Update on Survival in Osteosarcoma




Osteosarcoma is the most common primary bone malignancy in children. Treatment has evolved to include systemic chemotherapy and local control surgery. Although survival improved initially in a drastic fashion with this approach, recent decades have seen little to no further gains in this area. Limb salvage surgery evolved with effective chemotherapy and advances in imaging, and continues to improve in the recent era. This article serves as a review of survival in high-grade osteosarcoma: prognostic factors, advances in chemotherapy and surgery, late effects of chemotherapy and surgery in survivors, and future directions.


Key points








  • The development of effective chemotherapy for osteosarcoma in the 1980s led to a drastic improvement in survival. This, along with advances in imaging modalities, allowed safe and effective limb salvage surgery to evolve.



  • Survival has reached a plateau since the 1990s, while progress in limb salvage surgery continues to be made.



  • Following patients for late effects of chemotherapy and surgery for osteosarcoma is critical now that most patients are long-term survivors.



  • Future efforts are needed to identify effective systemic therapy and local surgery and reconstruction for patients with osteosarcoma.






Introduction


Survival in osteosarcoma is a story of success on many fronts. What was once a disease that was rarely curable even with ablative surgery now has a 5-year overall survival approaching 70% to 80%. This is uncommon in orphan diseases, and is a result of collaboration among pediatric oncologists, orthopedic oncology surgeons, biologists, their associated teams, and most importantly the children and parents who were willing to participate in clinical trials and forays into limb salvage surgery. Although the improvement in survival in osteosarcoma has been astounding on some levels, it can be deemed only a partial success, as few gains have been made in recent decades. This article is a review of survival in osteosarcoma with a focus on background information, advances in chemotherapy and limb salvage surgery, late effects in survivors, and future directions.




Introduction


Survival in osteosarcoma is a story of success on many fronts. What was once a disease that was rarely curable even with ablative surgery now has a 5-year overall survival approaching 70% to 80%. This is uncommon in orphan diseases, and is a result of collaboration among pediatric oncologists, orthopedic oncology surgeons, biologists, their associated teams, and most importantly the children and parents who were willing to participate in clinical trials and forays into limb salvage surgery. Although the improvement in survival in osteosarcoma has been astounding on some levels, it can be deemed only a partial success, as few gains have been made in recent decades. This article is a review of survival in osteosarcoma with a focus on background information, advances in chemotherapy and limb salvage surgery, late effects in survivors, and future directions.




History and background


Osteosarcoma is a primary malignant tumor that arises in bone, in which the malignant cells produce osteoid ( Fig. 1 ). There are many subtypes, but the most common and the focus of this article is high-grade conventional osteosarcoma. It is the most common primary sarcoma of bone, but is still quite rare. Osteosarcomas represent fewer than 1% of cancers overall, with an incidence of 5 per 1,000,000 children age 19 and younger in the United States. It is slightly more common in male than female patients and has a predilection for the metaphyseal regions adjacent to physes with the greatest growth: distal femur, proximal tibia, and proximal humerus.




Fig. 1


Photomicrograph of osteosarcoma pathology (hematoxylin-eosin, original magnification ×200). Note the cellular pleomorphism, abnormal mitotic figures, and lacy pink osteoid material.


It was recognized in some of the earliest medical reporting that even if the primary tumor in osteosarcoma was treated appropriately, many children still succumbed to the disease, mostly due to pulmonary metastases. It was determined that hematogenous dissemination of the disease was to blame, and that although only 20% of patients present with gross evidence of metastatic disease (a number that has not changed over time ), the vast majority have micro-metastatic disease. Roughly 80% of metastatic deposits involve the lung, the component of this disease that represents the life-threatening behavior of this cancer.


In the 1970s, some survival successes were achieved initially with methotrexate and then multiagent regimens, predominantly including doxorubicin, cisplatin, bleomycin, and other agents. Chemotherapy was given postoperatively in these reports with improvements in survival from 20% to 40%. In the 1980s, 2 randomized trials demonstrated improvement in survival to roughly 60% with a combination of agents. Thus, within 2 decades, survival improved from 20% to 60% to 70%, truly remarkable advancements. As patients were living longer and chemotherapy was demonstrated to be effective, orthopedic oncology surgeons recognized that there may be opportunities for limb salvage in these patients. Custom prostheses were developed, but required time for fabrication, so surgeons worked with oncologists to demonstrate outcomes were similar if surgery was performed up-front versus after several cycles of chemotherapy first. Thus, the era of limb salvage began and now roughly 80% of patients with osteosarcoma are treated for their primary tumor with limb salvage surgery.




