Orthopedics

Review Article 

Current Treatment Considerations for Osteosarcoma Metastatic at Presentation

Shinji Tsukamoto, MD; Costantino Errani, MD; Andrea Angelini, MD; Andreas F. Mavrogenis, MD

Abstract

Approximately one-fourth of osteosarcoma patients have metastases at presentation. The best treatment options for these patients include chemotherapy, surgery, and radiotherapy; however, the optimal scheme has not yet been defined. Standard chemotherapy for osteosarcoma metastatic at presentation is based on high-dose methotrexate, doxorubicin, and cisplatin (the MAP regimen), with the possible addition of ifosfamide. Surgical treatment continues to be fundamental; complete surgical resection of all sites of disease (primary and metastatic) remains essential for survival. In patients whose tumors do not respond to neoadjuvant chemotherapy, early surgical resection of the primary tumor with limb-salvage surgery or amputation and multiple metastasectomies, if feasible, after the completion of adjuvant chemotherapy is a reasonable option, as the reduction of the tumor volume could probably increase the effect of chemotherapy. Advanced radiotherapy techniques, such as carbon ion radiotherapy and stereotactic radiosurgery, and molecular targeted chemo-therapy with drugs such as pazopanib or apatinib have improved the dismal prognosis, especially for patients who are medically inoperable or who refuse surgery. Given that the presence of metastatic disease at diagnosis of a patient with osteosarcoma is a poor prognostic factor, a multidisciplinary approach by surgeons, medical oncologists, and radiotherapists is important. [Orthopedics. 2020;43(5):e345–e358.]

Abstract

Approximately one-fourth of osteosarcoma patients have metastases at presentation. The best treatment options for these patients include chemotherapy, surgery, and radiotherapy; however, the optimal scheme has not yet been defined. Standard chemotherapy for osteosarcoma metastatic at presentation is based on high-dose methotrexate, doxorubicin, and cisplatin (the MAP regimen), with the possible addition of ifosfamide. Surgical treatment continues to be fundamental; complete surgical resection of all sites of disease (primary and metastatic) remains essential for survival. In patients whose tumors do not respond to neoadjuvant chemotherapy, early surgical resection of the primary tumor with limb-salvage surgery or amputation and multiple metastasectomies, if feasible, after the completion of adjuvant chemotherapy is a reasonable option, as the reduction of the tumor volume could probably increase the effect of chemotherapy. Advanced radiotherapy techniques, such as carbon ion radiotherapy and stereotactic radiosurgery, and molecular targeted chemo-therapy with drugs such as pazopanib or apatinib have improved the dismal prognosis, especially for patients who are medically inoperable or who refuse surgery. Given that the presence of metastatic disease at diagnosis of a patient with osteosarcoma is a poor prognostic factor, a multidisciplinary approach by surgeons, medical oncologists, and radiotherapists is important. [Orthopedics. 2020;43(5):e345–e358.]

Osteosarcoma is the most common primary malignant bone tumor, having a peak frequency in adolescents and adults younger than 24 years.1 Prior to the introduction of high-dose chemotherapy, the 5-year survival rate for patients with osteosarcoma was approximately 20% after amputation2; most patients died with lung metastasis. After the introduction of effective (neo-) adjuvant chemotherapy and if feasible complete metastasectomy, the prognosis for these patients greatly improved to a 5-year survival rate of approximately 75%,3,4 most probably related to the eradication of micrometastases undetected by current imaging modalities at diagnosis.5 However, survival has not improved substantially during the past 30 years.4 Despite a combination of therapies, treatment failures occur within 5 years of diagnosis in more than 40% of patients, generally due to metastatic disease developing before or after diagnosis,1,4

Approximately 20% to 25% of patients with osteosarcoma have metastases at the time of their diagnosis.6–8 The most common sites for metastases are the lungs (85% to 90%) and the bones (15% to 30%).9 The presence of metastatic disease at diagnosis is a poor prognostic factor and is associated with a 5-year survival rate ranging from 16% to 53%.10–17 In this scenario, osteosarcoma metastatic at presentation is usually incurable and requires palliation.6–8

Although the efficacy of surgery in combination with systemic chemotherapy is well established for non-metastatic osteosarcoma, for patients with osteosarcoma metastatic at presentation, the best treatment options have not yet been defined.12 Patients with metastatic or recurrent osteosarcoma are generally excluded from clinical trials and therefore do not often receive homogeneous treatment.1,5,18 Additionally, there is no consensus or established guideline regarding the optimal timing of chemotherapy and primary tumor surgery for these patients. Most physicians are treating patients based on their own experiences and/or available protocols that are supported by controversial results and a lack of evidence.10,12,13

Despite some controversy,19 lung metastasectomy is generally recommended for patients who demonstrate stable disease or a partial response to neoadjuvant chemotherapy, as well as for patients with poor prognostic factors when a complete resection can be achieved.20 However, there are no clear guidelines or recommendations regarding the optimal timing for resection of the metastatic tumor in these patients or for resection of the primary tumor during treatment. With this article, the authors aim to enhance the literature on the above topics and to consolidate the best available data in an effort to help orthopedic surgeons with their decision making regarding the management of patients with metastatic osteosarcoma at presentation.

