marginal resection; two were treated with postoperative radiotherapy, and one was treated with surgery alone. The patient who did not receive irradiation had local relapse.
Adjuvant chemotherapy was administered to 70 (51%) of 136 patients. Seventy-two percent of these patients (36 of 50 patients) had synovial sarcoma, and 39% (34 of 86 patients) had other histotypes; the majority of these patients had grade 3 tumors (71%) and tumors greater than 5 cm (60%).
The possible benefit of adjuvant chemotherapy was evaluated in patients considerable at high risk of metastases because of high-grade (grade 3) and large tumor size (> 5 cm). This group included 27 patients (considering all histotypes first), and the 5-year EFS rate was 45.6%. If synovial sarcoma patients (generally considered more chemosensitive)13 were excluded from the analysis, the group included 15 patients, and the 5-year EFS and MFS rates were 27.7% and 35.8%, respectively. In this subset of patients (grade 3, size > 5 cm, and synovial sarcomas excluded), 5-year MFS rate was 53% in the patients who received adjuvant chemotherapy (n = 11) and 0% in patients who did not receive adjuvant chemotherapy (n = 4; all patients treated without chemotherapy experienced distant metastases; P = .2041).
Patients With Initially Unresected Disease
Forty patients were classified as IRS group III after biopsy (n = 27) or macroscopically incomplete resection (n = 13). The clinical findings of IRS group III patients were substantially different from those of group I to II patients; the percentages of patients were higher for MPNST (30% v 12%, respectively; P < .05) and high-grade tumor (70% v 45%, respectively; P < .05), as well as for tumor at sites other than the limbs (65% v 29%, respectively; P < .01), locally invasive tumor (90% v 38%, respectively; P < .01), and tumor larger than 5 cm (85% v 41%, respectively; P < .01).
For patients with initially unresected disease, 5-year EFS, LRFS, MFS, and OS rates were 45.2%, 55.6%, 59.0%, and 51.8%, respectively. Table 4 lists the survival rates according to different variables. The small number of patients in some subsets (ie, T1 tumor or size 5 cm) limited the statistical value of univariate analysis, but female sex, older age, and MPNST histotype were statistically significant adverse factors.
Neoadjuvant chemotherapy was administered to 38 patients. Two patients did not receive chemotherapy. The first patient had a huge MPNST of the gluteus; he received radiotherapy, but he had local and systemic spread 2 months after diagnosis and died of his tumor 1 month later. The second patient had a 2-cm, grade 1 fibrosarcoma of the gum; he was treated with radiotherapy and then complete tumor resection, and he was alive without evidence of disease at the time of the report (15 years after diagnosis).
Response to chemotherapy was as follows: one CR, 14 PRs, and seven MRs (16 patients had no response), for an overall response rate of 39% in terms of CR + PR and 58% when MR was included too. The response rate was 58% for CR + PR and 82% for CR + PR + MR in patients treated with regimens including ifosfamide and anthracyclines; and the response rate was 34% for CR + PR and 48% for CR + PR + MR in patients treated with vincristine, doxorubicin, cyclophosphamide, and dactinomycin. When patients with synovial sarcoma were excluded from the analysis, the rate of response to chemotherapy was still 55%.
Outcome was directly influenced by response to primary chemotherapy. Five-year OS rate was 71.4% in patients who responded well (CR + PR), 50.0% in patients with MR, and 36.5% in patients with no response.
After chemotherapy, 19 patients underwent complete delayed surgery (gross total resection with negative microscopic margins), which had been considered unfeasible at diagnosis. The definitive local treatment was complete delayed surgery alone in 11 patients, complete delayed surgery plus radiotherapy in eight patients (seven patients postoperatively and one patient preoperatively), radiotherapy alone in 14 patients, and incomplete surgery in seven patients. The outcome correlated with the achievement of complete tumor resection; 5-year OS rate was 80.0% in patients who had complete delayed surgery, 85.7% in patients who had complete delayed surgery plus radiotherapy, 35.7% in patients treated with radiotherapy without adequate resection, and 14.3% in incompletely resected patients who did not receive radiotherapy.
