Dr Katja Zils
Resident Klinikum Stuttgart, Olgahospital, Paediatrics 5 (Oncology, Haematology, Immunology), Stuttgart, Germany
Prof Dr Stefan Bielack,
Head of Department Klinikum Stuttgart, Olgahospital, Paediatrics 5 (Oncology, Haematology, Immunology), Stuttgart, Germany
With an incidence of 2–3 million per year in the general population, osteosarcoma is a rare disease. Nevertheless, it is the most frequent primary cancer of bone. The malignancy is most common in adolescence, with an incidence peak of 8–11 per million per year for 15- to 19-year-olds.1 However, at least one third of all patients with osteosarcoma are adults.
By definition, osteosarcoma is characterised by malignant mesenchymal tumour cells producing osteoid and/or immature bone.1 It most frequently affects the metaphysis of the long bones and almost 70% of all paediatric and adolescent cases arise around the knee.1,2 The most common primary sites are distal femur, proximal tibia and proximal humerus.
At time of diagnosis, 10–15% of all patients will present with detectable metastases, mostly localised in the lungs.2 Diagnosis has to be confirmed histologically. Staging must include imaging of the primary tumour with X-rays and magnetic resonance imaging (MRI). Lung metastases must be excluded by X-rays and computer tomography (CT) of the chest, bone metastases by a technetium bone scan.
Principles of therapy
Treatment of osteosarcoma must include both local and systemic elements. Adequate local therapy implies complete surgical removal of the tumour. Without additional systemic chemotherapy, 80–90% of patients will develop (lung) metastases and die.2 Compared with surgery alone, multimodal treatment, including both surgery and multi-agent chemotherapy, increases disease-free survival rates from only 10–20% to >60%.2
Current treatment regimens divide chemotherapy into a pre-operative (also called neo-adjuvant or induction) phase, followed by definitive surgery, and a postoperative (adjuvant) period.2 The total duration of therapy is usually eight to 12 months.
Due to the rarity of osteosarcoma, therapy has to be standardised. In many countries, patients are routinely treated within prospective multicentre trials. Such trials are essential in guaranteeing that as many patients as possible can benefit from modern treatment regimens.
In order to achieve best results, various medical specialists such as paediatric or medical oncologists, orthopaedic surgeons, pathologists and radiologists must work in close co-operation within a multidisciplinary team. Therefore, therapy usually takes place in a specialised centre that can offer the necessary level of experience and provide access to the full spectrum of care.3
The aim of surgery is to remove all of the detectable tumour. This has to be done in a safe manner and requires adequate surgical margins. This implies at least a ‘wide’ resection according to Enneking’s classification (see Table 1),4 meaning that the tumour and the biopsy scar must be removed en bloc surrounded by an unviolated cuff of healthy tissue. Otherwise, the risk for local recurrence is markedly increased.
In addition to achieving adequate surgical margins, surgeons should also aim to preserve as much function as possible. In principle, surgical options can be divided into limb salvage and ablative procedures (for example amputations). Advances in imaging techniques and in biomedical engineering as well as positive effects of pre-operative chemotherapy have led to a major shift away from amputation towards limb-salvage surgery.2
Today, most patients can be treated with limb-salvage surgery, but a minority will still require amputation. Opportunities for reconstruction after limb-sparing tumour resections are multifarious and include endoprosthetic devices, biological reconstruction and combinations of both.
Endoprostheses are currently regarded by many as the treatment of choice for osteosarcomas arising in the proximity of a joint. In the long run, however, use of such devices is frequently followed by the necessity for additional operations due to prosthetic failure, be it because of deep infection, necrosis or wear.5
Another well-established biological reconstruction method for tumours around the knee is rotationplasty. It consists of en bloc resection of the knee, bone shortening and rotation of the lower leg by 180° to allow the ankle to function as a neo-knee joint. This method can result in functional and psychosocial outcomes equal or even superior to endoprosthetic reconstruction, but it is, of course, cosmetically challenging.6
The decision for or against limb salvage has to be made together with the patient and his/her family after considering the age and wishes of the patient, size and location of the tumour and the tumour’s relationship to the neurovascular bundle, as well as the effects of pre-operative chemotherapy.
While the role of radiotherapy in the treatment of osteosarcoma is still very limited, it has changed over the past years. Recent data suggest that radiotherapy may be beneficial in patients treated with multi-agent chemotherapy who have unresectable tumours, inadequate resection margins or microscopic tumour rests after surgery.7
Multi-agent chemotherapy has become an indispensable part of multimodal osteosarcoma treatment and, together with surgery, is one of the cornerstones for cure. This is due to the high rate of (micro-) metastatic spread at diagnosis and due to chemotherapy’s proven efficacy.