Primary Tumor Surgery

Neoadjuvant chemotherapy followed by resection of the primary tumor and adjuvant chemotherapy are considered the treatments of choice for osteosarcoma patients with and without metastases at presentation.3,9–24 Neoadjuvant chemotherapy seems to offer several advantages, including (1) gaining time to prepare for definitive surgery for limb-salvage procedures and metastasectomy; (2) delineating the tumor boundary via the chemotherapy-induced formation of a well-formed avascular, collagenous capsule, which improves the quality and adequacy of the surgical margin; and (3) permitting histological evaluation of the response to the neoadjuvant chemotherapy, which is the most reliable prognostic indicator available to date.21–23,25–27

Osteosarcomas that are pre-treated with chemotherapy are better demarcated against surrounding tissues and are easier to operate on.21 Effective neoadjuvant chemotherapy is also associated with reduced rates of local recurrence; therefore, limb-salvage surgery becomes safer.22 The response to neoadjuvant chemotherapy is graded on the basis of the amount of viable tumor remaining in the resected specimen. A 10% cutoff is often used to distinguish between good and poor responses. Sub-classifications into 6 (Salzer-Kuntschik) or 4 (Huvos) grades are currently used and allow treatment effects to be described in greater detail.28,29

However, the optimal timing of primary tumor surgery for patients with osteosarcoma that is metastatic at presentation is unclear.10–14,19,20,24,30 Meyers et al13 reported the outcomes of 62 patients with previously untreated osteosarcoma with metastasis at the lungs, bones, and lymph nodes at presentation. Seventeen patients had re-sections of their lung metastases after primary tumor surgery before administration of neoadjuvant chemotherapy, while 39 patients had surgery after neoadjuvant chemotherapy. No difference in survival was observed between the groups.13 In a study by Goorin et al,30 1 patient who initially was considered eligible for limb-salvage surgery had amputation after neoadjuvant chemotherapy because of disease progression during treatment, and 2 patients who were assessed initially as requiring amputations were able to have limb-salvage surgery because of tumor regression after neoadjuvant chemotherapy.30 In the European Osteosarcoma Intergroup study, 22 patients were initially considered feasible for limb-salvage surgery but instead had amputations, and 8 patients who were assessed initially as requiring amputations were able to have limb-salvage surgery.31 It seems that a long interval between diagnosis and primary tumor surgery for patients with osteosarcoma metastatic at presentation is a negative predictor for limb-salvage surgery if the tumor does not respond to neoadjuvant chemotherapy. Most likely, in these cases, the tumors are aggressive and will not respond even to additional cycles of neoadjuvant treatment.

In contrast, reducing the volume of the primary tumor by resection (limb-salvage surgery), if feasible, or amputation may increase the effect of chemotherapy.32 Theoretically, a high tumor volume at initiation of treatment could be associated with poor response to chemotherapy.32 Bacci et al33 reported the results of 560 patients with osteosarcoma of the extremities and correlated the 5-year disease-free survival with the size of the primary tumor. Opting for early surgical resection of the primary tumor, regardless of whether the patient has metastases at presentation or is responsive to neoadjuvant chemotherapy, is important.32 If microscopically negative margins resection is not feasible for the primary tumor or if complex reconstructions with an increased risk for related complications after limb-salvage surgery are expected, then amputation should be offered as the optimal treatment for these patients.

In summary, neoadjuvant chemotherapy allows for demarcation of margins of the primary tumor, and possibly for limb-salvage surgery and reduced rates of local recurrence.21,22 However, a long interval between diagnosis and primary tumor surgery for patients with osteosarcoma meta-static at presentation is a negative predictor for limb-salvage surgery, especially if the tumor does not respond to neoadjuvant chemotherapy. Therefore, reducing the volume of the primary tumor by resection (limb-salvage surgery), if feasible, or amputation may increase the effect of chemotherapy.32

Lung Metastasectomy

Lung metastasectomy, if feasible, is generally recommended for patients with osteosarcoma and lung metastases.19,20 However, controversy exists regarding the optimal timing for metastasectomy.10–14,19,20,24,30 Bacci et al12 retrospectively studied 162 patients with osteosarcoma of the extremities and lung metastases at presentation treated with neoadjuvant chemotherapy, simultaneous resection of the primary tumor and, when feasible, the metastatic lesions, and adjuvant chemotherapy. After neoadjuvant chemotherapy, the lung metastases disappeared in 14 patients; 16 patients were judged unresectable by their thoracic surgeons; and 132 (81.5%) patients had primary tumors and lung metastases removed simultaneously. The total number of lung nodules detected by staging computed tomography scan of the chest at diagnosis was 1196 (mean, 7.4 per patient; range, 1–24 nodules), decreasing to 862 (mean, 5.3 per patient; range, 1–22 nodules) after neoadjuvant chemotherapy. During surgery, the thoracic surgeons found another 220 nodules. However, histological examination of the excised lung nodules in 32 of these patients (24.2%) showed that they were benign lesions. That is, 32 patients (24.2%) received useless thoracotomies.