Twenty-three patients experienced tumor progression or relapse. Treatment failure was local in 13 patients, local and with distant metastases in four patients, nodal in one patient, and metastatic in four patients. Among the 13 patients who relapsed locally, six successively developed distant spread. If local progression or relapse was the major cause of treatment failure, metastatic disease represented the predominant cause of death; 13 patients died from metastatic disease, and seven died from local tumor progression.
DISCUSSION
This study retrospectively analyzes the clinical features, treatment, and outcome of a large single-institution series of pediatric patients with NRSTS, focusing on a relatively homogeneous group of adult-type histotypes. Our series is comparable with other reported studies,14,15 particularly the two recently published series from the St Jude Children's Research Hospital,16,17 which describe the prognostic variables that can predict survival and that should be used to stratify patients for a risk-adapted therapy.
The relatively small number of patients in some treatment subsets and the retrospective nature of our analysis prevent any certain conclusions from being drawn on the role of adjuvant therapies, which remains controversial. Nevertheless, our data (like other recent reports) would suggest that chemotherapy might have a more significant role in high-risk patients (ie, large tumor and high grade) than is generally believed.3,5,18-20
In the last two decades, treatment strategies for these tumors have changed to some degree, and multimodalities have been used increasingly.18 Although the effectiveness of radiotherapy is now appreciated,21,22 systemic chemotherapy still represents an open question for oncologists3,18; adult soft tissue sarcomas continue to be considered scarcely chemosensitive.
To date, only a minority of the several randomized adjuvant chemotherapy trials on adults soft tissue sarcomas has shown a significant survival advantage for chemotherapy,5,19,20,23-25 whereas the only trial performed in patients of pediatric age failed in its aim because the majority of patients refused randomization.26 Fourteen randomized trials comprising 1,568 adult patients were nonetheless included in a meta-analysis that demonstrated a lower risk of local and distant failures in patients treated with intensified doxorubicin-based chemotherapy.19,20 Moreover, an Italian randomized trial on high-risk patients (high grade and large, deep tumor) was concluded in advance because of an early striking improvement in EFS and OS among patients who received intensive ifosfamide-doxorubicin chemotherapy versus patients treated with local therapy alone.5 This trial has been defined as the first modern study on adjuvant chemotherapy in soft tissue sarcoma.18 The ifosfamide-doxorubicin regimen currently needs to be considered the regimen with the higher response rate, and several reports suggest that dose intensification (with hematopoietic growth factor support) has been associated with an improved response rate and disease-free survival.23-25, 27-30
Some of the negative results recorded in previous chemotherapy randomized studies probably need to be considered with caution. Future clinical trials should target high-risk patients properly, with accurate patient selection, and should deliver intensive chemotherapy including the most active drugs. In other words, adjuvant ifosfamide-doxorubicin chemotherapy cannot yet be considered as the standard of care in high-risk resected soft tissue sarcomas; however, recent suggestions would seem to support the beneficial impact of this approach.
Our subset of adult-type sarcomas arising in a pediatric population is comparable to the various reported series on soft tissue sarcoma in adult age. Some pediatric patients' clinical features are similar to those observed in adults (ie, the most frequent localization at extremities). Our findings confirm the known epidemiologic data that describe synovial sarcoma and MPNST as the most frequent histotypes in adolescents and young adults (in contrast, liposarcoma and malignant fibrous histiocytoma are the most frequent histotypes in adult series, with picks of incidence in the fifth and sixth decades).1 The prognostic factors of adult sarcomas (ie, large tumor size, local invasiveness, high-grade tumors, older age, and sites other than the extremities) confirm their value in our series, but the proportion of pediatric patients with unfavorable features seems quite lower than in adults (ie, tumors larger than 5 cm and high-grade tumors are present in approximately one half of the patients in our series, whereas they usually are present in two thirds of patients in adult series).13-16,21,26,31-35
As for adult series, this study emphasizes that outcome in patients with grossly resected NRSTS was good enough for low-grade, small, and noninvasive tumors, but not high-grade, large, and invasive tumors, to be treated with surgery alone. In our small subset of patients with group I to II, grade 3, and more than 5 cm tumors (synovial sarcoma excluded), the 5-year MFS rate was 35.8%; it was 53.0% for patients treated with chemotherapy, whereas it decreased to 0% for the few patients who were not administered chemotherapy (the P value was not significant, given also the small number of patients in this comparison). The high rate of metastatic spread would suggest the use of systemic chemotherapy in such patients, given also that the high mitotic rate of grade 3 tumors might, in principle, be indicative of some chance of response to chemotherapy.
