What Is the Best Treatment of Malignant Bone Tumors in Children?

Published on 11/03/2015 by admin

Filed under Orthopaedics

Last modified 11/03/2015

Print this page

This article have been viewed 851 times

Chapter 38 What Is the Best Treatment of Malignant Bone Tumors in Children?

ABHA. GUPTA, MD, MSC, FRCPC, SEVAN. HOPYAN, MD, PHD, FRCSC

SYSTEMIC THERAPY

The two most common primary tumors of bone are osteosarcoma (OS) and Ewing’s sarcoma (ES) with an incidence of 4.8 cases/million and 2.9 cases/million, respectively, in people younger than 20 years.¹ ES is part of a family of small, round, blue cell tumors whose exact cell of origin remains unknown. The mainstay of therapy includes multiagent cytotoxic chemotherapy and effective local control with surgery and/or radiation. The following section focuses on the medical therapy of localized OS. Improvement in the survival of patients with OS has been elusive since the therapeutic breakthroughs of the late 1970s to early 1980s, despite the efforts of large multinational cooperative groups.

CHEMOTHERAPY IN OSTEOSARCOMA

It is clear that with surgery alone, 80% of patients with malignant bone tumors will develop pulmonary metastases.² Therefore, the treatment of OS has evolved to include systemic chemotherapy in addition to surgical resection. OS is relatively resistant to radiotherapy, so this particular modality is not used with curative intent. With current chemotherapy regimens, event-free survival remains at approximately 70% at 5 years.

Multiple fundamental issues regarding the treatment of OS remain incompletely resolved:

1. Which drugs are most effective?

2. Should postsurgical chemotherapy be tailored to percentage necrosis at the time of resection?

3. What are the relative merits of intra-arterial versus intravenous chemotherapy?

4. Should patients be treated with chemotherapy before or after surgery?

Since the late 1980s, many centers have conducted trials to attempt to answer the above questions. However, many studies are uncontrolled case series that document the outcomes of a given treatment according to an institutional protocol.

Which Drugs Are Most Effective?

It is generally accepted that cisplatin, adriamycin, ifosfamide, and methotrexate are active against OS. Various combinations of chemotherapy have been tested in randomized, controlled trials, none of which has demonstrated robust superiority over another in improving survival. A recent large trial involving 677 patients demonstrated a 6-year event-free survival rate of 64% with the use of these agents; survival did not improve with the addition of ifosfamide.³ Although it is widely used, the role of methotrexate in OS remains uncertain⁴ and is currently under investigation^4a (Table 38-1).

TABLE 38-1 Randomized, Controlled Trials (Excluding Intra-arterial Chemotherapy)

Does Tailoring Postsurgical Chemotherapy According to the Degree of Tumor Response Improve Survival?

One advantage to neoadjuvant (pre-operative) chemotherapy is the opportunity provided for assessment of the tumor’s response to the drugs being administered. Histologic assessment of the tumor after resection is most commonly described as per the Huvos system. A major distinction is drawn between tumors in which there are fewer than 10% residual viable cells and those with more than 10%.⁹ The degree of histologic response to chemotherapy is of prognostic relevance with “responders” (patients >90% necrosis) having significantly better outcome than “nonresponders” (patients <90% necrosis). It is less clear whether changing the therapeutic regimen in patients with poor response will improve survival. Unfortunately, all studies that have attempted to address this question have been single-arm case series. None of these studies demonstrated the ability to salvage patients who had a poor response by an alteration in postoperative therapy.¹⁰^–¹³ Currently, an international study is under way to address this question in a randomized fashion.^13a

Is Intra-Arterial or Intravenous Chemotherapy Better?

Some investigators have advocated the use of intra-arterial cisplatin or adriamycin to increase the local response rate that was found to be predictive of survival. Although many centers have attempted intra-arterial chemotherapy in OS, only a few randomized studies exist. Histologic response at the time of surgery improved from 43%–46% good response to 64%–77% with intravenous cisplatin compared with intra-arterial administration, respectively.¹⁴^–¹⁶ However, there was no difference in survival.

Should Patients Be Treated with Chemotherapy before or after Surgery?

Neo-adjuvant chemotherapy, which is the current standard in the treatment of OS, initially evolved in order to allow time for the construction of endoprosthetic devices. The rationale for the administration of neo-adjuvant chemotherapy includes the early treatment of micrometastatic disease, optimization of the opportunity for limb salvage procedures, and the ability to gauge tumor response to therapy. The impact of timing of surgery was recently evaluated.¹⁷ No difference was found in survival between patients randomized to immediate surgery or neoadjuvant chemotherapy.

LOCAL CONTROL

The current basic principles for the surgical management of malignant pediatric musculoskeletal tumors were developed approximately 25 to 30 years ago when limb salvage surgery became commonly feasible. The primary basis for these principles included case series, anecdotes, and expert opinion. These principles are not disputed in the main, so few comparative studies challenge them directly. Techniques developed in this manner include safe biopsy principles and the necessity for wide en bloc resection. Here, we consider only those issues relating to local control for which there is at least Level III evidence and where the study population at least substantially involves skeletally immature patients. Comparative studies in musculoskeletal tumor surgery are primarily focused on reconstruction of defects after en bloc resection.

General Issues

Biopsy.

What constitutes a safe biopsy is taught by experts, and there is no prospective study to confirm the validity of expert opinion and anecdotal evidence in this regard. Nonetheless, a comparison of outcomes in patients who underwent appropriately or poorly performed biopsy as judged retrospectively by experts revealed the latter result in about a 10% incidence rate of otherwise unnecessary functional or anatomic loss.¹⁸

Limb Salvage Surgery.

To investigate oncologic outcomes from the late 1970s through the 1980s when limb salvage surgery was supplanting amputation for local control of bone sarcoma, researchers performed retrospective comparative studies. Survival is equivalent between amputation and limb salvage cohorts of patients with OS.^19,²⁰

Surgical Margins.

The incidence of local recurrence after limb salvage procedures of the distal femur is greater than that after above-knee amputation. Local recurrence is less likely with more proximal levels of amputation.^19,^{21, 22} These findings imply that the magnitude of a negative surgical margin is related to the ability to obtain local control but cannot specify what constitutes an adequate margin. Contradictory findings regarding rates of local recurrence after limb salvage or amputation have also been published,²³ suggesting that surgical selection bias influences the outcome in these retrospective comparisons.

It takes great care to plan the distal resection margin of a malignant metaphyseal bone tumor in a skeletally immature individual. Preservation of the epiphysis, and therefore the native adjacent joint, would likely be a functionally optimal and durable option. However, it is often difficult to be certain of the distal extent of the tumor. It has been shown that the accuracy of magnetic resonance imaging (MRI) in detecting involvement of the epiphysis by tumor is 90.3% using histology of the same tumors as a reference. Importantly, there are no false-negative results by computed tomography or MRI.²⁴ The surgical margin is therefore likely to safely correlate with preoperative MRI findings.