Localized osteosarcoma

Localized osteosarcoma is treated with neoadjuvant chemotherapy followed by surgery (Figure 15.4) and adjuvant chemotherapy.

Figure 15.4 X-ray of knee showing endoprosthetic replacement for osteosarcoma of the right tibia.

Metastatic osteosarcoma

In one study 11.4% osteosarcoma patients had metastases at the time of presentation. Metastases can occur in the lungs, bone and bone marrow. Lymph node and brain metastases are exceptionally rare. Isolated pulmonary metastases have the best prognosis and bone metastases the worst prognosis. Overall survival at 5 years ranges from 10–50%. Up to 30% of patients with lung metastases survive over 10 years with a combination of surgery, combination chemotherapy and occasionally radiotherapy. Although the chance of cure is small, patients particularly with limited and potentially resectable lung metastases should be treated aggressively with chemotherapy and surgery.

Chemotherapy

As in the adjuvant setting, the most effective agents are cisplatin, doxorubicin, methotrexate and ifosfamide (Box 15.3). Response rates are between 20–40% although some tumours and metastases may not reduce in size. Apparent calcification of lung metastases can occur (Figure 15.5). If the presentation is with metastases, combination chemotherapy should be the primary treatment.

Box 15.3
Chemotherapy for metastatic osteosarcoma

• In younger patients: cisplatin, doxorubicin and methotrexate (PAM)

• In older patients the methotrexate is often omitted due to increased toxicity

• If the patient has relapsed with metastases within 1–2 years of original treatment, ifosfamide with or without etoposide can be effective

• High-dose methotrexate with folinic acid rescue can be effective if previously treatment was with cisplatin and doxorubicin alone

Figure 15.5 Axial CT of chest showing pleurally based and calcified metastases characteristic of osteosarcoma (arrow). These lung metastases can bleed giving rise to bloody pleural effusions.

High-dose treatment with stem cell rescue has shown no improvement in survival. Trials are underway to evaluate biological agents such as insulin like growth factor 1 receptor (IGF1-R) antagonists. Immunotherapy may have a role and the use of liposomal muramyl tripeptide-phosphatidyl-ethanolamine has been shown to produce a survival benefit in the adjuvant setting.

Recurrent osteosarcoma

Approximately 40% of patients treated with a primary osteosarcoma will recur either locally or with metastatic disease. Management of local recurrence can involve chemotherapy, surgery or radiotherapy. Chemotherapy drugs are the same as those used for metastatic disease. Surgery may be possible but limb sparing surgery is less likely for local recurrence of extremity tumours. Radiotherapy may be useful for local control but is less effective than surgery.

Presentation

Unlike osteosarcomas which present most often in the epiphyses of long bones, Ewing’s sarcomas occur within the diaphysis and are often associated with a soft tissue mass. The soft tissue reaction may be confused for infection and contribute to delay in diagnosis. The median delay from symptoms (Box 15.1) to diagnosis is 6–9 months. The most common sites are long bones (53%) or the axial skeleton (47%). 25% have a soft tissue primary. Systemic symptoms (fever, anorexia, weight loss, and lethargy) may be present and are associated with advanced disease. 25% patients have metastases at presentation. Subclinical metastases are present in 80–90% with apparently localized disease, necessitating multimodality treatment even in apparently small volume localized disease. Prognostic factors are listed in Box 15.4.

X-ray may show a characteristic destructive lesion within the bone with surrounding periosteal reaction known as an onion skin appearance (Figure 15.6). A soft tissue reaction may also be seen on X-ray and a pathological fracture is seen in 15%. Ewing’s sarcomas, like osteosarcomas, show intense tracer uptake in bone scan (Figure 15.7). Staging is given in Table 15.1 and Figure 15.8 shows an overview of management.

Figure 15.6 X-ray of Ewing’s sarcoma of right proximal femur with destructive lesion and onion skin appearance of periosteal reaction.

Courtesy of Mr Rob Grimer.

Figure 15.7 Bone scintigram of Ewing’s sarcoma of left proximal radius showing localized uptake at the site of the tumour.

Figure 15.8 Management of Ewing’s sarcomas (VIDE – vincristine, ifosfamide, doxorubicin & etoposide; VAI – vincristine, actinomycin-D & ifosfamide; VAC – vincristine, actinomycin-D & cyclophosphamide).

Management of localized disease

Chemotherapy

Combination chemotherapy is usually given pre- and postoperatively. Alkylating agents have the highest response rate and have been combined with doxorubicin, vincristine, actinomycin D and etoposide. Trials such as IESS-III showed that alternating ifosfamide and etoposide with vincristine, doxorubicin and cyclophosphamide (VAC) improved survival from 54 to 69% in localized disease. High-dose treatment in localized low-risk disease has not been shown to improve survival. Response to chemotherapy at the time of surgery reflects prognosis.