Nataraj et al10 reported the results of a retrospective series of 102 patients with osteosarcoma metastatic at presentation. Their treatment protocol consisted of neoadjuvant chemotherapy for 9 weeks (3 cycles), primary tumor surgery, and then adjuvant chemotherapy for up to 37 weeks (additional 8 cycles) followed by metastatectomy. In that series, 69 patients (67.6%) had only lung metastases, 23 patients (22.5%) had combined lung and bone metastases, and 10 patients (9%) had only bone metastases. Their treatment consisted of primary tumor surgery without neoadjuvant chemotherapy in 7 patients (6.9%; 1 patient had limb-salvage surgery and 6 patients had amputation), and primary tumor surgery after neoadjuvant chemotherapy in 95 patients (93.1%). By the completion of adjuvant chemotherapy, 23 patients were lost to follow-up. After adjuvant chemotherapy, 12 patients experienced complete resolution of the lung metastases, so metastasectomy was not necessary; 3 patients with bone-only metastases continued to be in remission; and 5 patients (6.3%) with a partial response of the lung metastases underwent metastasectomy. The 5-year overall survival rate was 28.1%,10 while the 5-year survival rates of the patients with lung or bone metastases at presentation who had metastasectomy along with the primary tumor surgery were 16% to 29%.11,15,17 The strategy of Nataraj et al10 to perform metastasectomy after completion of the adjuvant chemotherapy resulted in outcomes comparable to those of metastasectomy along with the primary tumor surgery. Therefore, their strategy may contribute to the reduction of the number of patients who receive unnecessary thoracotomies that do not improve survival.

Many physicians do not recommend surgical treatment for patients with osteosarcoma metastatic at presentation who experience progression of their lung metastases during neoadjuvant chemotherapy.11,14,24 However, in the reported related series, all patients who experienced progression of their lung metastases and who did not have metastasectomies eventually died.11,14,24 In the current authors' opinion, primary tumor surgery and metastasectomies even with multiple thoracotomies should be performed if a thoracic surgeon deems the lung disease resectable, even if the lung metastases progress during neoadjuvant chemotherapy. Only patients who have undergone complete surgical resection of all sites of disease (primary and metastatic) have a chance for long-term survival. Repeated metastasectomies can be an option for some patients with relapsed lung disease.

In summary, because only patients who have undergone complete surgical resection of all sites of disease have a chance for long-term survival, primary tumor surgery and lung metastasectomies, if feasible, should be performed. However, to avoid unnecessary thoracotomies, metastasectomy should be performed after completion of adjuvant chemotherapy, as this results in outcomes comparable to those of metastasectomy along with the primary tumor surgery.

Bone Metastasectomy

When additional bone lesions are simultaneously present at diagnosis, the tumor is defined as synchronous multifocal osteosarcoma.34 In the pre-chemotherapy era, synchronous multifocal osteosarcoma was considered a highly malignant tumor with a short expected survival.34,35 Bacci et al36 reported the outcomes of 42 patients with synchronous multifocal osteosarcoma who were treated with chemotherapy and surgery for the primary and the synchronous tumors. After neoadjuvant chemotherapy, 26 patients were excluded from simultaneous resection of their synchronous bone lesions because their disease was advanced, and 16 patients had simultaneous operations to excise the primary and synchronous lesions. Most of these patients experienced a relapse of disease and died within 2 years.36 The prognosis for synchronous multifocal osteosarcoma remains extremely poor, despite combined chemotherapy and surgery.36

In summary, bone metastasectomy is recommended for multifocal osteosarcoma. However, the prognosis is poor and survival is short.

Radiotherapy

Primary Tumor

It is not always possible to obtain microscopically negative margins resection for osteosarcoma because of the extent and location of the tumor37 or the patient's clinical condition. In such cases, high-dose radiotherapy may be an important treatment option for the primary tumor, especially after resection with marginal or microscopically positive margins,38 and for the metastases for pain palliation.39 Osteosarcoma was considered to be radioresistant. However, in a small series of osteosarcoma patients, it has been shown that radiotherapy may achieve local tumor control.37,40 Ozaki et al40 reported that, among 17 patients with osteosarcoma of the spine who underwent no surgery or intralesional surgery, the overall survival tended to be better in 7 patients who were administered radiotherapy compared with 10 patients who did not receive radiotherapy (P=.059). In another study,37 they reported that among 30 patients with osteosarcoma of the pelvis who underwent intralesional surgery or no surgery, 11 patients who were administered radiotherapy experienced a better overall survival compared with 19 patients who did not receive radiotherapy (P=.003).