An intensified treatment in high-risk resected patients would also include radiotherapy. Our data seem to confirm that the local recurrence rate was lower in group II patients (5-year LRFS, 75.7% in patients not treated with radiotherapy v 55.6% in patients treated with radiotherapy) and group I patients with large tumors (5-year LRFS, 91.7% in patients not treated with radiotherapy v 69.8% in patients treated with radiotherapy) when radiotherapy was delivered, although the small number of patients hindered significant P values and certain conclusions. However, these suggestions would be comparable to the hints available from larger adult series that prompt a possible role of radiotherapy after marginal resection and after wide excision of large tumors.21,22
The beneficial effect of radiotherapy on LRFS (in completely resected tumors > 5 cm) seemed to influence OS too, although there was an imbalance in the proportion of patients who received chemotherapy in the subsets of patients who received and who did not receive irradiation, and this nonrandom use of chemotherapy could have influenced the survival rates. It is known, in fact, that data from larger series have questioned the real impact of local control on survival.22 Regardless, the morbidity of radiotherapy is a more important matter in dealing with children than with adults.
As for the patients with initially unresected tumors, the 5-year OS rate remained approximately 50%. Few improvements have been seen in the results obtained over the years in this group. As reported elsewhere,34 MPNST was the most frequent histotype and was associated with a poor outcome. Age under 10 years was confirmed as a favorable prognostic factor,31 despite our excluding infantile fibrosarcomas from this study, whereas the unfavorable effect of female sex remains unexplained. Our analysis showed that a better chance of cure coincided with the chance to ensure adequate surgery after shrinking the tumor with chemotherapy17,29,30; patients who responded well to neoadjuvant chemotherapy and underwent delayed complete resection had a 5-year EFS rate of approximately 70%. This would suggest the need to increase the intensity of primary chemotherapy. Although several patients in our series were administered chemotherapy regimens definable as mild by comparison with protocols used today for adult sarcomas or pediatric small round-cell sarcomas, the overall response rate was 58% in terms of CR + PR + MR and increased to 82% when only regimens including ifosfamide and anthracyclines were considered. These results are questionable, given the small group of patients and the decision to include MR in calculating the response rate; nonetheless, together with the suggestion of a possible benefit of adjuvant chemotherapy in high-risk resected patients, these findings would point to a more important role for chemotherapy than what has been hitherto reported.
In conclusion, unlike RMS (for which numerous cooperative trials over the years have yielded great improvements in our knowledge and the results of treatment), the management of pediatric adult-type soft tissue sarcomas still poses several unsolved questions, although pediatricians can draw important information from the experience of adult oncologists. The identification of prognostic variables strongly influencing outcome would enable us to plan risk-adapted therapies. Considering the unsatisfactory outcome in patients with advanced unresectable disease and in patients with high-grade and/or large tumors even after complete surgery, more intensive therapies and new strategies are needed. The success of the antityrosine kinase imatinib mesylate in the treatment of c-kit–positive gastrointestinal mesenchymal tumors provides important insight for the development of new molecular therapies specifically designed for targets critical to a tumor's biology.36 While awaiting new therapies directed against the product of some of the several chromosomal translocations occurring in sarcomas, a better use of the standard therapies has to be sought. Although chemotherapy cannot be considered a standard treatment for these malignancies as of yet, we are getting glimpses of its efficacy, particularly when intensive ifosfamide-doxorubicin regimens have been delivered to patients with high-grade and high-risk tumors.5 Large international cooperative trials are needed to define the best treatment for each risk group of NRSTS patients.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
Supported in part by the Associazione Bianca Garavaglia.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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