Stratifying treatment according to risk is under investigation in the EUROEWING99 trial (Figure 15.9). Low-risk patients are randomized between standard treatment and less intense treatment. High-risk/metastatic patients are randomized between standard treatment and high-dose with stem cell rescue.

Figure 15.9 Management of Ewing’s sarcoma Euro Ewing 99 Protocol.

Management of metastatic disease

Some patients with limited pulmonary metastases at presentation may still be cured with combination treatment.

Prognosis of Ewing’s sarcoma

Prognosis in localized disease has improved significantly since the introduction of chemotherapy. Poor prognostic features are listed in Box 15.4. With combination chemotherapy and surgery or radiotherapy 5-year survival is 70%. With limited lung metastases and treatment with chemotherapy plus surgery or radiotherapy 5-year survival of 20–40% can be expected. With more extensive disease 5-year survival falls to less than 25%.

Recurrent Ewing’s sarcoma

Recurrence usually occurs within the first 2–5 years and the prognosis for these patients is poor. Relapse after 5–10 years is associated with a survival similar to that of advanced disease at presentation.

After 10 years very few patients relapse but it does occur. Treatment depends on the nature of relapse (local/systemic), nature of initial chemotherapy and time from the end of primary treatment. Isolated lung metastases after a long treatment interval may be suitable for surgical resection and further chemotherapy. To date high-dose regimens remain experimental in this group. The type of chemotherapy depends on the initial regimen but high-dose ifosfamide with etoposide has shown some activity. Trials of new agents such as insulin growth factor 1 receptor antagonists are underway.

Surgery

Resection has to extend beyond the tumour to a wide margin as an involved resection margin is the most important factor which predicts risk of recurrence. Margins have to be defined in terms of compartments and fascial or skin borders as well as distance. Surgery should be discussed within a sarcoma multidisciplinary team to ensure morbidity is minimized with the use of radiotherapy if required.

Radiotherapy

Surgery is the primary curative modality for soft tissue sarcomas; radiotherapy has a significant role in the prevention and treatment of local recurrence although there is no evidence that radiotherapy improves overall survival. Many soft tissue sarcomas are radiosensitive. A dose of >60 Gy is needed and the radiotherapy details are shown in Box 15.5.

For some patients who are unfit for surgery or in whom resection is technically not feasible, radiotherapy may be considered as a primary treatment modality. However, unless the tumour is very small and superficial, local control will not be as good as with surgery.

Limb sarcoma radiotherapy presents several challenges including positioning and immobilizing the limb to ensure consistent placement and accurate dose to the tumour bed with a margin. An adequate dose must be delivered to the tumour bed but must not cross the fascial compartment to avoid lymphoedema and delayed fibrosis which significantly affects mobility.

Chest wall sarcomas may be close to the heart or spinal cord making planning complex and potentially limiting doses delivered. They may follow the pleural contour of the chest wall making it difficult to avoid significant lung volumes within the treatment field.

Adjuvant chemotherapy

The use of adjuvant chemotherapy in soft tissue sarcomas remains controversial and is compounded by different histological subtypes of sarcoma with varied chemo-sensitivities being included as a group in the majority of studies. There are some sarcomas, which tend to predominate in the paediatric setting, in which adjuvant treatment has been shown to be useful, e.g. rhabdomyosarcomas and the extraskeletal Ewing’s sarcoma. However, for the majority there is no consensus concerning the use of adjuvant chemotherapy (Box 15.7). A meta-analysis showed a statistically significant improvement in local and distant recurrence if adjuvant chemotherapy was given. There was a trend towards an improved overall survival of 4% at 10 years, but this was not statistically significant. A multi-centre international EORTC study randomized 351 patients to standard treatment versus ifosfamide with doxorubicin. A preliminary analysis has shown no statistically significant difference between the two groups in either local recurrence rates or overall survival.

Treatment recommendations

Surgical resection with wide margins remains the mainstay of treatment for soft tissue sarcoma. This should be performed by specialist sarcoma surgeons. Radiotherapy is recommended for the majority of cases except low-grade tumours which have been excised with a wide margin. Radiotherapy is indicated for low grade tumours with involved resection margin when further surgery is not contemplated. The role of adjuvant chemotherapy for most subgroups remains controversial but could be considered within the context of a clinical trial (Box 15.8).

Chemotherapy

Systemic treatment with chemotherapy can be useful but its role is more complex than in other malignancies. There is little evidence that chemotherapy prolongs survival but it can provide significant benefits in symptom control. Response rates as determined by RECIST criteria often do not reflect symptomatic benefit or disease control, especially in response to certain agents such as trabectedin. Different tumour types show different responses to chemotherapy in general and to specific drugs (Box 15.10).