Photons emit maximal energy near the surface of the body and gradually decreasing energy at deeper points. By contrast, charged particles such as protons and carbon ions deposit a relatively low dose near the surface of the body and emit their maximum energy just before they stop inside the body; this is called the Bragg peak effect and may spread out depending on the location and size of the tumor,41,42 thereby making it possible to deliver high-dose radiation to the tumor while limiting the dose delivered to nearby organs. The relative biological effectiveness of protons is almost identical to the biological effects of photons.43 Carbon ion beams deliver a larger mean energy per unit length of their trajectory (higher linear energy transfer) to the body tissues than photon and proton beams (Table 1).44–47

Recent Studies of Particle Therapies for Osteosarcoma

Table 1:

Recent Studies of Particle Therapies for Osteosarcoma

Recent studies of particle therapy for osteosarcoma showed that patients with radiotherapy with and without surgery seemed to have an improved 5-year overall survival rate compared with patients without radiotherapy.45–47 In addition, patients who were treated with photon or proton with and without surgery seemed to have an improved 5-year local control compared with patients without radiotherapy.45–47 Sixty-six (85%) of 78 patients who underwent carbon ion radiotherapy did not undergo resection (biopsy alone),44 and 12 (22%) patients with photon and proton radiotherapy did not undergo resection.46,47 The two groups of patients (carbon ion radiotherapy vs photon and proton radiotherapy) experienced similar local tumor control.44,46,47 Complication rates were comparable among surgery alone, photon and proton radiotherapy, and carbon ion radiotherapy with and without surgery.44–47 Carbon ion radiotherapy can facilitate the delivery of an optimal dose to the tumor while limiting exposure to critical organs surrounding the tumor.44 However, complications such as fractures, skin reactions, or neurological disorders should be considered.

Lung Metastases

Administering radiotherapy for lung metastases has been traditionally reserved for patients who are unfit for surgery. However, with recent technological improvements, the indications for radiation therapy have broadened.48,49 Stereotactic radiosurgery is based on the ability to use multiple radiation beams that intersect in a specific volume in 3-dimensional space. One of the greatest differences between stereotactic radiosurgery and conventional radiotherapy is that in the former the software system allows for a precise delimitation of the volume to receive the highest radiation dose. This allows for a steep fall-off dose gradient to adjacent tissue.48 With a satisfying local tumor control rate and a limited toxicity to surrounding tissues, stereotactic radiosurgery has been widely accepted in intracranial and noncranial neoplasms, including primary or secondary pulmonary lesions.49 Yu et al49 reported that of 73 osteosarcoma patients who developed lung metastases during adjuvant chemotherapy or follow-up, 33 were treated with stereotactic radiosurgery and the remaining 40 were treated with lung metastasectomy. The 4-year progression-free survival rate, 4-year survival rate, median time of post-relapse progression-free survival, and post-relapse overall survival in the stereotactic radiosurgery group were equivalent to those in the surgical group; the patients tolerated stereotactic radiosurgery well, with excellent local control and few complications.49 Therefore, stereotactic radiosurgery should be considered a potential option for patients with lung metastases from osteosarcoma, especially in those who are medically inoperable or who refuse surgery.49

Bone Metastases

Mialou et al11 reported that 3 of 11 osteosarcoma patients with bone metastases alone at presentation remained alive at the time of publication of their study. These patients had isolated bone metastases; 2 of these patients had resectable bone metastases, and 1 patient was administered photon radiotherapy (45 Gy) for an inoperable metastatic site. Eight patients had several bone metastases; all of these patients died of their tumor, although 3 had undergone complete resection of the primary and metastatic tumor.11

Samarium-153 ethylene diamine tetramethylene phosphonate is a radiopharmaceutical with a high bone uptake that is rapidly eliminated from the blood through urine. It can be useful for palliation of bone pain because it enables therapeutic irradiation to osteoblastic bone metastases.39 It can be given at a very high dose, followed by stem cell reinfusion, to achieve significant radiation doses in tumors with minimal toxicity.39 Samarium-153 ethylene diamine tetramethylene phosphonate can be administered alone or in combination with external beam radiotherapy. Some authors have also used gemcitabine as a radiosensitizer to improve the radiobiological efficacy of samarium-153 ethylene diamine tetramethylene phosphonate.50 Other authors have combined gemcitabine and docetaxel chemotherapy with external beam radiotherapy, reporting improvement in cases of osteosarcoma with refractory tumor and multiple bone metastases.51

Carbon ion radiotherapy for metastatic osteosarcoma inoperable at presentation may improve its dismal prognosis. Mohamad et al52 reported the outcomes of 3 patients with metastatic osteosarcoma inoperable at presentation who were administered carbon ion radiotherapy for bone metastases.52 All of these patients experienced local control at 5 years.52

In summary, radiotherapy may achieve tumor control for patients with osteosarcoma metastatic at presentation. Particle therapy for the primary tumor, stereo-tactic radiosurgery for the lung metastases, and samarium-153 ethylene diamine tetramethylene phosphonate or carbon ion radiotherapy for the bone metastases should be considered in the treatment plan because they seem to improve the local tumor control and overall survival rate compared with patients who do not receive radiotherapy.45–47,49–52

