Elsevier

Cancer Treatment Reviews

Volume 32, Issue 6, October 2006, Pages 423-436
Cancer Treatment Reviews

TUMOUR REVIEW
Primary bone osteosarcoma in the pediatric age: State of the art

https://doi.org/10.1016/j.ctrv.2006.05.005Get rights and content

Summary

The current combination treatment, chemotherapy and surgery, has significantly improved the cure rate and the survival rate of primary bone osteosarcoma. The 5-year survival rate has increased in the last 30 years from 10% to 70%. Even in patients with poor prognosis, such as those with metastases at diagnosis, the 5-year survival rate has reached 20–30% due to chemotherapy and the surgical removal of metastases and primary tumor. However, the most effective drugs are still the same as those employed over the last 20 years as front line neoadjuvant or adjuvant chemotherapy: Doxorubicin, Cisplatin, Methotrexate, Ifosfamide. No standard, second line therapy exists for those who relapse. At relapse, due to the lack of new non-cross-resistant drugs, surgery is still the main option when feasible. Other drugs have been employed in relapsed patients with poor results. This article reviews the state of the art of treatment for bone osteosarcoma in the pediatric age.

Introduction

Osteosarcoma (OS) is the most common primary bone tumor in childhood and adolescence. It usually involves long bones and is a highly aggressive tumor that metastasizes primarily to the lung.1 Until 30 years ago, when surgery was the only therapy, most patients died within 1 year from diagnosis, and the overall 5-year survival rate was 10%. With the present protocols of neoadjuvant chemotherapy (4–6 cycles with the four most effective drugs before surgery and 9–13 cycles postoperatively) the 10-year disease free survival (DFS) is about 60% in patients with localized disease, and around 30% in patients with metastatic disease at diagnosis.2, 3, 4 The incidence of OS is about 3 new cases per million people per year. The median peak age is 16 years, and males are affected more than females with a ratio of 1.6:1; females have a peak incidence a little earlier than males due to the earlier onset of their growth spurt.5, 6

Section snippets

Etiology

Exposure to radiation is the only proven exogenous risk factor but with a long interval, 10–20 years,7 so radiation-induced osteosarcoma is typical of adult age and is very rare.

There is an association with a number of rare inherited syndromes8, 9, 10, 11, 12 like hereditary bilateral retinoblastoma, Li–Fraumeni syndrome, Bloom syndrome, Rothmund–Thomson syndrome or in association with multiple exostoses, and Paget’s disease. But the majority of osteosarcomas occur without a familial

Clinical presentation and diagnosis

Pain is usually but not always the first symptom.1 It usually arises after strenuous exercise or a trauma, usually appearing 2–4 months before diagnosis,3 and progressing over time. Swelling appears later with a hard consistency mass. Pathologic fracture can occur. The laboratory findings may show an increase in alkaline phosphatase (AP) and in 30% of cases an increase in lactic de-hydrogenase.31 In the absence of metastases abnormal AP values are correlated with tumor volume and prognosis;32

Treatment of localized osteosarcoma

Surgery is still the cornerstone of OS treatment, but alone it cannot cure patients. Until the 1970s, OS was treated by surgery (mostly amputation) or radiotherapy alone. Despite good local control, most patients died within a short time as a result of metastases, the first location of which was nearly always pulmonary. With surgery alone, the 5-year DFS was 12%, and 3 out of 4 patients died within 2 years of diagnosis. For this reason, in 1970 adjuvant chemotherapy was conceived. Doxorubicin

Chemotherapy toxicity

Nearly a half of young adult survivors of childhood cancer have at least one major adverse outcome of their health status as a result of their cancer therapy.71

Early toxicity consists of hematological toxicity (manageable with growth factors), acute liver (MTX) and renal toxicity (CDP and IFO). Longer survival has led to the increase in late chemotherapy toxicity. The main late toxicities are: cardiac, second tumor, sterility, chronic renal failure and neurologic toxicities (mainly ototoxicity

Treatment of primary metastatic osteosarcoma and multifocal osteosarcoma

About 20% of osteosarcomas are metastatic at presentation. For patients with a good performance status a multiple aggressive treatment with chemotherapy and surgery of the primary tumor and all metastases is the standard therapy. However, despite aggressive treatment, mean 5-year EFS is 30% ranging from 16% (European Osteosarcoma Intergroup; 45 patient)84 to 53% (Pediatric Oncology Group; 30 pts).85.

In a COSS study86 on 202 patients with metastases at diagnosis only 60 were alive after a median

Treatment of metastatic relapsed osteosarcoma

Despite chemotherapy and surgical resection, 30–40% of patients with localized osteosarcoma of the extremities relapse, mostly within the first 3 years of diagnosis. Recurrence of osteosarcoma is most common in the lungs. The achievement of a complete remission of recurrent disease is the most important prognostic factor at first relapse with an overall survival after recurrence that ranges from 13% to 57%.90, 91 Series on relapsed osteosarcoma are small and often heterogeneous including

Radiotherapy

Osteosarcoma is known to be quite resistant to RT.

Anyway, in certain locations (pelvis, vertebra) where surgery is not feasible or for palliation in case of bone metastases or in multifocal osteosarcoma, radiotherapy can prolong survival and control pain. A recent study110 reported the results of radiotherapy in 41 patients who received 10–80 Gy for osteosarcoma located in the face/head (17 patients), spine (8), the pelvis (7), and in the trunk (1). The 5-year overall local control rate was 68% ± 

New experimental drugs

Some studies have been published on drugs not commonly used in first line treatments of osteosarcoma. Some of them are quite promising.

Topotecan, employed in 26 metastatic OS patients at presentation followed by multiagent chemotherapy, did not show an effective improvement over traditional chemotherapy.113

Gemcitabine was employed alone with minimal response,114 but in one study it was employed together with Docetaxel in 35 patients with different sarcomas and a RR of 43% was reported.115

Surgery

In the past 20 years, the use of amputation has progressively decreased and more patients have been treated by local resection and functional reconstruction of the limb in almost 90% of cases.124, 125 The type of surgical procedure depends not only on tumor stage, and response to adjuvant treatments, but also on the patient’s age, gender, general condition, life expectancy and quality of life. The percentage of local recurrence is strictly correlated to resection margins and to response to

Prognostic factors

Many studies have been performed to determine the most reliable prognostic factors.

Significant prognostic factors are: first of all metastatic vs localized disease with a difference in 5-year EFS of 60–70% vs. 20–30%, tumor necrosis after preoperative chemotherapy, tumor site (limbs vs. axial skeleton), surgical margins, and tumor volume.

Coss55 studied 1702 patients over 18 years and found that significant prognostic factors were: primary metastases vs. localized (10-year EFS of 26% vs. 64.4%, P

Conclusions

A lot of progress has been made in the treatment of osteosarcoma over the last 30 years, due to chemotherapy development and surgery improvement. A multi-disciplinary approach has increased the number of conservative procedures (85%) and the probability of a better prognosis up to a 70% 5-year DFS for non-metastatic patients.

We think that the best approach to osteosarcoma can be obtained in specialized centers with a very skilled multidisciplinary team and the possibility to evaluate

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