Doxorubicin is a standard first agent with response rates of 20–25%. Doses below 60 mg/m² have been shown to be ineffective and above 75 mg/m² to have increased toxicity without clinical benefit. Ifosfamide is often used as a second line agent and has a response rate of 25% overall. In general combination chemotherapy has been shown to improve response rates up to 46% but with no improvement in PFS or overall survival and with increased toxicity. Combination chemotherapy does have a role in the childhood and adolescent tumours such as rhabdomyosarcoma and extraskeletal Ewing’s sarcoma (Box 15.11).

Surgery

Despite the poor median overall survival with metastatic disease a small group of patients have a prolonged survival most of whom have disease which is amenable to surgery, e.g. lung metastases or isolated intra-abdominal recurrence. No randomized trial has evaluated the benefit of surgical resection of lung metastases but the 5-year survival of patients selected using strict criteria (Box 15.12) is up to 40%.

Resection of liver metastases, other than for GIST, is performed rarely and there is little evidence that it is of benefit either in terms of survival or symptom control.

Radiotherapy

The majority of soft tissue sarcomas are radiosensitive and radiotherapy can be an effective tool in symptom control. Doses used are in the range of 35–54 Gy.

Isolated limb perfusion

Some patients present with a massive inoperable limb sarcoma, often accompanied by significant symptoms, and too large to be encompassed within a radiotherapy field. For some there may be an option of isolated limb perfusion therapy (ILP) with melphalan and recombinant TNF-alpha within specialist centres.

Treatment recommendations

Metastatic soft tissue sarcomas should be managed by a multidisciplinary team of sarcoma specialists who can discuss all available options. Where appropriate, surgery should be performed for isolated recurrence or metastasis. Chemotherapy can provide effective symptom control in many sarcomas but an understanding of the specific differences in histological subtypes is required. There is no evidence that combination chemotherapy improves survival but it is useful in special situations and in adolescent sarcomas.

Pathology and genetics

The morphology can be spindle cell (70%), epithelioid (20%) or mixed type (10%). 95% of GISTs express c-KIT or the CD117 antigen. Mutations in the KIT gene occur in over 90% cases involving exon 11 (in 66%), 9 (in 13%), 13 (in 1.2%), and 17 (0.6%). GIST with mutations within the PDGFRA gene (7% cases) are more frequently associated with an epithelioid morphology, usually occurs in the stomach and tends to be indolent.

The malignant potential of GISTs has been shown to be related to size of the tumour, mitotic rate and location of the primary as described in the NIH consensus criteria (Table 15.3 and Box 15.13).

Table 15.3 Risk of aggressive behaviour in GISTs according to NIH consensus criteria

* hpf – high power field

Management

Definitive curative treatment is only possible with resection of the primary tumour in the absence of metastases. High risk (and intermediate risk) tumours are at risk of relapse after a clear resection. Several trials are examining the use of the drug imatinib in the adjuvant setting. Imatinib is an oral tyrosine kinase inhibitor (TKI) which blocks signalling via KIT by binding to the ATP-binding pocket which is essential for phosphorylation and activation of the c-KIT receptor (p. 370 and Box 15.14). Patients with inoperable primary tumours who do not have metastases may be rendered operable by the use of imatinib. Patients with metastatic disease should be treated initially with imatinib 400 mg per day.

The median time to progression for metastatic disease on imatinib is 2 years. Imatinib should be continued without a break (except for toxicity) until progression. It has been shown that interrupting treatment is associated with progression.

At progression dose escalation to 800 mg per day may enable temporary control of disease in 30–35% cases with a median time to progression of 4 months. For patients with an isolated liver metastasis who have responded to imatinib, local hepatic resection or radiofrequency ablation may be considered.

Sunitinib malate is a multi targeted TKI which has shown activity in GISTs which have progressed on imatinib. The median progression free survival in this clinical situation is 6 months. 68% patients achieved a partial response or stable disease on sunitinib.

Assessment of response

Assessment of response in GIST may be with CT scan but it has been shown that RECIST criteria may not be the only measure of response in these tumours. FDG-PET can detect reduction in tumour activity within days of commencing imatinib or can visualize small liver metastases which may not be visible on CT. Similarly it can detect increased activity should the tumour develop resistance (new mutations) once on imatinib. Choi described alternative criteria to evaluate GIST response. A 15% reduction in tumour density or 10% unidimensional reduction in tumour size was a better predictor of response than RECIST and these criteria have been shown to correlate better with survival than RECIST.