Systemic Therapies

First-Line Chemotherapy

In osteosarcoma, the single-agent chemotherapy response rate is 15% or less for many agents, including cyclophosphamide,53–55 melphalan,56 mitomycin,57 dacarbazine,58,59 and dactinomycin.60 Doxorubicin,61–63 high-dose methotrexate with leucovorin rescue,64–68 cisplatin,69–71 and ifosfamide14,72 have a response rate between 20% and 40%. Although the response rate with ifosfamide alone in relapsed osteosarcoma patients was 40%,73 the combination of etoposide and lower-dose ifosfamide seems to be more effective (48%) in patients with recurrent osteosarcoma compared with single-agent ifosfamide.74

Previous studies have reported the results of chemotherapy for patients with a primary osteosarcoma with a metastasis at presentation (Table 2).9,10,12–16,75–87 In 1993, Meyers et al13 reported the outcomes of intensive chemotherapy including high-dose methotrexate, doxorubicin and bleomycin, cyclophosphamide, and dactinomycin13; only 11% of these patients survived, with a median survival of 20 months.13 In 1998, Harris et al14 reported the outcomes of intensive chemotherapy including high-dose methotrexate, doxorubicin, cisplatin, and ifosfamide for patients with primary tumors determined to be resectable; the 5-year event-free survival rate was 46.7% and the 5-year survival rate was 53.3%.14 These results were considerably better than those of previous reports, and the ifosfamide-containing regimen seemed to be effective in the treatment of patients with osteosarcoma with lung metastases at presentation. However, these results may be partly attributed to the better prognosis of these patients with a resectable primary tumor. In 2002, Goorin et al75 reported the outcomes of intensive chemotherapy including high-dose methotrexate, doxorubicin, cisplatin, ifosfamide, and etoposide75; the 2-year event-free survival rate was 36% and the 2-year survival rate was 55%. However, significant hematological toxicity was reported, and complications included infections and renal toxicity (2 toxic deaths).75 In 2009, Chou et al77 reported the results of a prospective randomized phase 3 trial for the treatment of 91 patients newly diagnosed with osteosarcoma meta-static at presentation. They compared a 3-drug chemotherapy including high-dose methotrexate, doxorubicin, and cisplatin (regimen A) with the same 3 drugs with the addition of ifosfamide (regimen B).77 They also studied the addition of liposomal muramyl tripeptide phosphatidylethanolamine, a nonspecific immune modulator that is a synthetic analog of a bacterial cell wall component, with each chemotherapy regimen. The addition of liposomal muramyl tripeptide phosphatidylethanolamine or ifosfamide to the 3-drug chemotherapy regimen did not achieve a statistically significant improvement of patient outcomes. The 5-year event-free survival rate was 34% and the 5-year survival rate was 47%. To date, these are the best results reported in the literature for patients with osteosarcoma metastatic at presentation and inoperable primary tumor.77

Results of the Most Important Clinical Studies of Patients With Osteosarcoma Metastatic at Presentation

Table 2:

Results of the Most Important Clinical Studies of Patients With Osteosarcoma Metastatic at Presentation

In 2016, Marina et al81 reported the results of EURAMOS-1 (European and American Osteosarcoma Studies), an open-label, international, phase 3 randomized controlled trial that included patients with newly diagnosed, resectable, high-grade osteosarcoma. Sixty-six patients with a poor response to preoperative chemotherapy (≥10% viable tumor) and metastasis at presentation were randomly assigned. Of those 66 patients, 38 patients received high-dose methotrexate (cumulative dose, 144 g/m2), doxorubicin (450 mg/m2), and cisplatin (480 mg/m2), and 28 patients received high-dose methotrexate (144 g/m2), doxorubicin (450 mg/m2), cisplatin (480 mg/m2), ifosfamide (60 g/ m2), and etoposide (1500 mg/m2). Event-free survival did not differ between the treatment groups. Likewise, bone marrow toxicity was similar between the groups. However, the patients treated with methotrexate, doxorubicin, and cisplatin, with the additions of ifosfamide and etoposide, had a higher incidence of secondary malignancy.81 The addition of topotecan,76 trastuzumab,78 zoledronic acid,79 high-dose etoposide and carboplatin with stem cell rescue,80 or vincristine plus interleukin-29 to high-dose methotrexate, doxorubicin, cisplatin, and ifosfamide with or without etoposide did not produce a clinically substantial improvement; patients' outcomes were comparable with those obtained with conventional chemotherapy regimens. Based on these results, the addition of ifosfamide or etoposide to the combination of high-dose methotrexate, doxorubicin, and cisplatin did not improve patient outcomes. In contrast, the addition of ifosfamide or etoposide may increase the incidence of toxic effects. Therefore, the first-line chemotherapy for osteosarcoma metastatic at presentation is currently the combination of high-dose methotrexate (cumulative dose, 144 g/ m2), doxorubicin (450 mg/m2), and cisplatin (480 mg/m2).