Prognostic factors


Many of the clinical trials and several large retrospective studies have demonstrated the importance of several factors affecting prognosis in high-grade osteosarcoma.


Metastatic Disease


The presence of metastatic disease has the most impact on prognosis. Patients who present with metastatic disease have overall survival of roughly 20% to 30% compared with 70% to 80% in nonmetastatic patients. The location of the metastatic disease is important: patients with pulmonary-only disease fare better than those with bone metastases or other sites of metastases. Whether the disease is resectable or not also has a large impact on prognosis. Timing is important as well: those who present with metastatic disease later, at least 2 years after the end of initial chemotherapy, have a slightly better prognosis, roughly 40% 5-year overall survival.


Chemotherapy Response


The next most important prognostic factor for survival in osteosarcoma is response to chemotherapy. Now that most patients are treated with neoadjuvant chemotherapy, then surgery followed by further adjuvant chemotherapy, there is an opportunity to examine the pathologic specimen to determine the percent necrosis in response to the therapy. Patients with greater than 90% necrosis have improved overall and disease-specific survival compared with those with lower histologic response to chemotherapy.


Tumor Characteristics


The size of the primary tumor is an important prognostic factor, and closely tied to it is the location of the tumor. Axial tumors tend to be larger at diagnosis, and thus associated with poorer overall survival than tumors in the appendicular skeleton. However, when larger studies have been able to control for size, axial location often still holds as a significantly worse factor for overall and disease-specific survival.


Histologic subtype can affect prognosis as well. It is linked to chemotherapy response for some subtypes but not all. Fibroblastic and telangiectatic subtypes are associated with higher rates of good response to chemotherapy (>90% necrosis) and in turn better 5-year overall survival compared with osteoblastic and chondroblastic subtypes. However, although better overall survival is associated with good histologic responses in most subtypes, that is not the case for chondroblastic osteosarcomas, in which survival in poor responders is not statistically different from good responders.


Patient Characteristics


Age of the patient affects prognosis as well. Older patients tend to have worse outcomes compared with younger patients. This may be in part associated with older patients’ inability to tolerate the chemotherapy, but also may be related to the higher number of secondary osteosarcomas and axial location in adult populations compared with children. Osteosarcomas that arise in a preexisting lesions, especially as in Paget disease, are associated with poorer prognoses.




Chemotherapy


Nonmetastatic


The determination of which chemotherapeutic agents to use for patients with osteosarcoma was largely empiric, based on some agents’ success in other tumor types. Collaboration across centers and countries has demonstrated the effectiveness of current regimens, although there is no consensus on which medications and what dosing should be used. Most protocols today involve doxorubicin, cisplatin, and high-dose methotrexate, termed MAP ( M ethotrexate, doxorubicin/ A driamycin, cis P latin). High-dose methotrexate may not be as effective for adult patients and is associated with greater toxicity in adults, so although the 3-drug regimen with MAP is considered standard in most countries for children and young adults, those older than 40 are most commonly treated with doxorubicin and cisplatin only. Controversy exists regarding the addition of ifosfamide alone or in combination with etoposide, and investigations regarding these agents are ongoing.


It is important to keep in mind that these medications are associated with significant toxicity. Alopecia, mucositis, and nausea and vomiting are not life-threatening, but myelosuppression and doxorubicin-related cardiac failure can be. Renal dysfunction also can be severe in some cases due to both the cisplatin and high-dose methotrexate. With the knowledge that probably 10% to 20% of patients with localized disease could be cured with surgery only and not exposed to these toxic effects of chemotherapy, it would be extremely helpful to determine which osteosarcomas have little metastatic potential and thus be able to stratify treatment. To date, there have been no markers to allow such stratification among high-grade osteosarcomas.