Dividing chemotherapy into a pre- and a postoperative part has some advantages: Physicians have the opportunity to assess tumour response to the agents used preoperatively by histological analysis of the resected specimen. The extent of this histological tumour response to induction chemotherapy is one of the strongest prognostic factors currently available.2
Ongoing prospective trials evaluate whether changing postoperative chemotherapy in poor responders improves outcome. Furthermore, surgeons and patients can plan and prepare for local therapy without time stress and pressure. Preoperative chemotherapy may also help to demarcate the tumour and hence facilitate surgery.
Overall and event-free survival expectancies, however, seem to be quite similar regardless of whether part of an otherwise identical regimen is administered preoperatively or the whole protocol is given postoperatively.
Most modern osteosarcoma regimens include combinations including three or all of the following four agents: doxorubicin, cisplatin, high-dose methotrexate and ifosfamide. At present, these four are regarded as the most active agents against osteosarcoma. Their ideal combination remains to be defined.
Ever since its introduction into osteosarcoma chemotherapy almost 40 years ago, the anthracycline antibiotic doxorubicin has been part of basically all successful osteosarcoma protocols. It is active in all phases of the cell cycles, with maximal activity in S phase by several modes of action.
Cisplatin, also part of almost all osteosarcoma protocols, is a platinum complex that inhibits DNA-synthesis by directly binding to DNA.
The folic acid analogue methotrexate (MTX) inhibits the intracellular enzyme dihydrofolate reductase, resulting in reduced synthesis of both purines and pyrimidines.
High-dose MTX (HD-MTX) regimens with dosages in the range of 8–12g/m² have been designed to circumvent MTX resistance. Their use against osteosarcoma has been intensely debated and no general consensus could be obtained. Nevertheless, most study groups continue to incorporate HD-MTX into their combination chemotherapy protocols, as it is not particularly myelosuppressive and can therefore be administered at times when other chemotherapy cannot.
To prevent life-threatening toxicities that would otherwise inevitably develop due to precipitation of MTX and its metabolite 7-hydroxy-MTX in the renal tubules with consecutive renal failure and markedly delayed drug elimination, HD-MTX can only be administered if it is accompanied by elaborate supportive care measures. These include hyperhydration and urine alkalinisation as well as ‘leucovorin rescue’, administration of the antidote folinic acid.
The dosage and duration of leucovorin rescue must be guided by the results of repeated MTX serum level measurements. Particular care must be taken to avoid combining HD-MTX with drugs such as nonsteroidal anti-inflammatory agents, probenecid or penicillin, as these will interfere with renal MTX elimination, and co-administration will hence lead to increased MTX exposure and toxicity.
Delayed elimination may, however, also occur in the absence of identifiable predisposing factors. In case of delayed MTX elimination, the volume and duration of hydration and alkalinisation and particularly the leucovorin rescue must be increased. The use of glucarpidase (formerly known as carboxypeptidase G2), an enzyme that cleaves MTX, should be considered in cases of nephrotoxicity with delayed MTX elimination.
Ifosfamide, a structural analogue of cyclophosphamide, is an alkylating agent that serves as a carrier molecule for phosphoramide mustard. Like other oxazaphosphorines, it requires metabolic activation by hepatic microsomal enzymes.
Following the results of a US trial in which the addition of ifosfamide to a three-drug combination of the aforementioned agents did not result in improved outcomes, its use is no longer considered indispensible. The activity of the drug may be related to the dose administered, and high-dose ifosfamide regimens are the subject of current investigation.8
General risks and complications of chemotherapy include anaemia, thrombocytopenia and leucocytopenia with concurrent infections, nausea and vomiting, mucositis and alopecia.
Specific side effects of the drugs most frequently used against osteosarcoma include:
- Impaired renal function
- Haemorrhagic cystitis
- Hearing loss
- Gonadal dysfunction
- Cardiac dysfunction (see Table 2).
Close monitoring during chemotherapy is mandatory to appropriately detect abnormalities and to adapt therapy accordingly. Long-term follow-up is required not only to monitor the remission status, but also to screen for and to manage late effects (see Table 3).
A number of agents can help to reduce chemotherapy-related toxicity. For example granulocyte stimulating factor (G-CSF) can reduce the incidence and the duration of granulocytopenia. A recent randomised trial by the European Osteosarcoma Intergroup proved that the intervals between treatment cycles can be reduced by prophylactic G-CSF administration, resulting in an increased dose density of treatment. Unfortunately, this did not translate into improved event-free or overall survival rates.9
The introduction of serotonin antagonists was a great advance in reducing chemotherapy- and especially cisplatin-induced emesis. Such agents alone or in combination with dexamethasone or neurokinin receptor antagonists have dramatically reduced the severity of this side effect and have become part of the standard of care with highly emetogenic osteosarcoma chemotherapy.