Second-Line Chemotherapy

When resorting to second-line chemotherapy, the prognosis for patients with metastatic osteosarcoma becomes more dismal, especially in cases with multiple unresectable metastases. In this setting, any proposed chemotherapy and/ or general therapeutic strategy must be carefully considered. It is crucial to identify and validate new agents that might be administered alone or as adjuvants to conventional chemotherapy. This is necessary to better control local and metastatic disease and thereby improve not only patients' chances of survival and cure but also their quality of life.88 The tumor responses and toxicities of new drugs as second-line chemotherapy for patients with recurrent or advanced osteosarcoma whose first-line chemotherapy failed vary (Table 3).73,74,89–118

Tumor Responses and Toxicities of New Drugs in the Trials With Published Results for Patients With Advanced Osteosarcoma Not Responding to First-Line ChemotherapyTumor Responses and Toxicities of New Drugs in the Trials With Published Results for Patients With Advanced Osteosarcoma Not Responding to First-Line Chemotherapy

Table 3:

Tumor Responses and Toxicities of New Drugs in the Trials With Published Results for Patients With Advanced Osteosarcoma Not Responding to First-Line Chemotherapy

The drugs with a response rate of 30% or greater were high-dose ifosfamide, the combination of ifosfamide and etoposide, and high-dose etoposide and carboplatin with stem cell rescue.73,74,89,91,93 In particular, patients receiving high-dose chemotherapy experienced severe toxicities, and there was 1 death due to toxicity.91 High-dose ifosfamide, or the combination of ifosfamide and etoposide, could be recommended for patients in relatively good general health. The response rate for gemcitabine plus docetaxel was 11.8%, the median progression-free survival of the patients was 11.2 months, and the toxicities of the drugs were well tolerated.109 This combination should also be administered as a second-line therapeutic option for metastatic osteosarcoma. Pazopanib and apatinib, when administered individually, showed a median progression-free survival of 6 months or more.116,117 Due to effective combination and tolerable toxicity profiles, these two drugs could be considered as treatment options when no conventional chemotherapy is available.

In summary, there are conflicting reports regarding the effect of a ifosfamide-containing regimen in the first-line chemotherapy treatment of patients with osteosarcoma with lung metastases at presentation.75,77,81 Further, the addition of ifosfamide and etoposide has been associated with a higher incidence of toxic effects and secondary malignancy.81 In contrast, high-dose ifosfamide, the combination of ifosfamide and etoposide, and high-dose etoposide and carboplatin as second-line chemotherapy have been associated with a response rate of 30% or greater.73,74,89,91,93 However, they should be administered with caution because of the high toxicity.91

Discussion

For patients whose tumors respond to neoadjuvant chemotherapy, the strategy of Nataraj et al10 to perform metastasectomy after the completion of adjuvant chemotherapy may be reasonable to reduce the number of patients who receive useless thoracotomies without reducing survival rates. For patients whose tumors do not respond to and/or progress after neoadjuvant chemotherapy, aggressive surgery and multiple metastasectomies should be performed if a thoracic surgeon considers the lung metastases resectable. Only patients who have undergone complete surgical resection of all sites of disease (primary and metastatic) have a chance of becoming long-term survivors. Stereotactic radiosurgery or carbon ion radiotherapy should be considered a potential option for lung or bone metastases originating from an osteosarcoma, especially in those patients who are medically inoperable or who refuse surgery.

Despite many physicians not recommending surgical treatment for patients with osteosarcoma metastatic at presentation who experience progression of their lung metastases during neoadjuvant chemotherapy,11,14,24 the current authors recommend neoadjuvant chemotherapy and early surgical resection of the primary tumor regardless of whether patients have metastases at presentation or are responsive to neoadjuvant chemotherapy. This is because the reduction of the tumor volume could probably increase the effect of chemotherapy. Limb-salvage surgery and reconstruction is the primary consideration. However, if the primary tumor is locally advanced, and the general health of the patient precludes complex reconstruction techniques, amputation should be recommended and performed early after neoadjuvant chemotherapy.

Continued progress in omics technology, including genomics, transcriptomics, proteomics and metabolomics, next-generation sequencing, and high-throughput screening, will provide new insights into the pathogenesis of osteosarcoma and will help to identify novel biomarkers that will contribute to improved therapeutic strategies. Immunotherapeutic techniques using nonspecific immunomodulators such as muramyl tripeptide phosphatidylethanolamine, interferons, interleukin-2, adoptive T-cell immunotherapy, vaccines, immunologic checkpoint blockades such as CTLA-4/PD-1 blockade, and oncolytic viral therapy are expected to evolve immunotherapeutic strategies, especially for patients with metastatic disease for whom effective systemic therapy is not a treatment option. Understanding the importance of the tumor microenvironment and signal-transduction pathways will allow for the development of novel target agents—agents targeting receptor tyrosine kinases, agents targeting signal-transduction pathways, agents interfering with the tumor microenvironment, immunomodulatory agents, and agents designed to overcome mechanisms of resistance. The authors consider it ethically acceptable to enroll patients with advanced osteosarcoma into trials using experimental protocols for improving outcomes in the near future.