Poor Response


Patients who have less than 90% necrosis in response to preoperative chemotherapy and those with disease progression on chemotherapy have a worse prognosis. Attempts have been made in several trials to “salvage” these patients by adding other agents or changing protocols entirely with postoperative chemotherapy, the vast majority without any improvement in survival. This is the subject of the recent EURAMOS ( Eur opean and Am erican O steosarcoma S tudy Group)-1 Intergroup collaboration: patients with poor histologic responses were randomized to continuing MAP or MAP with ifosfamide and etoposide. The results of this component of the trial have not been published yet.


Metastatic


Patients with metastatic disease at presentation have a worse prognosis as noted previously. When treated with 3-drug or 4-drug regimens, there are fewer good responders compared with patients presenting without metastases. This lack of response to standard chemotherapy indicates the need to identify other effective medications. Most investigations into new agents involve patients with metastatic disease. For patients not on trials, a standard approach would involve MAP or MAP with ifosfamide ± etoposide along with surgical resection of the primary tumor and all metastatic sites if feasible. If any of the disease is not resectable, the prognosis is grim. Palliative approaches involve systemic therapy along with limited surgery, radiation, and/or percutaneous ablative procedures.


Relapsed


Patients who relapse either at the local site or with distant metastases after an initial disease-free interval have an intermediate survival approaching 30% to 40%. As noted previously, timing of the relapse is an important prognostic factor. The longer the disease-free interval, the better the survival. The volume of disease relapse and whether all sites are resectable also greatly affect survival. Treatment approaches thus vary and are individualized based on where the site of relapse is located, whether surgical resection is possible, and what chemotherapy was used previously and how long before the development of the relapse ( Fig. 2 ). Most centers will treat patients with relapse with surgery and systemic therapy in some fashion, although patients with a solitary pulmonary relapse that develops over a year off therapy may be treated with surgery alone.




Fig. 2


Nineteen-year-old male patient who presented with localized osteosarcoma of the right distal femur ( A : sagittal MRI, proton density sequence). He was treated with extra-articular resection of his primary tumor and reconstruction with a megaprosthesis ( B ). His first relapse was a solitary pulmonary nodule ( C : chest CT), which developed 9 months off therapy and was treated with surgery and inhaled granulocyte-macrophage colony-stimulating factor as part of a research protocol. His second relapse was a local recurrence ( D : PET imaging of soft tissue recurrence posterior to prosthesis), which developed 3 years later and was treated with above-knee amputation. He has been disease free for 6 years.




Surgery


As survival in osteosarcoma has plateaued, the numbers of patients having limb salvage surgery continues to grow. The quality and nature of surgical resection for osteosarcoma has a great impact on survival. Although there are myriad approaches to resection and reconstruction of a bone affected by osteosarcoma, some important requirements hold true for all.


Margins


The goal of surgical resection for osteosarcoma is to achieve a wide margin, as defined by Enneking and colleagues. Over time, the definition of what constitutes a wide margin has changed and cannot be given as an absolute distance. It depends on the nature of the marginal tissue; for example, a wider margin of fat would be necessary compared with fascia due to the quality of the tissue and ability of the tumor to invade such tissue. It can depend on perceived response to chemotherapy; for example, amputation or rotationplasty may be recommended over limb salvage for a patient with disease progression on neoadjuvant chemotherapy ( Fig. 3 ). It also depends on the location of the tumor within the bone; for example, tumors that are localized to only a portion of the bone may be resected in an intercalary fashion, thus preserving an articular surface and/or more normal bone in an effort to improve function postoperatively ( Fig. 4 ).




Fig. 3


Eleven-year-old boy who presented with a large osteosarcoma of the proximal tibia ( A : sagittal MRI, short tau inversion recovery sequence; B : axial MRI, T2 with fat-saturation sequence). The tumor was larger in all dimensions after 2 cycles of MAP chemotherapy ( C : sagittal MRI, short tau inversion recovery sequence; D : axial MRI, T2 with fat-saturation sequence), and so he and his parents decided on rotationplasty for local control surgery.

Only gold members can continue reading. Log In or Register to continue

Oct 6, 2017 | Posted by in ORTHOPEDIC | Comments Off on Update on Survival in Osteosarcoma
Premium Wordpress Themes by UFO Themes