The treatment strategy for patients with detectable primary metastases is similar to that of those with localised disease: multi-agent chemotherapy plus surgical removal of all tumour manifestations.
Here, this implies additional mandatory surgical resection of all discernible metastases. For lung metastases, this should be attempted by open thoracotomy with bilateral exploration and manual palpation of both lungs. Some groups, including our own, also recommend such a bilateral approach for seemingly unilateral metastases and for metastases seeming to ‘disappear’ during chemotherapy.
No more than 30% of all patients with primary metastases will become long-term survivors, but this rate increases to over 40% for those who achieve a complete surgical remission.10
The prognosis of patients with osteosarcoma recurrences is unfavourable, as long-term overall survival expectancies are below 20%.11 A long time to relapse, a solitary lesion and, in case of pulmonary metastases, unilateral disease and the absence of pleural disruption are of positive prognostic value.11
Again, cure basically requires the total removal of every single tumour manifestation, regardless of location. Only few, if any, patients will survive without complete resection. Rules for thoracotomy at recurrence mirror those applicable for primary metastases.
The exact role of second-line chemotherapy is still under discussion. In the two largest reported series, the use of second-line chemotherapy correlated with limited prolongation of survival in patients with inoperable metastatic recurrences, while a positive correlation in operable disease was observed in only one of the two.
At present, there is no universally accepted standard chemotherapy regimen for recurrent osteosarcoma. Possible choices include any of the four standard agents not already given during first-line as well as a variety of other agents.
Current and future efforts
Today, 60–70% of all osteosarcoma patients will achieve long-term survival and cure. Unfortunately, survival expectancies have improved very little over the past 25 years. Few novel agents have become the subject of large-scale, randomised trials.
A recently published Paediatric Oncology Group/Children’s Cancer Group trial investigated the addition of liposomal microsomal muramyl tripeptide phosphatidyl ethanolamine (L-MTP-PE), a macrophage activating immunomodulator, to standard chemotherapy. The study had a complex factorial design with two potentially interacting randomisations, methotrexate/doxorubicin/cisplatin (MAP) +/- L-MTP-PE and +/- ifosfamide. Furthermore, in the MAP + ifosfamide arm, the latter was substituted for cisplatin preoperatively and added to cisplatin postoperatively. Sequential publications of outcome analyses performed at different time points came to varying conclusions regarding the efficacy of L-MTP-PE, and ifosfamide/L-MTP-PE interaction concerns were raised.
The most recent paper reported that the addition of L-MTP-PE to chemotherapy resulted in a statistically significant advantage in overall survival, but only a non-significant trend for improved event-free survival.12 Usually, event-free and overall survival are extremely closely linked together in osteosarcoma. The reasons why this should not be the case for MTP remain obscure.
The study design and the associated statistical limitations have been criticised and many believe that the potential role of L-MTP-PE requires further investigation before the agent should be considered part of standard osteosarcoma therapy.13
At present, four well-established multinational groups are jointly investigating risk-adapted postoperative treatment based on histological tumour response to induction chemotherapy in the European and American Osteosarcoma Study EURAMOS-1. In this largest osteosarcoma trial ever, all patients are scheduled to receive 10 weeks of preoperative induction chemotherapy with high-dose methotrexate, cisplatin and doxorubin (MAP).
All patients also receive additional postoperative treatment including the same three drugs. In patients with a good histological response to pre-operative chemotherapy, maintenance treatment with pegylated α-Interferon given after completion of standard chemotherapy is subject of a randomised comparison with end of treatment at end of chemotherapy. In poor responders, treatment intensification by adding high-dose ifosfamide and etoposide to MAP is tested.14
Developing novel agents against osteosarcoma requires translational research to identify new targets and further clinical trials evaluating the addition of innovative therapies to conventional regimens.
Agents that are currently of interest include L-MTP-PE, bisphosphonates, antibodies against RANK-ligand or the IGF1-receptor, mTOR-inhibitors, the multikinase inhibitor sorafenib and metformin.
It remains to be seen which, if any, of these agents will prove its value in prospective, randomised trials.
Osteosarcoma is the most frequent primary malignant tumour of bone and it is considered the typical cause of cancer seen in adolescence.
With complete surgical removal of all detectable tumour manifestations and dedicated administration of intensive multi-agent chemotherapy, more than 60% of all patients can become long-term survivors.
Treatment should be administered within prospective multicentre trials.
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