Conclusion

Neoadjuvant chemotherapy followed by resection of the primary tumor and adjuvant chemotherapy are the treatments of choice for osteosarcoma patients with metastases at presentation. Neoadjuvant chemotherapy allows for demarcation of the margins of the primary tumor, and possibly for limb-salvage surgery and reduced rates of local recurrence.21,22 However, a long interval between diagnosis and primary tumor surgery for patients with osteosarcoma metastatic at presentation is a negative predictor for limb-salvage surgery, especially if the tumor does not respond to neoadjuvant chemotherapy. Therefore, reducing the volume of the primary tumor by resection (limb-salvage surgery), if feasible, or amputation may increase the effect of chemotherapy.32 Because only patients who have undergone complete surgical resection of all sites of disease have a chance for long-term survival, neoadjuvant chemotherapy followed by early primary tumor surgery, with limb salvage or amputation, and lung metastasectomies, if feasible, should be performed. However, to avoid unnecessary thoracotomies, metastasectomy should be performed after completion of the adjuvant chemotherapy, as this leads to outcomes comparable to those of metastasectomy along with the primary tumor surgery. The prognosis for synchronous multifocal osteosarcoma is extremely poor. Particle therapy for the primary tumor, stereotactic radiosurgery for the lung metastases, and samarium-153 ethylene diamine tetramethylene phosphonate or carbon ion radiotherapy for the bone metastases should be considered in the treatment plan because these seem to improve the local tumor control and overall survival compared with patients who do not receive radiotherapy.

Standard chemotherapy for osteosarcoma metastatic at presentation is still based on high-dose methotrexate, doxorubicin, and cisplatin. There are conflicting reports regarding the effect of an ifosfamide-containing regimen in the first-line chemotherapy of patients with osteosarcoma with lung metastases at presentation. In contrast, high-dose ifosfamide, the combination of ifosfamide and etoposide, and high-dose etoposide and carboplatin as second-line chemotherapy have been associated with a response rate of 30% or greater. However, they should be administered with caution because of high toxicity.

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Recent Studies of Particle Therapies for Osteosarcoma

StudyNo. of PatientsMean Size, cmTreatmentMean Radiotherapy Dose, GyNo. of Patients5-Year Local Control5-Year Overall SurvivalNo. of Patients With Complications (G3, G4)

Wide ResectionMarginal ResectionIntralesional ExcisionBiopsy Alone
Matsunobu et al447810C±S70.40011 (14%)66 (85%)62%33%16 (21%)
DeLaney et al46415.3X±P±S6622 (54%)3 (7%)9 (22%)5 (12%)68%66%10 (24%)
Ciernik et al4755NAP±X±S68.4024 (44%)19 (35%)12 (22%)72%67%17 (31%)

Results of the Most Important Clinical Studies of Patients With Osteosarcoma Metastatic at Presentation

StudyNo. of PatientsChemotherapy (Cumulative Dose)Site of Metastatic Tumor (No. of Patients)2-Year EFS2-Year OS5-Year EFS5-Year OS

Lung AloneBone AloneBone and LungLymph Nodes
Ferrari et al8211M+A+P+IFO9200NANA1 patient was AWD 2 patients were CDFNA
Bacci et al8326M+A+P+IFO+VP1624200NANANA6 patients were CDF
Meyers et al1362M+A+P+BCDNA27NANANANA11%
Bacci et al8423M+A+P+IFO23000NA45%NANA
Harris et al1430aM+A+P+IFO27121NANA46.7%53.3%
Voûte et al1545A+P+IFO42210NANANA16%
Bacci et al8528M+A+P+IFO2800036%59%NANA
Goorin et al7541M+A+P+IFO+VP161417NANA43%55%NANA
Janinis et al1616bM+A+P+IFO+VP16+HDCBDCA, VP16 and Cy12110NA50%NANA
Bacci et al8657M+A+P+IFO4339221%55%28%18%
Daw et al8712M+A+P+IFO11100NANA6.9%24%
7M+A+CBDCA+IFO12221NANA
Seibel et al7628A+P+IFO+CBDCA+VP16+topotecan172907.1%44.4%3.6%22.2%
Bacci et al12162M+A+P+IFO162000NANA17.2%19.1%
Chou et al7791M+A+PNANA29%53%
M+A+P+MTP-PE56NANANANANA41%50%
M+A+P+IFONANA23%30%
M+A+P+IFO+MTP-PENANA44%57%
Ebb et al7841M+A+P+IFO+VP16+trastuzumabNA59NA35%70%27%33%
Goldsby et al7924M+A+P+IFO+VP16+zoledronic acid1228NA30%60%NANA
Boye et al8071bM+A+P+IFO+Cy+VP16+HDCBDCA and VP16539NANANANA27%31%
Nataraj et al10102A+P+IFO+VP166910230NANA12.7%28.1%
38cM+A+PNANANANANANANANA
Marina et al81
28cM+A+P+IFO+VP16NANANANANANANANA
Meazza et al935M+A+P+IFO+VCR+IL22933NANANA28.6%37.1%

Tumor Responses and Toxicities of New Drugs in the Trials With Published Results for Patients With Advanced Osteosarcoma Not Responding to First-Line Chemotherapy

StudyNo. of PatientsDrugNo. of PatientsMedian PFS, moMedian OS, moNo. of Patients


CRPRSDPDHematologic Toxicity G3Hematologic Toxicity G4Non-hematologic Toxicity G3Non-hematologic Toxicity G4
Miser et al898IFO, VP1603 (37.5%)NANANANANANANANA
Gentet et al7427IFO, VP166 (22%)7 (26%)9 (33%)5 (19%)NANANA21 (78%)00
Patel et al7318IFO1 (6%)6 (33%)NANANANAG3+G4: 74%G3+G4: 16%
Saylors et al9018Cyclophosphamide, topotecan02 (11%)5 (28%)11 (61%)NANAG3+G4: 53%G3+G4: 2%
Fagioli et al9132High-dose etoposide and carboplatin with stem cell rescue15 (47%)3 (9%)8 (25%)5 (16%)NANA100%100%5 (16%)
Laverdiere et al9225Ecteinascidin 7430011 (44%)14 (56%)NANA28%20%56%4%
Berrak et al9316IFO06 (37.5%)4 (25%)6 (37.5%)NANANA8 (50%)2 (13%)1 (6%)
Bond et al9410Imatinib00NANANANANANANANA
Berger et al9526Cyclophosphamide, VP162 (8%)3 (11%)9 (35%)12 (46%)1926026 (100%)23%23%
Kindler et al967L-alanosine002 (28.6%)5 (71.4%)29.69%011%0
Chawla et al9717Rexin-G0010 (58.8%)7 (41%)36.90000
Jacobs et al9810Ixabepilone001 (10%)9 (90%)NANAG3+G4: 5.9%G3+G4: 3.4%
Beaty et al9910Oxaliplatin00010 (100%)NANA6.60%4.30%1.70%0
Loeb et al10011Samarium-153006 (55%)5 (45%)2.6NANA5 (45%)00
Geoerger et al10112Gemcitabine Oxaliplatin01 (8.3%)4 (33.3%)7 (58%)NANAG3+G4: 82%G3+G4: 58%
Grignani et al10235Sorafenib03 (9%)14 (40%)18 (51%)473 (9%)0 (0%)11 (33%)4 (12%)
Duffaud et al10332Pemetrexed01 (3.1%)5 (15.6%)22 (68.6%)1.45.53 (9.4%)1 (3.1%)3 (9.4%)1 (3.1%)
Minard-Colin et al10410Vinorelbine Cyclophosphamide001 (10%)9 (90%)NANAG3+G4: 62%2%1%
Schwartz et al10524Cixutumumab Temsirolimus03 (13%)NANANANATotal 8%
Chou et al10619Inhaled lipid cisplatin3 (15.8%)1 (5%)7 (37%)8 (42%)1.6NANANA31%NA
Pappo et al10738R150702 (5%)10 (26%)26 (68%)NANA0015 (39%)2 (5%)
Weigel et al10811Cixutumumab001 (9.1%)10 (91%)NANANA6%3%0
Song et al10928Gemcitabine Docetaxel1 (5.9%)1 (5.9%)5 (29.4%)10 (58.8%)11.2NA4 (14.3%)4 (14.2%)2 (7.1%)1 (3.6%)
Wagner et al11010Cixutumumab Temsirolimus00010 (100%)NANANANANANA
Grignani et al11138Sorafenib Everolimus02 (5%)22 (58%)14 (37%)51112 (33%)3 (8%)28 (32%)0
Schuetze et al11246Dasatinib03 (6.5%)3 (6.5%)40 (87%)NANAG3+G4: 10%G3+G4: 21%
Anderson et al11329Robatumumab006 (21%)23 (79%)NA11Total 50%
Martin-Broto et al11435Gemcitabine Sirolimus02 (6%)14 (42%)17 (49%)2.37.1G3+G4: 37%G3+G4: 3(9%)
Tawbi et al11522Pembrolizumab01 (5%)6 (27%)15 (68%)NANA007%2%
Longhi et al11615Pazopanib01 (6.7%)8 (53.3%)5 (33.3%)672 (13.3%)1 (6.7%)2 (13.3%)1 (6.7%)
Zheng et al11710Apatinib02 (20%)5 (50%)3 (30%)7.514002 (20%)0
Duffaud et al11826Regorafenib02 (8%)15 (58%)9 (35%)4.111.31 (3%)012 (41%)1 (3%)
Authors

The authors are from the Department of Orthopaedics (ST), Nara Medical University, Nara, Japan; the Department Orthopaedic Oncology (CE), IRCCS Istituto Ortopedico Rizzoli, Bologna, and the Department of Orthopaedics and Orthopaedic Oncology (AA), University of Padova, Padova, Italy; and the First Department of Orthopaedics (AFM), National and Kapodistrian University of Athens, School of Medicine, Athens, Greece.

The authors have no relevant financial relationships to disclose.

Correspondence should be addressed to: Andreas F. Mavrogenis, MD, First Department of Orthopaedics, National and Kapodistrian University of Athens, School of Medicine, 41 Ventouri St, 15562, Holargos, Athens, Greece ( afm@otenet.gr).

Received: May 05, 2019
Accepted: August 12, 2019
Posted Online: August 06, 2020

10.3928/01477447-20200721-05

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